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The motor features of Parkinson's disease result from loss of dopaminergic neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. While a large body of work focusing on protein effectors of autophagy has been reported, regulation of autophagy by lipids has garnered far less attention. Therefore, we sought to identify endogenous lipid molecules that act as signaling mediators of autophagy in differentiated SH-SY5Y cells, a commonly used dopaminergic neuron-like cell model. In order to accomplish this goal, we assessed the role of a fatty acid-binding protein (FABP) family member on autophagy due to its function as an intracellular lipid chaperone. We focused specifically upon FABP5 due to its heightened expression in dopaminergic neurons within the substantia nigra and SH-SY5Y cells. Here, we report that knockdown of FABP5 resulted in suppression of autophagy in differentiated SH-SY5Y cells suggesting the possibility of an autophagic role for an interacting lipid. A lipidomic screen of FABP5-interacting lipids uncovered hits that include 5-oxo-eicosatetraenoic acid (5OE) and its precursor metabolite, arachidonic acid (AA). Additionally, other long-chain fatty acids were found to bind FABP5, such as stearic acid (SA), hydroxystearic acid (HSA), and palmitic acid (PA). The addition of 5OE, SA, and HSA but not AA or PA, led to potent inhibition of autophagy in SH-SY5Y cells. To identify potential molecular mechanisms for autophagy inhibition by these lipids, RNA-Seq was performed which revealed both shared and divergent signaling pathways between the lipid-treated groups. These findings suggest a role for these lipids in modulating autophagy through diverse signaling pathways and could represent novel therapeutic targets for Parkinson's disease. [ABSTRACT FROM AUTHOR]

The current study aimed to assess the influence of dietary inclusion of cyanobacterium Arthrospira platensis NIOF17/003 as a dry material and as a free-lipid biomass (FL) on the growth performance, body composition, redox status, immune responses, and gene expression of whiteleg shrimp, Litopenaeus vannamei postlarvae. L. vannamei were fed five different supplemented diets; the first group was fed on an un-supplemented diet as a negative control group (C-N), the second group was fed on a commercial diet supplemented with 2% of A. platensis complete biomass as a positive control group (C-P20), whereas, the three remaining groups were fed on a commercial diet supplemented with graded amounts of FL at 1%, 2%, and 3% (FL10, FL20, and FL30, respectively). The obtained results indicated that the diet containing 1% FL significantly increased the growth performance, efficiency of consumed feed, and survival percentage of L. vannamei compared to both C-N and C-P20 groups. As for the carcass analysis, diets containing A. platensis or its FL at higher levels significantly increased the protein, lipid, and ash content compared to the C-N group. Moreover, the shrimp group fed on C-P20 and FL10 gave significantly stimulated higher digestive enzyme activities compared with C-N. The shrimp fed C-P20 or FL exhibited higher innate immune responses and promoted their redox status profile. Also, the shrimp fed a low FL levels significantly upregulated the expression of both the peroxiredoxin (Prx) and prophenoloxidase (PPO1) genes than those receiving C-N. The current results recommended that dietary supplementation with 1% FL is the most effective treatment in promoting the performance and immunity of whiteleg shrimp. [ABSTRACT FROM AUTHOR]

This retrospective study aimed to evaluate the effects on the clinical signs of poisoning and adverse effects of intravenous lipid emulsion treatment in 82 animals (dogs and cats) with suspected poisonings over 18 months. Physical examination parameters and state of consciousness were documented every hour after the intravenous administration of a bolus of 2 ml/kg and 0.25 ml/kg/min over 60 minutes of a 20% intravenous lipid emulsion. The modified Glasgow coma scale and laboratory findings (blood gas analysis, triglyceride, lactate) were evaluated initially and three hours after discontinuing intravenous lipid emulsion administration. A statistical evaluation of the occurrence of adverse effects and the development of laboratory values was performed. A decrease in respiratory rate in the second control (8–12 hours) after ILE was observed. Three hours after completing of the intravenous lipid emulsion, triglyceride concentration increased about 10 times (p <0.001). Venous carbon dioxide partial pressure, bicarbonate, base excess, as well as the electrolytes sodium, potassium and ionized calcium decreased significantly (p <0.001). Patients who experienced a worsening of the modified Glasgow coma scale had a higher increase in triglyceride concentrations (p = 0.041) and plasma lactate (p = 0.034) and a larger decrease in bicarbonate concentrations (p = 0.053) compared to others. About 54% (n = 44) of the patients showed adverse effects which could be attributed to the administration of intravenous lipid emulsion and may be associated with a higher triglyceride increase. All of them were completely reversible within 33 hours. Adverse effects associated with intravenous lipid emulsion therapy were observed in half of the patients and were associated with a higher increase in triglycerides. [ABSTRACT FROM AUTHOR]

Food allergy is widely recognized as a significant health issue, having escalated into a global epidemic, subsequently giving rise to the development of numerous additional complications. Currently, the sole efficient method to curb the progression of allergy is through the implementation of an elimination diet. The increasing number of newly identified allergens makes it harder to completely remove or avoid them effectively. The immunoreactivity of proteins of bacterial origin remains an unexplored topic. Despite the substantial consumption of microbial proteins in our diets, the immunologic mechanisms they might induce require thorough validation. This stands as the primary objective of this study. The primary objective of this study was to evaluate the effects of bacterial proteins on the intestinal barrier and immune system parameters during hypersensitivity induction in both developing and mature organisms. The secondary objective was to evaluate the role of lipids in the immunoreactivity programming of these bacterial proteins. Notably, in this complex, comprehensively designed in vitro, in vivo, and ex vivo trial, the immunoreactivity of various bacterial proteins will be examined. In summary, the proposed study intends to address the knowledge gaps regarding the effects of Lactobacillus microbial proteins on inflammation, apoptosis, autophagy, and intestinal barrier integrity in a single study. [ABSTRACT FROM AUTHOR]

Peptidoglycan (PG) and most surface glycopolymers and their modifications are built in the cytoplasm on the lipid carrier undecaprenyl phosphate (UndP). These lipid-linked precursors are then flipped across the membrane and polymerized or directly transferred to surface polymers, lipids, or proteins. Despite its essential role in envelope biogenesis, UndP is maintained at low levels in the cytoplasmic membrane. The mechanisms by which bacteria distribute this limited resource among competing pathways is currently unknown. Here, we report that the Bacillus subtilis transcription factor SigM and its membrane-anchored anti-sigma factor respond to UndP levels and prioritize its use for the synthesis of the only essential surface polymer, the cell wall. Antibiotics that target virtually every step in PG synthesis activate SigM-directed gene expression, confounding identification of the signal and the logic of this stress-response pathway. Through systematic analyses, we discovered 2 distinct responses to these antibiotics. Drugs that trap UndP, UndP-linked intermediates, or precursors trigger SigM release from the membrane in <2 min, rapidly activating transcription. By contrasts, antibiotics that inhibited cell wall synthesis without directly affecting UndP induce SigM more slowly. We show that activation in the latter case can be explained by the accumulation of UndP-linked wall teichoic acids precursors that cannot be transferred to the PG due to the block in its synthesis. Furthermore, we report that reduction in UndP synthesis rapidly induces SigM, while increasing UndP production can dampen the SigM response. Finally, we show that SigM becomes essential for viability when the availability of UndP is restricted. Altogether, our data support a model in which the SigM pathway functions to homeostatically control UndP usage. When UndP levels are sufficiently high, the anti-sigma factor complex holds SigM inactive. When levels of UndP are reduced, SigM activates genes that increase flux through the PG synthesis pathway, boost UndP recycling, and liberate the lipid carrier from nonessential surface polymer pathways. Analogous homeostatic pathways that prioritize UndP usage are likely to be common in bacteria. How do bacteria distribute the use of the lipid carrier, UndP, to the various pathways that require it? This study shows that the Bacillus subtilis transcription factor sigma-M and its membrane-anchored anti-sigma factor monitor UndP levels and prioritize its use for cell wall synthesis. [ABSTRACT FROM AUTHOR]

Background: Past studies have demonstrated that patients diagnosed with rheumatoid arthritis (RA) often exhibit abnormal levels of lipids. Furthermore, certain lipid-modifying medications have shown effectiveness in alleviating clinical symptoms associated with RA. However, the current understanding of the causal relationship between lipids, lipid-modifying medications, and the risk of developing RA remains inconclusive. This study employed Mendelian randomization (MR) to investigate the causal connection between lipids, lipid-modifying drugs, and the occurrence of RA. Methods: We obtained genetic variation for lipid traits and drug targets related to lipid modification from three sources: the Global Lipids Genetics Consortium (GLGC), UK Biobank, and Nightingale Health 2020. The genetic data for RA were acquired from two comprehensive meta-analyses and the R8 of FINNGEN, respectively. These variants were employed in drug-target MR analyses to establish a causal relationship between genetically predicted lipid-modifying drug targets and the risk of RA. For suggestive lipid-modified drug targets, we conducted Summary-data-based Mendelian Randomization (SMR) analyses and using expression quantitative trait loci (eQTL) data in relevant tissues. In addition, we performed co-localization analyses to assess genetic confounders. Results: Our analysis revealed no significant causal relationship between lipid and RA. We observed that the genetically predicted 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) -mediated low density lipoprotein cholesterol (LDL-C) (OR 0.704; 95% CI 0.56, 0.89; P = 3.43×10−3), Apolipoprotein C-III (APOC3) -mediated triglyceride (TG) (OR 0.844; 95% CI 0.77, 0.92; P = 1.50×10−4) and low density lipoprotein receptor (LDLR) -mediated LDL-C (OR 0.835; 95% CI 0.73, 0.95; P = 8.81×10−3) were significantly associated with a lowered risk of RA. while Apolipoprotein B-100 (APOB) -mediated LDL-C (OR 1.212; 95%CI 1.05,1.40; P = 9.66×10−3) was significantly associated with an increased risk of RA. Conclusions: Our study did not find any supporting evidence to suggest that lipids are a risk factor for RA. However, we observed significant associations between HMGCR, APOC3, LDLR, and APOB with the risk of RA. [ABSTRACT FROM AUTHOR]

Lipids stored in lipid-bodies (LBs) in host cells are potential sources of fatty acids for pathogens. However, the mechanism of recruitment of LBs from the host cells by pathogens to acquire fatty acids is not known. Here, we have found that Leishmania specifically upregulates the expression of host Rab18 and its GEF, TRAPPC9 by downregulating the expression of miR-1914-3p by reducing the level of Dicer in macrophages via their metalloprotease gp63. Our results also show that miR-1914-3p negatively regulates the expression of Rab18 and its GEF in cells. Subsequently, Leishmania containing parasitophorous vacuoles (Ld-PVs) recruit and retain host Rab18 and TRAPPC9. Leishmania infection also induces LB biogenesis in host cells and recruits LBs on Ld-PVs and acquires FLC12-labeled fatty acids from LBs. Moreover, overexpression of miR-1914-3p in macrophages significantly inhibits the recruitment of LBs and thereby suppresses the multiplication of parasites in macrophages as parasites are unable to acquire fatty acids. These results demonstrate a novel mechanism how Leishmania acquire fatty acids from LBs for their growth in macrophages. Author summary: Leishmania donovani which causes fatal disease known as visceral leishmaniasis, is dependent on its host to scavenge fatty acids for its survival. But, how Leishmania get fatty acids from host macrophages is not known. Lipid bodies are unique organelles that contain neutral lipids and fatty acids, therefore, LBs in macrophages could be the potential source of fatty acids for parasites. We have found that Leishmania upregulate the expression of host Rab18 and its GEF by downregulating the expression of miR-1914-3p in infected macrophages via the Ld-gp63-mediated inhibition of dicer expression. As biogenesis of LBs is shown to be regulated by Rab18, we have found that Leishmania infection induces LB biogenesis in macrophages and subsequently recruits LBs along with Rab18 and its GEF on Leishmania containing parasitophorous vacuoles. Finally, parasites-containing vacuoles acquire FLC12-labeled fatty acids from LBs to meet their nutritional requirement. We have also shown that overexpression of miR-1914-3p in macrophages significantly inhibits the recruitment of LBs and thereby suppresses the growth of parasites in macrophages as parasites are unable to acquire nutrients from LBs. These results demonstrate how Leishmania acquire nutrients like fatty acids from LBs for their proliferation in macrophages. [ABSTRACT FROM AUTHOR]

Vacuolar pathogens reside in membrane-bound compartments within host cells. Maintaining the integrity of this compartment is paramount to bacterial survival and replication as it protects against certain host surveillance mechanisms that function to eradicate invading pathogens. Preserving this compartment during bacterial replication requires expansion of the vacuole membrane to accommodate the increasing number of bacteria, and yet, how this is accomplished remains largely unknown. Here, we show that the vacuolar pathogen Legionella pneumophila exploits multiple sources of host cell fatty acids, including inducing host cell fatty acid scavenging pathways, in order to promote expansion of the replication vacuole and bacteria growth. Conversely, when exogenous lipids are limited, the decrease in host lipid availability restricts expansion of the replication vacuole membrane, resulting in a higher density of bacteria within the vacuole. Modifying the architecture of the vacuole prioritizes bacterial growth by allowing the greatest number of bacteria to remain protected by the vacuole membrane despite limited resources for its expansion. However, this trade-off is not without risk, as it can lead to vacuole destabilization, which is detrimental to the pathogen. However, when host lipid resources become extremely scarce, for example by inhibiting host lipid scavenging, de novo biosynthetic pathways, and/or diverting host fatty acids to storage compartments, bacterial replication becomes severely impaired, indicating that host cell fatty acid availability also directly regulates L. pneumophila growth. Collectively, these data demonstrate dual roles for host cell fatty acids in replication vacuole expansion and bacterial proliferation, revealing the central functions for these molecules and their metabolic pathways in L. pneumophila pathogenesis. Author summary: The pathogenesis of bacteria depends on their ability to avoid detection and killing by the host immune system while simultaneously competing with the host for nutrients. Here, we demonstrate that host cell fatty acids are paramount to the intracellular survival and replication of the bacterial pathogen Legionella. Legionella infection induces host cell fatty acid scavenging allowing for critical expansion of its replication vacuole, which protects against recognition by host surveillance pathways, and mediates robust bacterial proliferation. However, if host cell fatty acid availability becomes limited, vacuole membrane expansion is constrained, often leading to vacuole destabilization, and bacterial growth is restricted. Our findings reveal a central role for host cell fatty acids and their metabolic pathways in bacterial pathogenesis, whereby both the host and the pathogen define a gradient of available host fatty acids that can be manipulated by either organism to their benefit. [ABSTRACT FROM AUTHOR]

Objective: To investigate the anti-cancer efficacy of ENB101-LNP, an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16, in combination therapy with cisplatin in cervical cancer in vitro and in vivo. Methods: CaSki cells were treated with ENB101-LNP, cisplatin, or combination. Cell viability assessed the cytotoxicity of the treatment. HPV16 E6/E7 gene knockdown was verified with RT-PCR both in vitro and in vivo. HLA class I and PD-L1 were checked by flow cytometry. A xenograft model was made using CaSki cells in BALB/c nude mice. To evaluate anticancer efficacy, mice were grouped. ENB101-LNP was given three times weekly for 3 weeks intravenously, and cisplatin was given once weekly intraperitoneally. Tumor growth was monitored. On day 25, mice were euthanized; tumors were collected, weighed, and imaged. Tumor samples were analyzed through histopathology, immunostaining, and western blot. Results: ENB101-LNP and cisplatin synergistically inhibit CaSki cell growth. The combination reduces HPV 16 E6/E7 mRNA and boosts p21 mRNA, p53, p21, and HLA class I proteins. In mice, the treatment significantly blocked tumor growth and promoted apoptosis. Tumor inhibition rates were 29.7% (1 mpk ENB101-LNP), 29.6% (3 mpk), 34.0% (cisplatin), 47.0% (1 mpk ENB101-LNP-cisplatin), and 68.8% (3 mpk ENB101-LNP-cisplatin). RT-PCR confirmed up to 80% knockdown of HPV16 E6/E7 in the ENB101-LNP groups. Immunohistochemistry revealed increased p53, p21, and HLA-A expression with ENB101-LNP treatments, alone or combined. Conclusion: The combination of ENB101-LNP, which inhibits E6/E7 of HPV 16, with cisplatin, demonstrated significant anticancer activity in the xenograft mouse model of cervical cancer. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) occurs worldwide and is characterized by lipid accumulation in hepatocytes, hepatic inflammation, fibrosis, and an increased risk of cirrhosis. Although a major proportion of NASH patients exhibit obesity and insulin resistance, 20% lack a high body mass and are categorized as "non-obese NASH". Time-restricted feeding (TRF), limiting daily food intake within certain hours, improves obesity, lipid metabolism, and liver inflammation. Here, we determined whether TRF affects NASH pathology induced by a choline-deficient high-fat diet (CDAHFD), which does not involve obesity. TRF ameliorated the increase in epididymal white adipose tissue and plasma alanine transaminase and aspartate transaminase levels after 8 weeks of a CDAHFD. Although gene expression of TNF alpha in the liver was suppressed by TRF, it did not exhibit a suppressive effect on hepatic lipid accumulation, gene expression of cytokines and macrophage markers (Mcp1, IL1b, F4/80), or fibrosis, as evaluated by Sirius red staining and western blot analysis of alpha-smooth muscle actin. A CDAHFD-induced increase in gene expression related to fibrogenesis (Collagen 1a1 and TGFβ) was neither suppressed by TRF nor that of alpha-smooth muscle actin but was increased by TRF. Our results indicated that TRF has a limited suppressive effect on CDAHFD-induced NASH pathology. [ABSTRACT FROM AUTHOR]

Stable isotope ratios in organisms can be used to estimate dietary source contributions, but lipids must first be accounted for to interpret values meaningfully. Lipids are depleted in heavy isotopes because during lipid synthesis light isotopes of carbon (12C) and hydrogen (1H) are preferentially incorporated. Prior work in larval lampreys has noted unusual lipid effects, which suggest lipids are enriched in the heavy isotope of carbon (13C), but still depleted in the heavy isotope of hydrogen (deuterium; 2H); nitrogen, a relatively rare element in lipids, has not been identified as being as sensitive to lipid content. Our objective was to determine if stable isotope ratios of hydrogen, carbon, and nitrogen behaved as expected in larval lampreys, or if their lipids presented different isotopic behavior. The δ2H, δ13C, and δ15N were measured from the muscle of four lamprey species before and after lipid extraction. In addition, muscle of least brook lamprey (Lampetra aepyptera) was collected every three months for a year from two streams in Maryland. Isotopic ratios were measured in bulk and lipid-extracted muscles, as well as in extracted lipids. The difference between muscle samples before and after lipid extraction (Δδ2H, Δδ13C, Δδ15N) was positively related to lipid proxy (%H or C:N ratio) and were fit best by linear models for Δδ2H and Δδ15N, and by a non-linear model for Δδ13C. The difference between lipid-extracted muscle and lipid δ13C (ΔMLδ13C) was negative and varied between months (ANOVA, F3,53 = 5.05, p < 0.005). Our work suggests that while lipids are often depleted in 13C, this is not a universal rule; however, the depletion of 2H in lipid synthesis appears broadly true. [ABSTRACT FROM AUTHOR]