-
BioRxiv : the Preprint Server For... Jun 2024X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy...
X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Similar mutations in ABCD1 may result in a spectrum of phenotypes in males with slow progressing adrenomyeloneuropathy (AMN) and fatal cerebral adrenoleukodystrophy (cALD) dominating the majority of cases. Mouse model of X-ALD does not capture the phenotype differences and an appropriate model to investigate mechanism of disease onset and progress remains a critical need. Induced pluripotent stem cell (iPSC)-derived and cell models derived from them have provided useful tools for investigating cell-type specific disease mechanisms. Here, we generated induced pluripotent stem cell (iPSC) lines from skin fibroblasts of two each of apparently healthy control, AMN and cALD patients with non-integrating mRNA-based reprogramming. iPSC lines expanded normally and expressed pluripotency markers Oct4, SOX2, Nanog, SSEA and TRA-1-60. Expression of markers SOX17, brachyury, Desmin, Oxt2 and beta tubulin III demonstrated the ability of the iPSCs to differentiate into all three germ layers. iPSC-derived lines from CTL, AMN and cALD male patients were differentiated into astrocytes. Differentiated AMN and cALD astrocytes lacked ABCD1 expression and accumulated VLCFA, a hallmark of X-ALD. These patient astrocytes provide disease-relevant tools to investigate mechanism of differential neuroinflammatory response and metabolic reprogramming in X-ALD. Further these patient-derived human astrocyte cell models will be valuable for testing new therapeutics.
PubMed: 38854155
DOI: 10.1101/2024.05.31.596696 -
International Immunopharmacology Jun 2024Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to...
BACKGROUND
Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to investigate the anti-angiogenic and anti-inflammatory effects of cannabidiol and its mechanism of action.
METHOD
An in vivo corneal neovascularization (CNV) model was established using the suture method to investigate the inhibitory effects of CBD on suture-induced corneal inflammation, pathological blood vessel formation, and lymphangiogenesis. Additionally, the impact of CBD on immune cells was studied. In vitro methodologies, including cell sorting and co-culture, were employed to elucidate its mechanism of action.
RESULTS
Compared with the CNV group, CBD can inhibit CNV, lymphangiogenesis, and inflammation induced via the suture method. In addition, CBD specifically induced CD45CD11bGr-1 cell upregulation, which significantly inhibited the proliferation of CD4 T lymphocytes in vitro and exhibited a CD31 phenotype, proving that they were myeloid-derived suppressor cells (MDSCs). We administered anti-Gr-1 to mice to eliminate MDSCs in vivo and found that anti-Gr-1 partially reversed the anti-inflammatory and angiogenic effects of CBD. Furthermore, we found that compared with MDSCs in the normal group, CBD-induced MDSCs overexpress peroxisome proliferator-activated receptor-gamma (PPAR-γ). Administering PPAR-γ inhibitor in mice almost reversed the induction of MDSCs by CBD, demonstrating the role of PPAR-γ in the function of CBD.
CONCLUSION
This study indicates that CBD may induce MDSCs upregulation by activating the nuclear receptor PPAR-γ, exerting anti-inflammatory, antiangiogenic, and lymphangiogenic effects, and revealing potential therapeutic targets for corneal neovascularization and lymphangiogenesis.
PubMed: 38851157
DOI: 10.1016/j.intimp.2024.112429 -
Ecotoxicology and Environmental Safety Jul 2024Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The...
Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.
Topics: Animals; Podophyllotoxin; Rats; Male; Gastrointestinal Microbiome; Rats, Sprague-Dawley; Peroxisome Proliferator-Activated Receptors; PPAR gamma; Microbiota
PubMed: 38850705
DOI: 10.1016/j.ecoenv.2024.116548 -
Biomedicine & Pharmacotherapy =... Jul 2024Non-alcoholic fatty liver disease (NAFLD), particularly advanced non-alcoholic steatohepatitis (NASH), leads to irreversible liver damage. This study investigated the...
Non-alcoholic fatty liver disease (NAFLD), particularly advanced non-alcoholic steatohepatitis (NASH), leads to irreversible liver damage. This study investigated the therapeutic effects and potential mechanism of a novel extract from traditional Chinese medicine Alisma orientale (Sam.) Juzep (AE) on free fatty acid (FFA)-induced HepG2 cell model and high-fat diet (HFD) + carbon tetrachloride (CCl)-induced mouse model of NASH. C57BL/6 J mice were fed a HFD for 10 weeks. Subsequently, the mice were injected with CCl to induce NASH and simultaneously treated with AE at daily doses of 50, 100, and 200 mg/kg for 4 weeks. At the end of the treatment, animals were fasted for 12 h and then sacrificed. Blood samples and liver tissues were collected for analysis. Lipid profiles, oxidative stress, and histopathology were examined. Additionally, a polymerase chain reaction (PCR) array was used to predict the molecular targets and potential mechanisms involved, which were further validated in vivo and in vitro. The results demonstrated that AE reversed liver damage (plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatocyte ballooning, hepatic steatosis, and NAS score), the accumulation of hepatic lipids (TG and TC), and oxidative stress (MDA and GSH). PCR array analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that AE protects against NASH by regulating the adipocytokine signaling pathway and influencing nuclear receptors such as PPARα. Furthermore, AE increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1α) and reversed the decreased expression of PPARα in NASH mice. Moreover, in HepG2 cells, AE reduced FFA-induced lipid accumulation and oxidative stress, which was dependent on PPARα up-regulation. Overall, our findings suggest that AE may serve as a potential therapeutic approach for NASH by inhibiting lipid accumulation and reducing oxidative stress specifically through the PPARα pathway.
Topics: Animals; Non-alcoholic Fatty Liver Disease; PPAR alpha; Mice, Inbred C57BL; Signal Transduction; Humans; Alisma; Male; Plant Extracts; Hep G2 Cells; Diet, High-Fat; Mice; Oxidative Stress; Liver; Disease Models, Animal; Carbon Tetrachloride; Lipid Metabolism
PubMed: 38850668
DOI: 10.1016/j.biopha.2024.116908 -
Annals of Medicine and Surgery (2012) Jun 2024Infertility and the pathogenesis of polycystic ovarian syndrome (PCOS) are both influenced by insulin resistance and dyslipidemia. Presumably, adding coenzyme Q10...
OBJECTIVE
Infertility and the pathogenesis of polycystic ovarian syndrome (PCOS) are both influenced by insulin resistance and dyslipidemia. Presumably, adding coenzyme Q10 (CoQ10) to these patients' diets will be beneficial. Therefore, this study aimed to examine the effects of CoQ10 supplementation on metabolic profiles in women candidates for in-vitro fertilization (IVF).
TRIAL DESIGN AND METHODS
For this randomized, double-blinded, parallel, placebo-controlled clinical experiment, 40 PCOS-positive infertile women who were IVF candidates were included. They ranged in age from 18 to 40. The 20 participants in the two intervention groups received either CoQ10 or a placebo for 8 weeks. The expression of glucose transporter 1 (GLUT-1), peroxisome proliferator-activated receptor gamma (PPAR-γ), low-density lipoprotein receptor (LDLR), as well as metabolic profiles such as insulin metabolism and lipid profiles were evaluated. Quantitative RT-PCR determined the expression of GLUT-1, PPAR-γ, and LDLR on peripheral blood mononuclear cells. Lipid profiles and fasting glucose were assessed using enzymatic kits, and insulin was determined using Elisa kit.
RESULTS
In comparison to the placebo, CoQ10 supplementation significantly reduced blood insulin levels (-0.3±1.0 vs. 0.5±0.7, =0.01) and insulin resistance (-0.1±0.2 vs. 0.1±0.2, =0.01), and increased PPAR-γ expression (=0.01). In infertile PCOS patients' candidates for IVF, CoQ10 supplementation showed no appreciable impact on other metabolic profiles. Also, CoQ10 supplementation revealed no significant impact on GLUT-1 (=0.30), or LDLR (=0.27) expression. Within-group changes in insulin levels (=0.01) and insulin resistance (=0.01) showed a significant elevation in the placebo group. When we adjusted the analysis for baseline BMI, baseline values of variables, and age, our findings were not affected.
CONCLUSIONS
Eight weeks of CoQ10 supplementation demonstrated positive benefits on PPAR-γ expression, insulin resistance, and serum insulin in infertile PCOS women candidates for IVF.
PubMed: 38846853
DOI: 10.1097/MS9.0000000000001732 -
Heliyon Jun 2024Bge. (. ) is a well-known traditional Chinese medicine for the treatment of cardiovascular diseases. The processing of . requires the raw herbs to sweat first and then...
Bge. (. ) is a well-known traditional Chinese medicine for the treatment of cardiovascular diseases. The processing of . requires the raw herbs to sweat first and then dry. The aim of this study was to investigate the anti-acute myocardial ischemia (AMI) of . extracts (including tanshinones and phenolic acids) before and after sweating, and to further explore whether the "sweating" primary processing affected the efficacy of The AMI animal model was established by subcutaneous injection of isoprenaline hydrochloride (ISO). After treatment, the cardiac function of rats was evaluated by electrocardiogram (ECG), biochemical, and histochemical analysis. Moreover, the regulation of . extracts on the peroxisome proliferator-activated receptor α (PPARα)/retinoid X receptor α (RXRα)/nuclear transcription factor-kappa B (NF-κB) signaling pathway of rats was assessed by the Western blotting. The results showed that sweated and non-sweated extracts including tanshinones and phenolic acids significantly reduced ST-segment elevation in ECG and the myocardial infarction area in varying degrees. Meanwhile, sweated and non-sweated reversed the activities of aspartate transaminase (AST), lactic dehydrogenase (LDH), creatine kinase-MB (CK-MB), and superoxide dismutase (SOD), as well as the levels of interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) in AMI rats. Concurrently, the results of Western blotting revealed that . extracts regulated the PPARα/RXRα/NF-κB signaling pathway to exert an anti-inflammatory effect. Most importantly, sweated tanshinones extracts are more effective than the non-sweated , and the anti-inflammatory efficacy of tanshinones extract was also better than that of phenolic acid extract. Although phenolic acid extracts before and after sweating were effective in anti-AMI, there was no significant difference between them. In conclusion, both tanshinones and phenolic acids extracts of sweated and non-sweated . promote anti-oxidative stress and anti-inflammatory against AMI via regulating the PPARα/RXRα/NF-κB signaling pathway. Further, the comparations between sweated and non-sweated . extracts indicate that sweated . tanshinones extracts have better therapeutic effects on AMI.
PubMed: 38845919
DOI: 10.1016/j.heliyon.2024.e31923 -
The Journal of Biological Chemistry Jun 2024A high level of PD-L1 in cancer cells promotes tumor immune escape and inhibits tumor immunotherapy. Although PD-L1 gene expression is upregulated by multiple pathways,...
A high level of PD-L1 in cancer cells promotes tumor immune escape and inhibits tumor immunotherapy. Although PD-L1 gene expression is upregulated by multiple pathways, its gene transcriptional repression is still unclear. Here we found that loss of PPARα, one of the peroxisome-proliferator-activated receptors (PPARs) family members, promoted colorectal tumor immune escape. Mechanistically, PPARα directly bound to the PD-L1 promoter resulting in its gene transcriptional repression, which in turn increased T cell activity, and PPARα agonist enhanced this event. However, ERK induced PPARα-S12 phosphorylation leading to blockade of PPARα-mediated PD-L1 transcriptional repression, and the combination of ERK inhibitor with PPARα agonist significantly inhibited tumor immune escape. These findings suggest that the ERK-PPARα pathway inhibited PD-L1 gene transcriptional repression and promoted colorectal tumor immune escape.
PubMed: 38844134
DOI: 10.1016/j.jbc.2024.107447 -
Frontiers in Genetics 2024Obesity is a multifactorial disease associated with the development of many comorbidities. This disease is associated with several metabolic alterations; however, it has...
INTRODUCTION
Obesity is a multifactorial disease associated with the development of many comorbidities. This disease is associated with several metabolic alterations; however, it has been shown that some individuals with obesity do not exhibit metabolic syndrome. Adipose tissue neutralizes the detrimental effects of circulating fatty acids, ectopic deposition, and inflammation, among others, through its esterification into neutral lipids that are stored in the adipocyte. However, when the adipocyte is overloaded, i.e., its expansion capacity is exceeded, this protection is lost, resulting in fatty acid toxicity with ectopic fat accumulation in peripheral tissues and inflammation. In this line, this study aimed to investigate whether polymorphisms in genes that control adipose tissue fat storage capacity are potential biomarkers for severe obesity susceptibility and also metabolic complications.
METHODS
This study enrolled 305 individuals with severe obesity (cases, BMI≥35 kg/m) and 196 individuals with normal weight (controls, 18.5≤BMI≤24.9 kg/m). Demographic, anthropometric, biochemical, and blood pressure variables were collected from the participants. Plasma levels of leptin, resistin, MCP1, and PAI1 were measured by Bio-Plex 200 Multiplexing Analyzer System. Genomic DNA was extracted and variants in (rs17060940), (rs7895833 and rs1467568), (rs660339), (rs1801282) and (rs1042713 and rs1042714) genes were genotyped by PCR allelic discrimination using TaqMan assays.
RESULTS
Our findings indicated that rs7895833 polymorphism was a risk factor for severe obesity development in the overdominant model. rs1467568 and rs660339 were associated with anthropometric traits. rs1467568 G allele was related to lower medians of body adipose index and hip circumference, while the rs660339 AA genotype was associate with increased body mass index. Additionally, rs17060940 influenced glycated hemoglobin. Regarding metabolic alterations, 27% of individuals with obesity presented balanced metabolic status in our cohort. Furthermore, rs1467568 AG genotype increased 2.5 times the risk of developing metabolic alterations. No statistically significant results were observed with and polymorphisms.
DISCUSSION/CONCLUSION
This study revealed that rs7895833 and rs1467568 are potential biomarkers for severe obesity susceptibility and the development of unbalanced metabolic status in obesity, respectively. rs660339 and rs17060940 also showed a significant role in obesity related-traits.
PubMed: 38841722
DOI: 10.3389/fgene.2024.1363417 -
Frontiers in Plant Science 2024Controlled environment agriculture (CEA) is critical for achieving year-round food security in many regions of the world. CEA is a resource-intensive endeavor, with...
Controlled environment agriculture (CEA) is critical for achieving year-round food security in many regions of the world. CEA is a resource-intensive endeavor, with lighting consuming a large fraction of the energy. To lessen the burden on the grid and save costs, an extended photoperiod strategy can take advantage of off-peak time-of-day options from utility suppliers. However, extending the photoperiod limits crop production morphologically and physiologically if pushed too long. Here, we present a continuous-light dynamic light-emitting diode (LED) strategy (involving changes in spectra, intensity, and timing), that overcomes these limitations. We focused on tomato, a well described photoperiodic injury-sensitive species, and mini-cucumber, a photoperiodic injury-tolerant species to first assess morphological responses under control (16-h photoperiod, unchanging spectrum), constant (24-h photoperiod, unchanging spectrum), and two variations of a dynamic LED strategy, dynamic 1 (16-h "day", 3-h "peak", 8-h "night" spectra) and dynamic 2 (20-h "day", 5-h "peak", 4-h "night" spectra). Next, we tested the hypothesis of photorespiration's involvement in photoperiodic injury by using a leaf gas exchange coupled with chlorophyll fluorescence protocol. We further explored Adenosine triphosphate (ATP): Nicotinamide adenine dinucleotide phosphate (NADPH) ratio supply/demand responses by probing photosynthetic electron flow and proton flow with the MultispeQ instrument. We found canopy architecture can be tuned by minor variations of the same dynamic LED strategy, and we highlight dynamic 1 as the optimal choice for both tomato and mini-cucumber as it improved biomass/architecture and first-yield, respectively. A central discovery was that dynamic 1 had a significantly higher level of photorespiration than control, for both species. Unexpectedly, photorespiration was comparable between species under the same treatments, except under constant. However, preliminary data on a fully tolerant tomato genotype grown under constant treatment upregulated photorespiration similar to mini-cucumber. These results suggest that photoperiodic injury tolerance involves a sustained higher level of photorespiration under extended photoperiods. Interestingly, diurnal MultispeQ measurements point to the importance of cyclic electron flow at subjective nighttime that may also partially explain why dynamic LED strategies mitigate photoperiodic injury. We propose an ontology of photoperiodic injury involving photorespiration, triose phosphate utilization, peroxisomal HO-catalase balance, and a circadian external coincidence model of sensitivity that initiates programmed cell death.
PubMed: 38841277
DOI: 10.3389/fpls.2024.1384518