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International Journal of Molecular... Feb 2024Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we...
Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we report a series of in vitro studies conducted with human-bone-marrow-derived pluripotent stromal cells (MSCs). First, we show that during osteogenic differentiation, mRNA levels of most polyamine-associated enzymes are relatively constant, except for the catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), which is strongly increased at both mRNA and protein levels. As a result, the intracellular spermidine to spermine ratio is significantly reduced during the early stages of osteoblastogenesis. Supplementation of cells with exogenous spermidine or spermine decreases matrix mineralization in a dose-dependent manner. Employing N-cyclohexyl-1,3-propanediamine (CDAP) to chemically inhibit spermine synthase (SMS), the enzyme catalyzing conversion of spermidine into spermine, also suppresses mineralization. Intriguingly, this reduced mineralization is rescued with DFMO, an inhibitor of the upstream polyamine enzyme ornithine decarboxylase (ODC1). Similarly, high concentrations of CDAP cause cytoplasmic vacuolization and alter mitochondrial function, which are also reversible with the addition of DFMO. Altogether, these studies suggest that excess polyamines, especially spermidine, negatively affect hydroxyapatite synthesis of primary MSCs, whereas inhibition of polyamine synthesis with DFMO rescues most, but not all of these defects. These findings are relevant for patients with Snyder-Robinson syndrome (SRS), as the presenting skeletal defects-associated with SMS deficiency-could potentially be ameliorated by treatment with DFMO.
Topics: Humans; Spermidine; Spermine; Spermine Synthase; Ornithine Decarboxylase; Osteogenesis; Polyamines; Mesenchymal Stem Cells; RNA, Messenger
PubMed: 38473716
DOI: 10.3390/ijms25052463 -
Animals : An Open Access Journal From... Feb 2024The 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...
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.
PubMed: 38473074
DOI: 10.3390/ani14050689 -
Molecular Genetics and Metabolism... Mar 2024GAMT deficiency is a rare autosomal recessive disease within the group of cerebral creatine deficiency syndromes. Cerebral creatine depletion and accumulation of...
GAMT deficiency is a rare autosomal recessive disease within the group of cerebral creatine deficiency syndromes. Cerebral creatine depletion and accumulation of guanidinoacetate (GAA) lead to clinical presentation with intellectual disability, seizures, speech disturbances and movement disorders. Treatment consists of daily creatine supplementation to increase cerebral creatine, reduction of arginine intake and supplementation of ornithine for reduction of toxic GAA levels. This study represents the first long-term follow-up over a period of 14 years, with detailed clinical data, biochemical and multimodal neuroimaging findings. Developmental milestones, brain MRI, quantitative single voxel H magnetic resonance spectroscopy (MRS) and biochemical analyses were assessed. The results reveal insights into the dose dependent effects of creatine/ornithine supplementation and expand the phenotypic spectrum of GAMT deficiency. Of note, the creatine concentrations, which were regularly monitored over a long follow-up period, increased significantly over time, but did not reach age matched control ranges. Our patient is the second reported to show normal neurocognitive outcome after an initial delay, stressing the importance of early diagnosis and treatment initiation.
PubMed: 38469086
DOI: 10.1016/j.ymgmr.2024.101053 -
Asian Journal of Surgery Jul 2024
Topics: Humans; Liver Transplantation; Hyperammonemia; Infant, Newborn; Urea Cycle Disorders, Inborn; Male; Ornithine; Citrulline; Female
PubMed: 38443250
DOI: 10.1016/j.asjsur.2024.02.143 -
Polish Journal of Microbiology Mar 2024Hydrocarbon constituents of petroleum are persistent, bioaccumulated, and bio-magnified in living tissues, transported to longer distances, and exert hazardous effects...
Hydrocarbon constituents of petroleum are persistent, bioaccumulated, and bio-magnified in living tissues, transported to longer distances, and exert hazardous effects on human health and the ecosystem. Bioaugmentation with microorganisms like bacteria is an emerging approach that can mitigate the toxins from environmental sources. The present study was initiated to target the petroleum-contaminated soil of gasoline stations situated in Lahore. Petroleum degrading bacteria were isolated by serial dilution method followed by growth analysis, biochemical and molecular characterization, removal efficiency estimation, metabolites extraction, and GC-MS of the metabolites. Molecular analysis identified the bacterium as Bacillus cereus, which exhibited maximum growth at 72 hours and removed 75% petroleum. Biochemical characterization via the Remel RapID ONE panel system showed positive results for arginine dehydrolase (ADH), ornithine decarboxylase (ODC), lysine decarboxylase (LDC), -nitrophenyl-β-D-galactosidase (ONPG), -nitrophenyl-β-D-glucosidase (βGLU), -nitrophenyl-N-acetyl-β-D-glucosaminidase (NAG), malonate (MAL), adonitol fermentation (ADON), and tryptophane utilization (IND). GC-MS-based metabolic profiling identified alcohols (methyl alcohol, -, - and -cresols, catechol, and 3-methyl catechol), aldehydes (methanone, acetaldehyde, and -tolualdehyde), carboxylic acid (methanoic acid, -muconic acid, cyclohexane carboxylic acid and benzoic acid), conjugate bases of carboxylic acids (benzoate, -muconate, 4-hydroxybenzoate, and pyruvate) and cycloalkane (cyclohexene). It suggested the presence of methane, methylcyclohexane, toluene, xylene, and benzene degradation pathways in .
Topics: Humans; Bacillus cereus; Ecosystem; Hydrocarbons; Methane; Carboxylic Acids
PubMed: 38437466
DOI: 10.33073/pjm-2024-012 -
Cureus Jan 2024There are no guidelines for the most effective medication to reduce hepatic encephalopathy (HE) or the associated mortality. The purpose of this study is to determine... (Review)
Review
There are no guidelines for the most effective medication to reduce hepatic encephalopathy (HE) or the associated mortality. The purpose of this study is to determine the most effective possible treatment among the single treatment options or the combined treatment options for decreasing the morbidity and mortality of HE. We evaluated the outcomes by various parameters such as the quality of life, reduction in ammonia, all causes of mortality, adverse events, reversal of minimal HE, and development of overt HE. We systematically searched PubMed, Cochrane, Web of Science, and Scopus till the 19th of January 2023 for studies that assess various treatment options for HE. Data were extracted from eligible studies and pooled in a frequentist network meta-analysis as standardized mean difference (SMD) and their 95% confidence interval (CI) using the MetaInsight web-based tool. The Cochrane Tool was used to assess the randomized controlled trials' quality (RCT), while the NIH tool was used to assess the quality of the included cohort studies. Utilizing the R software, the network meta-analysis was conducted. In addition to a significant variation in cases of (Lactulose and Rifaximin) compared with Rifaximin (RR= 0.39, 95% CI [0.17; 0.89]), the results demonstrated a significantly lower incidence of overt HE in (Lactulose and Rifaximin) compared with placebo (RR=0.19, 95% CI [0.09; 0.40]). Most arms demonstrated a statistically significant reduction in the incidence of overt HE compared to albumin and placebo. The results also demonstrated a significant reduction in ammonia between L-ornithine-L-aspartate (LOLA) and probiotics (MD= -19.17, 95% CI [-38.01; -0.32]), as well as a significant difference in the incidence of LOLA compared to placebo (MD= -22.62, 95% CI [-39.16; -6.07]). This network meta-analysis has significant data for managing subclinical HE in people without a history of overt HE. Our analysis showed that (Lactulose and Rifaximin), followed by (Rifaximin and L-carnitine), followed by (Lactulose and Rifaximin with zinc) were the best combinations regarding overt HE. LOLA reduced ammonia best, followed by Nitazoxanide and finally Lactulose. (Lactulose and Nitazoxanide) have the least adverse effects, followed by (Rifaximin and L-carnitine), then Probiotics. Yet, all mortality outcomes and quality of life changes yielded no useful findings. Future studies like RCTs must be done to compare our therapies directly.
PubMed: 38435950
DOI: 10.7759/cureus.53341 -
Experimental & Molecular Medicine Feb 2024Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous...
Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that the levels of ornithine aminotransferase (OAT), a principal enzyme in the proline metabolism pathway, were increased in the lungs of patients with IPF. However, the precise role played by OAT in the pathogenesis of IPF is not yet clear. The mechanism by which OAT affects fibrogenesis was assessed in vitro using OAT-overexpressing and OAT-knockdown lung fibroblasts. The therapeutic effects of OAT inhibition were assessed in the lungs of bleomycin-treated mice. OAT expression was increased in fibrotic areas, principally in interstitial fibroblasts, of lungs affected by IPF. OAT levels in the bronchoalveolar lavage fluid of IPF patients were inversely correlated with lung function. The survival rate was significantly lower in the group with an OAT level >75.659 ng/mL than in the group with an OAT level ≤75.659 ng/mL (HR, 29.53; p = 0.0008). OAT overexpression and knockdown increased and decreased ECM component production by lung fibroblasts, respectively. OAT knockdown also inhibited transforming growth factor-β1 (TGF)-β1 activity and TGF-β1 pathway signaling. OAT overexpression increased the generation of mitochondrial reactive oxygen species (ROS) by activating proline dehydrogenase. The OAT inhibitor L-canaline significantly attenuated bleomycin-induced lung injury and fibrosis. In conclusion, increased OAT levels in lungs affected by IPF contribute to the progression of fibrosis by promoting excessive mitochondrial ROS production, which in turn activates TGF-β1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.
Topics: Animals; Humans; Mice; Bleomycin; Extracellular Matrix Proteins; Fibrosis; Idiopathic Pulmonary Fibrosis; Lung; Ornithine-Oxo-Acid Transaminase; Reactive Oxygen Species; Transforming Growth Factor beta1
PubMed: 38413821
DOI: 10.1038/s12276-024-01170-w -
International Journal of Nanomedicine 2024The presence of cancer stem cells (CSCs) significantly limits the therapeutic efficacy of radiotherapy (RT). Efficient elimination of potential CSCs is crucial for...
INTRODUCTION
The presence of cancer stem cells (CSCs) significantly limits the therapeutic efficacy of radiotherapy (RT). Efficient elimination of potential CSCs is crucial for enhancing the effectiveness of RT.
METHODS
In this study, we developed a biomimetic hybrid nano-system (PMC) composed of MnCO as the inner core and platelet membrane (PM) as the outer shell. By exploiting the specific recognition properties of membrane surface proteins, PMC enables precise targeting of CSCs. Sonodynamic therapy (SDT) was employed using manganese carbonate nanoparticles (MnCO NPs), which generate abundant reactive oxygen species (ROS) upon ultrasound (US) irradiation, thereby impairing CSC self-renewal capacity and eradicating CSCs. Subsequent RT effectively eliminates common tumor cells.
RESULTS
Both in vitro cell experiments and in vivo animal studies demonstrate that SDT mediated by PMC synergistically enhances RT to selectively combat CSCs while inhibiting tumor growth without noticeable side effects.
DISCUSSION
Our findings offer novel insights for enhancing the efficacy and safety profiles of RT.
Topics: Animals; Cell Line, Tumor; Biomimetics; Nanoparticles; Reactive Oxygen Species; Neoplastic Stem Cells; Neoplasms; Carbonates; Manganese; Nitrosourea Compounds
PubMed: 38406602
DOI: 10.2147/IJN.S450018 -
Arab Journal of Gastroenterology : the... May 2024Minimal hepatic encephalopathy (MHE) is an early stage of hepatic encephalopathy (HE) and is highly prevalent. The efficacy of L-ornithine L-aspartate (LOLA) for the... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND STUDY AIMS
Minimal hepatic encephalopathy (MHE) is an early stage of hepatic encephalopathy (HE) and is highly prevalent. The efficacy of L-ornithine L-aspartate (LOLA) for the treatment of HE is well known but its role in MHE remains uncertain. The objectives of the current study were to evaluate the efficacy of LOLA for the treatment of MHE in patients with cirrhosis.
METHODS
The Cochrane Library, PubMed, EMBASE, Web of Science and Ovid databases were searched. Only randomized controlled trials (RCTs) that compared the efficacy of LOLA with placebo or no intervention for the treatment of MHE in patients with cirrhosis were included from inception to January 2023. The primary outcomes were reversal of MHE and development of overt hepatic encephalopathy (OHE).
RESULTS
Overall, six RCTs comprising 292 patients were included. Compared with placebo or no intervention, LOLA was more effective in reversing MHE (RR = 2.264, 95 % CI = 1.528, 3.352, P = 0.000, I = 0.0 %) and preventing progression of OHE (RR = 0.220, 95 % CI = 0.076, 0.637, P = 0.005, I = 0.0 %). Based on subgroup analyses, oral LOLA treatment appeared more likely to reverse MHE (RR = 2.648, 95 % CI = 1.593, 4.402, P = 0.000, I = 0.0 %), intravenous LOLA treatment yielded a similar probability of reversing MHE (RR = 1.669, 95 % CI = 0.904, 3.084, P = 0.102, I = 0.0 %). LOLA did not show a superior possibility in reducing mortality (RR = 0.422, 95 % CI = 0.064, 2.768, P = 0.368, I = 0.0 %) and ammonia levels (SMD = 0.044, 95 % CI = -0.290, 0.379, P = 0.795, I = 0.0 %) compared with placebo or no intervention.
CONCLUSIONS
LOLA has significant beneficial effects on reversal of MHE and prevention of OHE in patients with cirrhosis compared with placebo or no intervention.
Topics: Humans; Dipeptides; Hepatic Encephalopathy; Liver Cirrhosis; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 38403493
DOI: 10.1016/j.ajg.2024.01.006