scholarly journals Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Lei Jiang ◽  
Ji-Sun Park ◽  
Ling Yin ◽  
Rodrigo Laureano ◽  
Eric Jacquinet ◽  
...  
Keyword(s):  
Genetic Disorders ◽  
Propionic Acidemia ◽  
Repeat Dose ◽  
Dependent Manner ◽  
Messenger Rnas ◽  
Enzyme Replacement ◽  
Life Threatening ◽  
Mrna Technology ◽  
Dose Dependent

Abstract Propionic acidemia/aciduria (PA) is an ultra-rare, life-threatening, inherited metabolic disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC) composed of six alpha (PCCA) and six beta (PCCB) subunits. We herein report an enzyme replacement approach to treat PA using a combination of two messenger RNAs (mRNAs) (dual mRNAs) encoding both human PCCA (hPCCA) and PCCB (hPCCB) encapsulated in biodegradable lipid nanoparticles (LNPs) to produce functional PCC enzyme in liver. In patient fibroblasts, dual mRNAs encoded proteins localize in mitochondria and produce higher PCC enzyme activity vs. single (PCCA or PCCB) mRNA alone. In a hypomorphic murine model of PA, dual mRNAs normalize ammonia similarly to carglumic acid, a drug approved in Europe for the treatment of hyperammonemia due to PA. Dual mRNAs additionally restore functional PCC enzyme in liver and thus reduce primary disease-associated toxins in a dose-dependent manner in long-term 3- and 6-month repeat-dose studies in PA mice. Dual mRNAs are well-tolerated in these studies with no adverse findings. These studies demonstrate the potential of mRNA technology to chronically administer multiple mRNAs to produce large complex enzymes, with applicability to other genetic disorders.

scholarly journals Antifungal activity of dendritic cell lysosomal proteins against Cryptococcus neoformans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Benjamin N. Nelson ◽  
Savannah G. Beakley ◽  
Sierra Posey ◽  
Brittney Conn ◽  
Emma Maritz ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Mammalian Cells ◽  
Cysteine Proteases ◽  
Dependent Manner ◽  
Life Threatening ◽  
Opportunistic Fungal Pathogen ◽  
Dose Dependent ◽  
Lysosomal Proteins

AbstractCryptococcal meningitis is a life-threatening disease among immune compromised individuals that is caused by the opportunistic fungal pathogen Cryptococcus neoformans. Previous studies have shown that the fungus is phagocytosed by dendritic cells (DCs) and trafficked to the lysosome where it is killed by both oxidative and non-oxidative mechanisms. While certain molecules from the lysosome are known to kill or inhibit the growth of C. neoformans, the lysosome is an organelle containing many different proteins and enzymes that are designed to degrade phagocytosed material. We hypothesized that multiple lysosomal components, including cysteine proteases and antimicrobial peptides, could inhibit the growth of C. neoformans. Our study identified the contents of the DC lysosome and examined the anti-cryptococcal properties of different proteins found within the lysosome. Results showed several DC lysosomal proteins affected the growth of C. neoformans in vitro. The proteins that killed or inhibited the fungus did so in a dose-dependent manner. Furthermore, the concentration of protein needed for cryptococcal inhibition was found to be non-cytotoxic to mammalian cells. These data show that many DC lysosomal proteins have antifungal activity and have potential as immune-based therapeutics.

A dual approach to self-stimulation and locomotor trace affected by chronic methamphetamine treatment for an animal model of schizophrenia

1993 ◽  
Vol 71 (5-6) ◽  
pp. 321-325 ◽  
Author(s):  
Morikuni Takigawa ◽  
Hiroshi Maeda ◽  
Kenichi Ueyama ◽  
Hidefumi Tominaga ◽  
Kei Matsumoto
Keyword(s):  
Animal Model ◽  
Negative Symptoms ◽  
Disease Model ◽  
Stereotyped Behavior ◽  
Dependent Manner ◽  
Dual Approach ◽  
Reverse Tolerance ◽  
Self Stimulation ◽  
Dose Dependent

The effect of long-term methamphetamine (MAP) treatment on intracranial self-stimulation of the lateral hypotholamus and locomotor traces was assessed. An attempt was made to provide a useful animal model for understanding anhedonia, stereotypy, and reoccurrence of liability, which are analogous to symptoms of schizophrenia. The frequency of intracranial self-stimulation (ICSS) as used as a measure of the animals' "hedonic–anhedonic" state. Following long-term MAP treatment (3 mg/kg), rats gradually showed stereotyped behavior, and became inactive and unresponsive to ICSS. These behavioral changes and decreased ICSS lasted several weeks after cessation of chronic MAP treatment and seemed to suggest post-MAP chronic psychosis and (or) anhedonia, two of the negative symptoms of schizophrenia. The traces of rat behavior affected by chronic MAP treatment were classified into three types, peripheral, mixed, and fixed, occurring in a dose-dependent manner. Reverse tolerance, similar to the reoccurrence of schizophrenic symptoms, was observed as a fixed stereotypy associated with loss of ICSS. These abnormal phenomena were suppressed by pretreatment with haloperidol. In the present study, the combination of ICSS and locomotor trace affected by chronic MAP treatment was proposed as an animal model of schizophrenia and as a useful technique for gauging the effect of neuroleptics.Key words: self-stimulation, anhedonia, stereotypy, reverse tolerance, animal disease model, schizophrenia, methamphetamine.

p-Nitrophenylphosphatase Activity Catalyzed by Plasma Membrane (Ca2++Mg2+)ATPase: Correlation with Structural Changes Modulated by Glycerol and Ca2+

2001 ◽  
Vol 21 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Gutemberg G. Alves ◽  
Luis Maurício T. R. Lima ◽  
Maely P. Fávero-Retto ◽  
Adriana P. Lemos ◽  
Carlos E. Peres-Sampaio ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Synergistic Effect ◽  
Phosphatase Activity ◽  
Structural Changes ◽  
Center Of Mass ◽  
Binding Domain ◽  
Dependent Manner ◽  
Dose Dependent ◽  
Substrate Binding Domain

The plasma membrane (Ca2++Mg2+)ATPase hydrolyzes pseudo-substrates such as p-nitrophenylphosphate. Except when calmodulin is present, Ca2+ ions inhibit the p-nitrophenylphosphatase activity. In this report it is shown that, in the presence of glycerol, Ca2+ strongly stimulates phosphatase activity in a dose-dependent manner. The glycerol- and Ca2+-induced increase in activity is correlated with modifications in the spectral center of mass (average emission wavenumber) of the intrinsic fluorescence of the enzyme. It is concluded that the synergistic effect of glycerol and Ca2+ is related to opposite long-term hydration effects on the substrate binding domain and the Ca2+ binding domain.

Effect of retinoic acid on limb regeneration in Xenopus laevis

1983 ◽  
Vol 61 (12) ◽  
pp. 2698-2702 ◽  
Author(s):  
Steven R. Scadding
Keyword(s):  
Retinoic Acid ◽  
Xenopus Laevis ◽  
Limb Regeneration ◽  
Dependent Manner ◽  
African Clawed Frog ◽  
Long Term Effect ◽  
Aquarium Water ◽  
Dose Dependent ◽  
Clawed Frog

The objective of this experiment was to determine the effect of retinoic acid on the process of limb regeneration in the African clawed frog, Xenopus laevis. Limbs were bilaterally amputated through the radio-ulna and then treated for 15 days with retinoic acid in the aquarium water, at 3, 15, or 75 IU/mL. The retinoic acid inhibited limb regeneration in a dose-dependent manner, reduced the length of the regenerates, and produced irregularities in the morphogenesis of the cartilage rod in the regenerate. The regenerated limbs were removed after 150 days by amputation through the humerus, and the limbs were again allowed to regenerate. In the retinoic acid treated animals, despite the fact that retinoic acid treatment had been discontinued over 4 months previously, limb regeneration was still inhibited. These results suggest that retinoic acid has a long-term effect on the treated animals.

scholarly journals Activation Effects of Polysaccharides ofFlammulina velutipesMycorrhizae on the T Lymphocyte Immune Function

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Zheng-Fei Yan ◽  
Nai-Xu Liu ◽  
Xin-Xin Mao ◽  
Yu Li ◽  
Chang-Tian Li
Keyword(s):  
Immune Function ◽  
T Lymphocyte ◽  
Interleukin 2 ◽  
Potential Effect ◽  
Dependent Manner ◽  
Health Products ◽  
Immune Health ◽  
Spleen Lymphocytes ◽  
Dose Dependent

Flammulina velutipesmycorrhizae have increasingly been produced with increasing ofF. velutipesproduction. A mouse model was thus used to examine potential effect ofF. velutipesmycorrhizae on the immune function. Fifty female Wistar mice (5-weeks-old) weighed 15–20 g were randomly allocated into five groups. Polysaccharide ofF. velutipesmycorrhizae were treated with mice and mice spleen lymphocytes. The levels of CD3+, CD4+, and CD8+T lymphocyte, interleukin-2 (IL-2), and tumor necrosis factor-a (TNF-α) were determined. The results showed that the proportions of CD3+, and CD4+T lymphocyte, the ratio of CD4+/CD8+, and the levels of IL-2 and TNF-a were significantly increased in polysaccharide ofF. velutipesmycorrhizae, while the proportion of CD8+T lymphocyte was decreased in polysaccharide ofF. velutipesmycorrhizae-dose dependent manner. Our findings indicated that a long term exposure of polysaccharide ofF. velutipesmycorrhizae could activate the T lymphocyte immune function. Polysaccharide ofF. velutipesmycorrhizae was expected to develop into the immune health products.

scholarly journals Premature Puberty and Thimerosal-Containing Hepatitis B Vaccination: A Case-Control Study in the Vaccine Safety Datalink

Toxics ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 67
Author(s):  
David Geier ◽  
Janet Kern ◽  
Mark Geier
Keyword(s):  
Hepatitis B ◽  
Case Control Study ◽  
Vaccine Safety ◽  
Case Control ◽  
Hepatitis B Vaccination ◽  
Dependent Manner ◽  
Hepatitis B Vaccines ◽  
Dose Dependent ◽  
Control Study

Studies suggest a relationship between exposure to endocrine disrupters, such as mercury (Hg), and premature puberty. Hg exposure from Thimerosal-containing hepatitis B vaccine, administered at specific intervals within the first six months of life, and the child’s long-term risk of being diagnosed with premature puberty (ICD-9 code: 259.1), was retrospectively examined, using a hypothesis-testing, longitudinal case-control design on prospectively collected data, in the Vaccine Safety Datalink (VSD). Cases diagnosed with premature puberty were significantly more likely to have received increased exposure to Hg from hepatitis B vaccines preserved with Thimerosal given in the first month after birth (odds ratio (OR) = 1.803), first two months after birth (OR = 1.768), and first six months after birth (OR = 2.0955), compared to control subjects. When the data were separated by gender, the effects remained among females but not males. Female cases, as compared to female controls, were significantly more likely in a dose-dependent manner to have received a greater exposure to Hg from hepatitis B vaccines preserved with Thimerosal, given in the first six months after birth (OR = 1.0281 per µg Hg). The results of this study show a dose-dependent association between increasing organic Hg exposure from Thimerosal-containing hepatitis B vaccines administered within the first six months of life and the long-term risk of the child being diagnosed with premature puberty.

scholarly journals Increased mortality risk associated with serum sodium variations and borderline hypo- and hypernatremia in hospitalized adults

2019 ◽  
Vol 35 (10) ◽  
pp. 1746-1752 ◽  
Author(s):  
Charat Thongprayoon ◽  
Wisit Cheungpasitporn ◽  
John Q Yap ◽  
Qi Qian
Keyword(s):  
Hospital Stay ◽  
Serum Sodium ◽  
Reference Range ◽  
Length Of Hospital Stay ◽  
Sodium Concentration ◽  
Dependent Manner ◽  
Short And Long Term ◽  
Dose Dependent ◽  
Long Term Mortality

Abstract Background This study aimed to evaluate short-term and long-term mortalities in a cohort of unselected hospitalized patients with serum sodium concentration ([Na+]) variations within and outside of reference range. Methods All adult patients admitted to the Mayo Clinic, Rochester, MN, USA from January 2011 to December 2013 (n = 147358) were retrospectively screened. Unique patients admitted during the study period were examined. The main exposure was serum [Na+] variation. Outcome measures were hospital and 1-year all-cause mortalities. Results A total of 60944 patients, mean age 63 ± 17 years, were studied. On admission, 17% (n = 10066) and 1.4% (n = 852) had hypo- and hypernatremia, respectively. During the hospital stay, 11044 and 4128 developed hypo- and hypernatremia, respectively, accounting for 52.3 and 82.9% of the total hypo- and hypernatremic patients. Serum [Na+] variations of ≥6 mEq/L occurred in 40.6% (n = 24 740) of the 60 944 patients and were significantly associated with hospital and 1-year mortalities after adjusting potential confounders (including demographics, comorbidities, estimated glomerular filtration rate, admission serum [Na+], number of [Na+] measurements and length of hospital stay). Adjusted odds ratios for hospital and 1-year mortalities increased with increasing [Na+] variations in a dose-dependent manner, from 1.47 to 5.48 (all 95% confidence intervals >1.0). Moreover, in fully adjusted models, [Na+] variations (≥6 mEq/L) within the reference range (135–145 mEq/L) or borderline hypo- or hypernatremia (133–137 and 143–147 mEq/L, respectively) compared with 138–142 mEq/L were associated with increased hospital and 1-year mortalities. Conclusion In hospitalized adults, [Na+] fluctuation (≥6 mEq/L) irrespective of admission [Na+] and borderline hypo- or hypernatremia are independent predictors of progressively increasing short- and long-term mortality burdens.

scholarly journals Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Huan Du ◽  
Shuke Nie ◽  
Guiqin Chen ◽  
Kai Ma ◽  
Yan Xu ◽  
...  
Keyword(s):  
Antiepileptic Drug ◽  
Chronic Administration ◽  
Term Therapy ◽  
Dependent Manner ◽  
Abnormal Involuntary Movements ◽  
Extracellular Signal ◽  
6 Hydroxydopamine ◽  
Long Term Therapy ◽  
Dose Dependent

L-DOPA-induced dyskinesias (LID) remain a major problem of long-term therapy of Parkinson’s disease. Levetiracetam, a new antiepileptic drug, has been shown to reduce LID, but the mechanisms underlying its effects are unknown. In this study, we assessed the effect of levetiracetam on key mediators of LID in rats with 6-hydroxydopamine (6-OHDA) lesions. Following chronic administration of L-DOPA (12 mg/kg, twice daily for 14 days), rats developed abnormal involuntary movements (AIMs), but co-administration of levetiracetam (15, 30, and 60 mg/kg) with equivalent L-DOPA dosing significantly reduced AIMs scores in a dose dependent manner. The effects of levetiracetam were associated with changes in striatal expression ofΔFosB, phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2), and phosphorylated cAMP-regulated phosphoprotein of 32 kDa (p-DARPP-32). These data support that levetiracetam acts at multiple sites in the pathogenetic cascade of LID, and that further understanding of these actions of antiepileptics may contribute to developing new LID therapies.

scholarly journals Caffeine intake increases plasma ketones: an acute metabolic study in humans

2017 ◽  
Vol 95 (4) ◽  
pp. 455-458 ◽  
Author(s):  
Camille Vandenberghe ◽  
Valérie St-Pierre ◽  
Alexandre Courchesne-Loyer ◽  
Marie Hennebelle ◽  
Christian-Alexandre Castellano ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Caffeine Intake ◽  
Dependent Manner ◽  
Medium Chain Triglycerides ◽  
Metabolic Study ◽  
Brain Glucose ◽  
Glucose Reduction ◽  
Dose Dependent ◽  
The Brain

Brain glucose uptake declines during aging and is significantly impaired in Alzheimer’s disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.

Sign in / Sign up

Export Citation Format

Share Document