Genetically predicted blood metabolites mediate the association between circulating immune cells and pancreatic cancer: A Mendelian randomization study.

BACKGROUND: Pancreatic cancer is characterized by metabolic dysregulation and unique immunological profiles. Nevertheless, the comprehensive understanding of immune and metabolic dysregulation of pancreatic cancer remains unclear. In the present study, we aimed to investigate the causal relationship of circulating immune cells and pancreatic cancer and identify the blood metabolites as potential mediators. METHODS: The exposure and outcome genome-wide association studies (GWAS) data used in the present study were obtained from the GWAS open-access database (https://gwas.mrcieu.ac.uk). The study used 731 circulating immune cell features, 1400 types of blood metabolites and pancreatic cancer from GWAS. We then performed bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between the circulating immune cells and pancreatic cancer, and two-step MR to discover potential mediating blood metabolites in this process. All statistical analyses were performed in R software. The STROBE-MR (i.e. Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization) checklist for the reporting of MR studies was also used. RESULTS: MR analysis identified seven types of circulating immune cells causally associated with pancreatic cancer. Furthermore, there was no strong evidence that genetically predicted pancreatic cancer had an effect on these seven types of circulating immune cells. Further two-step MR analysis found 10 types of blood metabolites were causally associated with pancreatic cancer and the associations between circulating CD39+CD8+ T cells and pancreatic cancer were mediated by blood orotates with proportions of 5.18% (p = 0.016). CONCLUSIONS: The present study provides evidence supporting the causal relationships between various circulating immune cells, especially CD39+CD8+ T cells, and pancreatic cancer, with a potential effect mediated by blood orotates. Further research is needed on additional risk factors as potential mediators and establish a comprehensive immunity-metabolism network in pancreatic cancer.

Ring-Closure on the Rocks in a Prebiotic Environment.

Ring-closure is a key step in current pyrimidine anabolism and one may wonder whether cyclisation reactions could be promoted in the geochemical context at the origins of life, i. e. with the help of minerals. Various prebiotic minerals were tested in this work, including silica, carbonates, microporous minerals. In particular, the role of zinc ions supported on minerals was investigated in view of its presence in the catalytic site of cyclic amidohydrolase enzymes. Based on in situ (TGA: ThermoGravimetric Analysis, ATR-IR: Attenuated Total Reflectance-InfraRed) and ex situ (1 H NMR- Nuclear Magnetic Resonance) characterisations, we identified the products of thermal activation of NCA (N-carbamoyl-aspartic acid) in wetting-and-drying scenarios on the surface of minerals. NCA can cyclize extensively only on some surfaces, with the predominant product being 5-carboxymethylhydantoin (Hy) rather than dihydroorotate (DHO), while there is a competition with hydrolysis on others. Replacing the enzymes with heterogeneous catalysts also works with other reactions catalysed by enzymes of the cyclic amidohydrolases family. The role of the hydrophilicity/hydrophobicity of minerals as well as the regioselectivity of the cyclisation (5-carboxymethylhydantoin versus dihydroorotate) are examined.

A Facile Fluorometric Assay of Orotate Phosphoribosyltransferase Activity Using a Selective Fluorogenic Reaction for Orotic Acid.

Orotate phosphoribosyltransferase (OPRT) exists as a bifunctional enzyme, uridine 5'-monophosphate synthase, in mammalian cells and plays an important role in pyrimidine biosynthesis. Measuring OPRT activity has been considered important for understanding biological events and development of molecular-targeting drugs. In this study, we demonstrate a novel fluorescence method for measuring OPRT activity in living cells. The technique utilizes 4-trifluoromethylbenzamidoxime (4-TFMBAO) as a fluorogenic reagent, which produces selective fluorescence for orotic acid. To perform the OPRT reaction, orotic acid was added to HeLa cell lysate, and a portion of the enzyme reaction mixture was heated at 80 °C for 4 min in the presence of 4-TFMBAO under basic conditions. The resulting fluorescence was measured using a spectrofluorometer, which reflects the consumption of orotic acid by the OPRT. After optimization of the reaction conditions, the OPRT activity was successfully determined in 15 min of enzyme reaction time without further procedures such as purification of OPRT or deproteination for the analysis. The activity obtained was compatible with the value measured by the radiometric method with [3H]-5-FU as the substrate. The present method provides a reliable and facile measurement of OPRT activity and could be useful for a variety of research fields targeting pyrimidine metabolism.

Combination of Secondary Plant Metabolites and Micronutrients Improves Mitochondrial Function in a Cell Model of Early Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by excessive formation of beta-amyloid peptides (Aß), mitochondrial dysfunction, enhanced production of reactive oxygen species (ROS), and altered glycolysis. Since the disease is currently not curable, preventive and supportive approaches are in the focus of science. Based on studies of promising single substances, the present study used a mixture (cocktail, SC) of compounds consisting of hesperetin (HstP), magnesium-orotate (MgOr), and folic acid (Fol), as well as the combination (KCC) of caffeine (Cof), kahweol (KW) and cafestol (CF). For all compounds, we showed positive results in SH-SY5Y-APP695 cells-a model of early AD. Thus, SH-SY5Y-APP695 cells were incubated with SC and the activity of the mitochondrial respiration chain complexes were measured, as well as levels of ATP, Aß, ROS, lactate and pyruvate. Incubation of SH-SY5Y-APP695 cells with SC significantly increased the endogenous respiration of mitochondria and ATP levels, while Aß1-40 levels were significantly decreased. Incubation with SC showed no significant effects on oxidative stress and glycolysis. In summary, this combination of compounds with proven effects on mitochondrial parameters has the potential to improve mitochondrial dysfunction in a cellular model of AD.

A mutation in the putative CRP binding site of the dctA promoter of Salmonella enterica serovar Typhimurium enables growth with low orotate concentrations.

Salmonella enterica and Escherichia coli use the inner membrane transporter DctA to import the pyrimidine biosynthetic pathway intermediate orotate from the environment. To study the regulation of dctA expression, we used an S. enterica serovar Typhimurium pyrimidine auxotroph to select a mutant that could grow in an otherwise nonpermissive culture medium containing glucose and a low concentration of orotate. Whole genome sequencing revealed a point mutation upstream of dctA in the putative cyclic AMP receptor protein (CRP) binding site. The C→T transition converted the least favourable base to the most favourable base for CRP-DNA affinity. A dctA::lux transcriptional fusion confirmed that the mutant dctA promoter gained responsiveness to CRP even in the presence of glucose. Moreover, dctA expression was higher in the mutant than the wild type in the presence of alternative carbon sources that activate CRP.

Effects of Combining Biofactors on Bioenergetic Parameters, Aß Levels and Survival in Alzheimer Model Organisms.

Increased amyloid beta (Aß) levels and mitochondrial dysfunction (MD) in the human brain characterize Alzheimer disease (AD). Folic acid, magnesium and vitamin B6 are essential micro-nutrients that may provide neuroprotection. Bioenergetic parameters and amyloid precursor protein (APP) processing products were investigated in vitro in human neuroblastoma SH-SY5Y-APP695 cells, expressing neuronal APP, and in vivo, in the invertebrate Caenorhabditis elegans (CL2006 & GMC101) expressing muscular APP. Model organisms were incubated with either folic acid and magnesium-orotate (ID63) or folic acid, magnesium-orotate and vitamin B6 (ID64) in different concentrations. ID63 and ID64 reduced Aß, soluble alpha APP (sAPPα), and lactate levels in SH-SY5Y-APP695 cells. The latter might be explained by enhanced expression of lactate dehydrogenase (LDHA). Micronutrient combinations had no effects on mitochondrial parameters in SH-SY5Y-APP695 cells. ID64 showed a significant life-prolonging effect in C. elegans CL2006. Incubation of GMC101 with ID63 significantly lowered Aß aggregation. Both combinations significantly reduced paralysis and thus improved the phenotype in GMC101. Thus, the combinations of the tested biofactors are effective in pre-clinical models of AD by interfering with Aß related pathways and glycolysis.

A Nonenzymatic Analog of Pyrimidine Nucleobase Biosynthesis.

Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that make genetic molecules. Recently, experiments showing nonenzymatic versions of a number of core metabolic pathways have started to support this idea. However, experimental demonstrations of nonenzymatic reaction sequences along the de novo ribonucleotide biosynthesis pathways are limited. Here we show that all three reactions of pyrimidine nucleobase biosynthesis that convert aspartate to orotate proceed at 60 °C without photochemistry under aqueous conditions in the presence of metals such as Cu2+ and Mn4+ . Combining reactions into one-pot variants is also possible. Life may not have invented pyrimidine nucleobase biosynthesis from scratch, but simply refined existing nonenzymatic reaction channels. This work is a first step towards uniting metabolic theories of life's origin with those centered around genetic molecules.

A toxicological evaluation of lithium orotate.

Lithium orotate, the salt of lithium and orotic acid, has been marketed for decades as a supplemental source of lithium with few recorded adverse events. Nonetheless, there have been some concerns in the scientific literature regarding orotic acid, and pharmaceutical lithium salts are known to have a narrow therapeutic window, albeit, at lithium equivalent therapeutic doses 5.5-67 times greater than typically recommended for supplemental lithium orotate. To our knowledge, the potential toxicity of lithium orotate has not been investigated in preclinical studies; thus, we conducted a battery of genetic toxicity tests and an oral repeated-dose toxicity test in order to further explore its safety. Lithium orotate was not mutagenic or clastogenic in bacterial reverse mutation and in vitro mammalian chromosomal aberration tests, respectively, and did not exhibit in vivo genotoxicity in a micronucleus test in mice. In a 28-day, repeated-dose oral toxicity study, rats were administered 0, 100, 200, or 400 mg/kg body weight/day of lithium orotate by gavage. No toxicity or target organs were identified; therefore, a no observed adverse effect level was determined as 400 mg/kg body weight/day. These results are supportive of the lack of a postmarket safety signal from several decades of human consumption.

Studium anabolické aktivity suchých extraktů listů a oddenků Iris hungarica na modelu hydrokortizonem navozeného katabolismu bílkovin.

This article presents the results of the study of the anabolic effect of dry extracts of Iris hungarica leaves and rhizomes on the model of hydrocortisoneinduced protein catabolism. Previous studies have established the presence of anabolic activity of dry extracts of Iris hungarica leaves and rhizomes in intact animals. Therefore, it was reasonable to study the effect of the experimental extracts on the state of protein metabolism, which is regulated by glucocorticoids. The model of hydrocortisoneinduced protein catabolism was used to determine anabolic activity for dry extracts of Iris hungarica leaves and rhizomes at a  dose of 150  mg/kg by monitoring the recovery of body weight and the increase in the total protein in the cardiac muscle of rats and in muscle tissue homogenate, which is aimed to promote myofibrillar hypertrophy. Dry extract of Iris hungarica rhizomes reduced urea excretion, normalized metabolism, restored nitrogen balance, and inhibited protein catabolism. The results indicate that dry extract of Iris hungarica has the ability to correct protein metabolism, which is regulated in part by glucocorticoids, due to the high content of isoflavonoids and amino acids, and suggest that there is a  potential use for this herbal product in the development of a new drug aimed at correcting protein metabolism and muscular atrophy.

Study of anabolic activity of dry extracts of leaves and rhizomes of Iris hungarica on a model of hydrocortisone-induced protein catabolism.

This article presents the results of the study of the anabolic effect of dry extracts of Iris hungarica leaves and rhizomes on the model of hydrocortisoneinduced protein catabolism. Previous studies have established the presence of anabolic activity of dry extracts of Iris hungarica leaves and rhizomes in intact animals. Therefore, it was reasonable to study the effect of the experimental extracts on the state of protein metabolism, which is regulated by glucocorticoids. The model of hydrocortisoneinduced protein catabolism was used to determine anabolic activity for dry extracts of Iris hungarica leaves and rhizomes at a  dose of 150  mg/kg by monitoring the recovery of body weight and the increase in the total protein in the cardiac muscle of rats and in muscle tissue homogenate, which is aimed to promote myofibrillar hypertrophy. Dry extract of Iris hungarica rhizomes reduced urea excretion, normalized metabolism, restored nitrogen balance, and inhibited protein catabolism. The results indicate that dry extract of Iris hungarica has the ability to correct protein metabolism, which is regulated in part by glucocorticoids, due to the high content of isoflavonoids and amino acids, and suggest that there is a  potential use for this herbal product in the development of a new drug aimed at correcting protein metabolism and muscular atrophy.

Putative orotate transporter of Cryptococcus neoformans, Oat1, is a member of the NCS1/PRT transporter super family and its loss causes attenuation of virulence.

It is well known that 5-fluoroorotic acid (5-FOA)-resistant mutants isolated from wild-type Cryptococcus neoformans are exclusively either ura3 or ura5 mutants. Unexpectedly, many of the 5-FOA-resistant mutants isolated in our selective regime were Ura+. We identified CNM00460 as the gene responsible for these mutations. Cnm00460 belongs to the nucleobase cation symporter 1/purine-related transporter (NCS1/PRT) super family of fungal transporters, representative members of which are uracil transporter, uridine transporter and allantoin transporter of Saccharomyces cerevisiae. Since the CNM00460 gene turned out to be involved in utilization of orotic acid, most probably as transporter, we designated this gene Orotic Acid Transporter 1 (OAT1). This is the first report of orotic acid transporter in this family. C. neoformans has four members of the NCS1/PRT family, including Cnm00460, Cnm02550, Cnj00690, and Cnn02280. Since the cnm02550∆ strain showed resistance to 5-fluorouridine, we concluded that CNM02550 encodes uridine permease and designated it URidine Permease 1 (URP1). We found that oat1 mutants were sensitive to 5-FOA in the medium containing proline as nitrogen source. A mutation in the GAT1 gene, a positive transcriptional regulator of genes under the control of nitrogen metabolite repression, in the genetic background of oat1 conferred the phenotype of weak resistance to 5-FOA even in the medium using proline as nitrogen source. Thus, we proposed the existence of another orotic acid utilization system (tentatively designated OAT2) whose expression is under the control of nitrogen metabolite repression at least in part. We found that the OAT1 gene is necessary for full pathogenic activity of C. neoformans var. neoformans.

The mechanistic study of Leishmania major dihydro-orotate dehydrogenase based on steady- and pre-steady-state kinetic analysis.

Leishmania major dihydro-orotate dehydrogenase (DHODHLm) has been considered as a potential therapeutic target against leishmaniasis. DHODHLm, a member of class 1A DHODH, oxidizes dihydro-orotate (DHO) to orotate (ORO) during pyrimidine biosynthesis using fumarate (FUM) as the oxidizing substrate. In the present study, the chemistry of reduction and reoxidation of the flavin mononucleotide (FMN) cofactor in DHODHLm was examined by steady- and pre-steady state kinetics under both aerobic and anaerobic environments. Our results provide for the first time the experimental evidence of co-operative behaviour in class 1A DHODH regulated by DHO binding and reveal that the initial reductive flavin half-reaction follows a mechanism with two steps. The first step is consistent with FMN reduction and shows a hyperbolic dependence on the DHO concentration with a limiting rate (kred) of 110±6 s(-1) and a K(DHO) d of 180±27 µM. Dissociation of the reduced flavin-ORO complex corresponds to the second step, with a limiting rate of 6 s(-1). In the oxidative half-reaction, the oxygen-sensitive reoxidation of the reduced FMN cofactor of DHODHLm by FUM exhibited a hyperbolic saturation profile dependent on FUM concentration allowing estimation of K(FUM) d and the limiting rate (kreox) of 258±53 µM and 35±2 s(-1), respectively. Comparison between steady- and pre-steady-state parameters together with studies of interaction for DHODHLm with both ORO and succinate (SUC), suggests that ORO release is the rate-limiting step in overall catalysis. Our results provide evidence of mechanistic differences between class 1A and class 2 individual half-reactions to be exploited for the development of selective inhibitors.

A combination of probiotics and magnesium orotate attenuate depression in a small SSRI resistant cohort: an intestinal anti-inflammatory response is suggested.

Approximately, one-third of those who develop major depression will have a poor response to treatment and over time can become treatment resistant. Intestinal dysbiosis has been implicated in depression with systemic inflammation and vagal and enteric nerve impairment. We report on a sequel pilot study (n = 12) with a combination probiotics/magnesium orotate formulation adjuvant administered with SSRIs for treatment resistant depression. At the end of an 8-week intervention mean changes for depression scores and quality of life in the group was clinically significantly improved (p < 0.001) with all but 4 participants experiencing a benefit. An intestinal anti-inflammatory response was suggested. At 16-weeks follow-up while still on SSRI medications, the group had relapsed after cessation of the test intervention.

Orotate phosphoribosyl transferase MoPyr5 is involved in uridine 5'-phosphate synthesis and pathogenesis of Magnaporthe oryzae.

Orotate phosphoribosyl transferase (OPRTase) plays an important role in de novo and salvage pathways of nucleotide synthesis and is widely used as a screening marker in genetic transformation. However, the function of OPRTase in plant pathogens remains unclear. In this study, we characterized an ortholog of Saccharomyces cerevisiae Ura5, the OPRTase MoPyr5, from the rice blast fungus Magnaporthe oryzae. Targeted gene disruption revealed that MoPyr5 is required for mycelial growth, appressorial turgor pressure and penetration into plant tissues, invasive hyphal growth, and pathogenicity. Interestingly, the ∆Mopyr5 mutant is also involved in mycelial surface hydrophobicity. Exogenous uridine 5'-phosphate (UMP) restored vegetative growth and rescued the defect in pathogenicity on detached barley and rice leaf sheath. Collectively, our results show that MoPyr5 is an OPRTase for UMP biosynthesis in M. oryzae and indicate that UTP biosynthesis is closely linked with vegetative growth, cell wall integrity, and pathogenicity of fungus. Our results also suggest that UMP biosynthesis would be a good target for the development of novel fungicides against M. oryzae.

Catalytic site interactions in yeast OMP synthase.

The enigmatic kinetics, half-of-the-sites binding, and structural asymmetry of the homodimeric microbial OMP synthases (orotate phosphoribosyltransferase, EC 2.4.2.10) have been proposed to result from an alternating site mechanism in these domain-swapped enzymes [R.W. McClard et al., Biochemistry 45 (2006) 5330-5342]. This behavior was investigated in the yeast enzyme by mutations in the conserved catalytic loop and 5-phosphoribosyl-1-diphosphate (PRPP) binding motif. Although the reaction is mechanistically sequential, the wild-type (WT) enzyme shows parallel lines in double reciprocal initial velocity plots. Replacement of Lys106, the postulated intersubunit communication device, produced intersecting lines in kinetic plots with a 2-fold reduction of kcat. Loop (R105G K109S H111G) and PRPP-binding motif (D131N D132N) mutant proteins, each without detectable enzymatic activity and ablated ability to bind PRPP, complemented to produce a heterodimer with a single fully functional active site showing intersecting initial velocity plots. Equilibrium binding of PRPP and orotidine 5'-monophosphate showed a single class of two binding sites per dimer in WT and K106S enzymes. Evidence here shows that the enzyme does not follow half-of-the-sites cooperativity; that interplay between catalytic sites is not an essential feature of the catalytic mechanism; and that parallel lines in steady-state kinetics probably arise from tight substrate binding.

Effect of carnitine-orotate complex on glucose metabolism and fatty liver: a double-blind, placebo-controlled study.

BACKGROUND AND AIM: Effective medicines have not been introduced for insulin resistance-related fatty liver. The efficacy and safety of treatment between a combination of metformin and carnitine-orotate complex and metformin alone in a 12-week, double-blind, randomized, placebo-controlled study on drug-naïve patients with impaired glucose metabolism and fatty liver were compared. METHODS: Fifty-two patients with fasting glucose 100-240 mg/dL or glycosylated hemoglobin (HbA1c) ≥ 6.0% and alanine aminotransferase (ALT) 40-250 IU/L were randomized to receive metformin (250 mg t.i.d.), or metformin (250 mg t.i.d.) and carnitine-orotate complex (300 mg t.i.d.) for 12 weeks (n = 26 per group). The primary end-point was a change from baseline ALT level. Secondary end-points were changes in fasting glucose, HbA1c, aspartate aminotransferase levels, mitochondrial DNA (mtDNA) copy number in the peripheral blood, and urinary output of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress. RESULTS: The combined treatment reduced ALT level significantly more than metformin alone (-51.5 ± 33.2 IU/L vs -16.7 ± 31.3 IU/L, P = 0.001). The HbA1c levels also decreased significantly in both groups but there was no significant difference between them (-0.9% ± 1.0% vs -0.7% ± 0.9%). Treatment with the complex decreased the urinary 8-hydroxy-2'-deoxyguanosine level and increased mtDNA copy number significantly compared with metformin alone (both P < 0.05). No severe adverse events were observed. CONCLUSION: A 12-week treatment with metformin and carnitine-orotate complex significantly improved liver function enzyme levels. This was associated with changes in oxidative stress and mtDNA copy number compared with metformin alone in patients with impaired glucose metabolism and fatty liver (clinical trial number: KCT0000193).

Human brain 7Li-MRI following low-dose lithium dietary supplementation in healthy participants.

BACKGROUND: Lithium is an effective mood stabiliser, but its mechanism of action is incompletely defined. Even at very low doses, lithium may have neuroprotective effects, but it is not clear if these relate to brain lithium concentration in vivo. We have developed magnetic resonance imaging (7Li-MRI) methods to detect lithium in the brain following supplementation at a very low dose. METHODS: Lithium orotate supplements were taken by nine healthy adult male subjects (5 mg daily) for up to 28 days, providing 2-7 % of the lithium content of a typical therapeutic lithium carbonate dose. One-dimensional 7Li-images were acquired on a 3.0 T MRI scanner. All subjects were scanned on day 14 or 28; seven were scanned on both, one at baseline and one after 7-days washout. RESULTS: 7Li-MR signal amplitude was broadly stable between days 14 and 28. Two subjects had notably higher 7Li-signal intensities (approximately 2-4×) compared to other study participants. LIMITATIONS: Lithium adherence was self-reported by all participants without formal validation. The coarse spatial resolution necessary for detection of low concentrations of 7Li exhibits imperfect spatial separation of signal from adjacent pixels. CONCLUSIONS: 7Li-MRI performed using a clinical 3T scanner demonstrated detection of lithium in the brain at very low concentration, in the range of approximately 10-60 mM. The methods are suited to studies assessing low dose lithium administration in psychiatric and neurodegenerative disorders, and permit the comparison of different lithium salt preparations at a time of emerging interest in the field.

Different pharmacokinetics of lithium orotate inform why it is more potent, effective, and less toxic than lithium carbonate in a mouse model of mania.

Lithium carbonate (LiCO) is a mainstay therapeutic for the prevention of mood-episode recurrences in bipolar disorder (BD). Unfortunately, its narrow therapeutic index is associated with complications that may lead to treatment non-compliance. Intriguingly, lithium orotate (LiOr) is suggested to possess unique uptake characteristics that would allow for reduced dosing and mitigation of toxicity concerns. We hypothesized that due to differences in pharmacokinetics, LiOr is more potent with reduced adverse effects. Dose responses were established for LiOr and LiCO in male and female mice using an amphetamine-induced hyperlocomotion (AIH) model; AIH captures manic elements of BD and is sensitive to a dose-dependent lithium blockade. LiCO induced a partial block of AIH at doses of 15 mg/kg in males and 20 mg/kg in females. In contrast, LiOr elicited a near complete blockade at concentrations of just 1.5 mg/kg in both sexes, indicating improved efficacy and potency. Prior application of organic anion transport inhibitors, or inhibition of orotate uptake into the pentose pathway, completely blocked the effects of LiOr on AIH while sparing LiCO effects, confirming differences in transport and compartmentalization between the two compounds. Next, the relative toxicities of LiOr and LiCO were contrasted after 14 consecutive daily administrations. LiCO, but not LiOr, elicited polydipsia in both sexes, elevated serum creatinine levels in males, and increased serum TSH expression in females. LiOr demonstrates superior efficacy, potency, and tolerability to LiCO in both male and female mice because of select transport-mediated uptake and pentose pathway incorporation.

Magnesium Orotate and the Microbiome-Gut-Brain Axis Modulation: New Approaches in Psychological Comorbidities of Gastrointestinal Functional Disorders.

Magnesium orotate has been cited in the medical literature for the past three years as a possible adjuvant in some pediatric and adult gastroenterological disorders associated with dysbiosis. Studies also focus on the possibility of adding magnesium orotate in psychiatric disorders' treatment, such as major depression and anxiety. The most relevant element in these studies is the efficiency of magnesium orotate therapy in cases with both gastroenterological and psychiatric symptoms. This article proposes a literature review, focused on the studies published in the last three years, targeting magnesium orotate treatment and probiotic supplementation in patients with both digestive and psychiatric symptoms. Moreover, this review will compare the efficiency of magnesium orotate and probiotics within both the pediatric and adult communities, focusing on the possibility of gut-brain axis modulation and its involvement in the clinical evolution of these patients.

Impact of l-Carnitine Supplementation on Liver Enzyme Normalization in Patients with Chronic Liver Disease: A Meta-Analysis of Randomized Trials.

The effectiveness of l-carnitine in chronic liver disease remains controversial. We conducted this meta-analysis to assess the efficacy of various forms of l-carnitine in the treatment of chronic liver disease. METHODS: We searched the Cochrane Library, EMBASE, KMBASE, and Medline databases for all relevant studies published until April 2022 that examined the ability of l-carnitine or its derivatives to normalize liver enzymes in patients with chronic liver disease. We performed meta-analyses of the proportion of patients with alanine aminotransferase (ALT) normalization and post-treatment serum aspartate aminotransferase (AST) and ALT levels. A random effects model was used for meta-analyses. RESULTS: Fourteen randomized controlled trials (1217 patients) were included in this meta-analysis. The proportion of patients in whom ALT normalized was higher in the carnitine-orotate treatment group than in the control group (pooled odds ratio (OR), 95% confidence interval (CI) = 4.61 (1.48-14.39)). The proportion of patients in whom ALT normalized was also higher among those who received the carnitine-orotate complex, a combination of carnitine-orotate, biphenyl dimethyl dicarboxylate, and other minor supplementary compounds than in those who did not without significant heterogeneity (pooled OR (95% CI) = 18.88 (7.70-46.27); df = 1; p = 0.51; I2 = 0%). l-carnitine supplementation effectively lowered serum ALT levels compared to controls (pooled mean difference (95% CI) = -11.99 (-22.48 to -1.49)). CONCLUSIONS: l-carnitine supplementation significantly lowered ALT and AST levels and normalized ALT levels in patients with chronic liver disease.