Enhancement of the bioactive compounds and biological activities of maca (Lepidium meyenii) via solid-state fermentation with Rhizopus oligosporus.

Maca (Lepidium meyenii Walp) is renowned for its phytochemicals, including amino acids, saponins, and macamides, confer nutritional and medicinal benefits. This study analyzed the bioactive constituents of maca via solid-state fermentation with Rhizopus oligosporus for 0-15 days. After fermentation, the l-carnitine content reached 157.3 µg/g. A 93% increase in macamide B was recorded after 7-day fermentation. Total flavonoid and saponin contents increased by 88.2% and 110.3%, respectively. The fermentation process significantly enhanced the physicochemical attributes of maca; in particular, its water retention and cholesterol-binding capacities increased by 1.73- and 4.30-fold, respectively, compared with the non-fermented maca. Moreover, fermented maca exhibited stronger antioxidant and α-glucosidase-inhibiting effects than non-fermented maca. Finally, the neuroprotective effect of maca on HT-22 cells increased by 23% after 5-day fermentation. These findings demonstrate the potential of fermented maca as a novel ingredient for foods, beverages, and pharmaceuticals. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01508-6.

Transient Arginine Vasopressin Deficiency Induced by Valproic Acid Intoxication: A Case Report.

Valproic acid is commonly used for treating seizures and psychiatric disorders. Valproic acid is a common anticonvulsant drug causing overdose for suicidal purposes. The most common symptom of valproic acid poisoning is central nervous system damage. Most cases result in mild to moderate drowsiness, while in severe cases, fatal cerebral edema and coma have been reported. Other complications include respiratory depression, hepatotoxicity, thrombocytopenia, and multi-organ failure resulting in circulatory collapse. Herein, we present a case of a 42-year-old woman who ingested an overdose of 600 mg nitrazepam, 50 mg olanzapine, and 35,600 mg valproic acid. The maximum daily doses for nitrazepam, olanzapine, and valproic acid are 15, 20, and 1200 mg, respectively. This overdose led to reversible arginine vasopressin (AVP) deficiency as a rare but significant complication. The deficiency led to polyuria with dilute urine, which was effectively suppressed by AVP administration. This case highlights the potential for reversible AVP deficiency as a rare but significant complication of valproic acid overdose. Early diagnosis and appropriate management are crucial for favorable outcomes.

Diagnostic Challenges in the Myopathic Variant of Carnitine Palmitoyltransferase II Deficiency: A Case Report.

Carnitine palmitoyltransferase II deficiency is a rare metabolic disorder affecting the mitochondrial oxidation of fatty acids. We present a case of the myopathic form in a 10-year-old Bahraini male following an initial presentation of exercise-induced rhabdomyolysis and transaminitis. There was no consanguinity or findings suggestive of an underlying inborn metabolic disorder. Tandem mass spectrometry on dried blood spots showed no abnormal acyl-carnitines profile. The condition improved with hyperhydration, high glucose intake, carnitine, and alkalinization. Genetic testing revealed a compound heterozygous pathogenic variant c.338C>T (p.Ser113Leu) and a variant of unknown significance c.729_731del (p.Leu244del). The patient was kept on a high carbohydrate and low-fat diet with medium chain triglycerides supplementation and advised to avoid long fasting periods and strenuous exercise. Within the four years of follow-up, he had three further attacks. Exercise-induced myalgia or rhabdomyolysis should raise the suspicion of inherited metabolic disorders. Metabolic investigations should be taken during the acute illness, and an acylcarnitines profile should preferably be performed in the serum.

Trimethylamine N-Oxide and Related Gut Microbe-Derived Metabolites and Incident Heart Failure Development in Community-Based Populations.

BACKGROUND: Growing evidence indicates that trimethylamine N-oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine N-oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF). METHODS: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors. RESULTS: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine N-oxide (hazard ratio, 1.15 [95% CI, 1.09-1.20]; P<0.001), choline (hazard ratio, 1.44 [95% CI, 1.26-1.64]; P<0.001), and crotonobetaine (hazard ratio, 1.24 [95% CI, 1.16-1.32]; P<0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance (P=0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF (P<0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race. CONCLUSIONS: In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine N-oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF. REGISTRATION: URL: https://www.clinicaltrials.gov/; Unique identifiers: NCT00005133 and NCT00005487.

Impaired intestinal FXR signaling is involved in aberrant stem cell function leading to intestinal failure-associated liver disease in pediatric patients with short bowel syndrome.

Intestinal failure-associated liver disease (IFALD) is a serious complication of long-term parenteral nutrition in patients with short bowel syndrome (SBS), and is the main cause of death in SBS patients. Prevention of IFALD is one of the major challenges in the treatment of SBS. Impairment of intestinal barrier function is a key factor in triggering IFALD, therefore promoting intestinal repair is particularly important. Intestinal repair mainly relies on the function of intestinal stem cells (ISC), which require robust mitochondrial fatty acid oxidation (FAO) for self-renewal. Herein, we report that aberrant LGR5+ ISC function in IFALD may be attributed to impaired farnesoid X receptor (FXR) signaling, a transcriptional factor activated by steroids and bile acids. In both surgical biopsies and patient-derived organoids (PDOs), SBS patients with IFALD represented lower population of LGR5+ cells and decreased FXR expression. Moreover, treatment with T-ßMCA in PDOs (an antagonist for FXR) dose-dependently reduced the population of LGR5+ cells and the proliferation rate of enterocytes, concomitant with decreased key genes involved in FAO including CPT1a. Interestingly, however, treatment with Tropifexor in PDOs (an agonist for FXR) only enhanced FAO capacity, without improvement in ISC function and enterocyte proliferation. In conclusion, these findings suggested that impaired FXR may accelerate the depletion of LGR5 + ISC population through disrupted FAO processes, which may serve as a new potential target of preventive interventions against IFALD for SBS patients.

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Our comprehensive analysis revealed that adrenoceptor alpha 2A (ADRA2A) was downregulated in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

l-Carnitine relieves cachexia-related skeletal muscle fibrosis by inducing deltex E3 ubiquitin ligase 3L to negatively regulate the Runx2/COL1A1 axis.

BACKGROUND: Cancer cachexia-induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. l-Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia-associated fibrosis and the involvement of Runx2 in the process remain unexplored. METHODS: Female C57 mice (48 weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5 mg/kg dose of l-carnitine or an equivalent volume of water was administered for 14 days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1-stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real-time PCR, western blot analysis, co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model. RESULTS: l-Carnitine supplementation reduced cancer cachexia-induced declines in grip strength (>88.2%, P < 0.05) and the collagen fibre area within the gastrocnemius (>57.9%, P < 0.05). At the 5 mg/kg dose, l-carnitine also suppressed COL1A1 and alpha-smooth muscle actin (α-SMA) protein expression, which are markers of SMF and myofibroblasts. Analyses of the TRRUST database indicated that Runx2 regulates both COL1A1 and COL1A2. In vitro, l-carnitine diminished Runx2 protein levels and promoted its ubiquitination. Overexpression of Runx2 abolished the effects of l-carnitine on COL1A1 and α-SMA. Co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays confirmed an interaction between DTX3L and Runx2, with l-carnitine enhancing this interaction to promote Runx2 ubiquitination. l-Carnitine supplementation restored DTX3L levels to those observed under non-cachectic conditions, both in vitro and in vivo. Knockdown of DTX3L abolished the effects of l-carnitine on Runx2, COL1A1 and α-SMA in vitro. The expression of DTX3L was negatively correlated with the levels of Runx2 and COL1A1 in untreated NIH/3T3 cells. CONCLUSIONS: This study revealed a previously unrecognized link between Runx2 and DTX3L in SMF and demonstrated that l-carnitine exerted a significant therapeutic impact on cancer cachexia-associated SMF, potentially through the upregulation of DTX3L.

Liver Extracellular Vesicles and Particles Enriched ß-Sitosterol Effectively Promote Liver Regeneration in Mice.

Background: The liver's regenerative capacity allows it to repair itself after injury. Extracellular vesicles and particles (EVPs) in the liver's interstitial space are crucial for signal transduction, metabolism, and immune regulation. Understanding the role and mechanism of liver-derived EVPs in regeneration is significant, particularly after partial hepatectomy, where the mechanisms remain unclear. Methods: A 70% hepatectomy model was established in mice, and EVPs were isolated and characterized using electron microscopy, nanocharacterization, and Western blot analysis. Combined metabolomic and transcriptomic analyses revealed ß-sitosterol enrichment in EVPs and activation of the Hedgehog signaling pathway during regeneration. The role of ß-sitosterol in EVPs on the Hedgehog pathway and its targets were identified using qRT-PCR, Western blot analysis. The regulation of carnitine synthesis by this pathway was determined using a dual luciferase assay. The effect of a ß-sitosterol diet on liver regeneration was verified in mice. Results: After 70% hepatectomy, the liver successfully regenerated without liver failure or death. At 24 hours post-surgery, tissue staining showed transient regeneration-associated steatosis (TRAS), with increased Ki67 positivity at 48 hours. EVPs displayed a spherical lipid bilayer structure with particle sizes of 70-130 nm. CD9, CD63, and CD81 in liver-derived EVPs were confirmed. Transcriptomic and metabolomic analyses showed EVPs supplementation significantly promoted carnitine synthesis and fatty acid oxidation. Tissue staining confirmed accelerated TRAS resolution and enhanced liver regeneration with EVP supplementation. Mass spectrometry identified ß-sitosterol in EVPs, which binds to Smo protein, activating the Hedgehog pathway. This led to the nuclear transport of Gli3, stimulating Setd5 transcription and inducing carnitine synthesis, thereby accelerating fatty acid oxidation. Mice with increased ß-sitosterol intake showed faster TRAS resolution and liver regeneration compared to controls. Conclusion: Liver-derived EVPs promote regeneration after partial hepatectomy. ß-sitosterol from EVPs accelerates fatty acid oxidation and promotes liver regeneration by activating Hedgehog signaling pathway.

Protective effects of L-carnitine against Beta-amyloid-induced memory impairment and anxiety-like behavior in a rat model of Alzheimer's disease.

Alzheimer's disease (AD), the most common cause of dementia, leads to neurodegeneration and cognitive decline. We investigated the therapeutic effects of L-carnitine on cognitive performance and anxiety-like behavior in a rat model of AD induced by unilateral intracerebroventricular injection of ß-amyloid1-42 (Aß1-42). L-carnitine (100 mg/kg/day) was administered intraperitoneally for 28 consecutive days. Following this, the open-field test, novel object recognition test, elevated plus-maze test, Barnes maze test, and passive avoidance learning test were used to assess locomotor activity, recognition memory, anxiety-like behavior, spatial memory, and passive avoidance memory, respectively. Plasma and hippocampal oxidative stress markers, including total oxidant status (TOS) and total antioxidant capacity (TAC), were examined. In addition, histological investigations were performed in the dentate gyrus of the hippocampus using Congo red staining and hematoxylin and eosin staining. The injection of Aß1-42 resulted in cognitive deficits and increased anxiety-like behavior. These changes were associated with an imbalance of oxidants and antioxidants in plasma and the hippocampus. Also, neuronal death and Aß plaque accumulation were increased in the hippocampal dentate gyrus region. However, injection of L-carnitine improved recognition memory, spatial memory, and passive avoidance memory in AD rats. These findings provide evidence that L-carnitine may alleviate anxiety-like behavior and cognitive deficits induced by Aß1-42 through modulating oxidative-antioxidant status and preventing Aß plaque accumulation and neuronal death.

Thiopentone-based total intravenous anaesthesia for a patient with carnitine palmitoyltransferase II deficiency and malignant hyperthermia susceptibility.

In this case report, we discuss the use of a thiopentone infusion for the maintenance of anaesthesia in a patient with confirmed malignant hyperthermia susceptibility and carnitine palmitoyltransferase 2 deficiency. The concurrence of both diagnoses precluded the use of both propofol-based total intravenous anaesthesia and volatile inhalational anaesthesia. This patient had been anaesthetised previously with a triple infusion regimen of thiopentone, midazolam and remifentanil and this was a unique opportunity to compare the two instances. Electroencephalogram-based depth of anaesthesia monitoring was in routine use by the time of the second anaesthetic, and thus, the thiopentone infusion could be adjusted accordingly, resulting in a more rapid emergence time. We hope that this case may serve as an example of suitable anaesthetic alternative should both propofol infusion and inhalational anaesthesia not be an option.

Unraveling cardiomyocyte responses and intercellular communication alterations in primary carnitine deficiency cardiomyopathy via single-nucleus RNA sequencing.

Background: Primary Carnitine Deficiency (PCD) is a potentially life-threatening autosomal recessive monogenic disorder arising from mutations in the organic cation transporter 2 (OCTN2) gene. Dilated cardiomyopathy (DCM) is a prevalent symptom associated with this condition, and episodes of metabolic disturbance may lead to sudden death. However, the pathogenic mechanism remains unclear. Here, we sought to investigate the response of cardiomyocytes and alterations in the intercellular communication in individuals with PCD DCM. Methods: The GSE211650 dataset was downloaded. Subsequently, modular analysis was performed using hdWGCNA. SCENIC was employed for transcription factor analysis. Monocle2 and SCP were applied to conduct trajectory inference and characterize dynamic features. CellChat was used to investigate intercellular interactions. Results: OCTN2-deficient cardiomyocytes displayed transcriptomic alterations indicative of reduced contractility, developmental abnormalities, and fibrosis. The reduced expression of genes encoding troponin, myosin, and calcium ion transporters may underlie the observed decrease in contractility. Suppressed Wnt signaling and downregulated transcription factors associated with myocardial development suggest potential developmental disturbances in cardiomyocytes. Growth arrest-specific 6 (GAS6) secreted by TNNC1 high cardiomyocytes is implicated in myocardial inflammation and fibrosis. Macrophages-derived secreted phosphoprotein 1 (SPP1) promotes the activation of fibroblasts. Furthermore, there was a reduction in neuronal genes in the OCTN2-deficient group. Conclusions: Our research has unveiled, for the first time, the responses of cardiomyocytes and alterations in the intercellular communication in PCD DCM, offering valuable insights for the precision treatment of this condition.

Meldonium Supplementation in Professional Athletes: Career Destroyer or Lifesaver?

Meldonium is a substance with known anti-anginal effects demonstrated by numerous studies and human clinical trials; however, it does not possess marketing authorization within the European Union, only in ex-Soviet republics. Since 2016, meldonium has been included by the World Anti-doping Agency (WADA) on the S4 list of metabolic modulators. In performance athletes, meldonium is now considered a doping agent due to its capacity to decrease lactate production during and after exercise, its capability to enhance the storage and utilization of glycogen, and its protective action against oxidative stress. Together, these attributes can significantly improve aerobic endurance, cardiac function, and capacity as well as shorten recovery times (allowing higher intensity training), thereby enhancing performance. The purpose of this review is to highlight the most important mechanisms underlying the protective effect of meldonium against mitochondrial dysfunction (MD), which is responsible for oxidative stress, inflammation, and the cardiac changes known as "athletic heart syndrome." Meldonium acts as an inhibitor of γ-butyrobetaine hydroxylase (BBOX), preventing the de novo synthesis of carnitine and its absorption at the intestinal level via the organic cation/carnitine transporter 2 (OCTN2) and directing the oxidation of fatty acids to the peroxisomes. The decrease in mitochondrial ß-oxidation of fatty acids leads to a reduction in lipid peroxidation products that cause oxidative stress and prevent the formation of acyl/acetyl-carnitines involved in numerous pathological disorders. Given the recent findings of the potentially detrimental effects of prolonged high-intensity exercise on cardiovascular health and coronary atherosclerosis, there may be legitimate arguments for the justification of the use of substances like meldonium as protective supplements for athletes.

Etomoxir-carnitine, a novel pharmaco-metabolite of etomoxir, inhibits phospholipases A2 and mitochondrial respiration.

Mitochondrial fatty acid oxidation serves as an essential process for cellular survival, differentiation, proliferation, and energy metabolism. Numerous studies have utilized etomoxir (ETO) for the irreversible inhibition of carnitine palmitoylcarnitine transferase 1 (CPT1) which catalyzes the rate-limiting step for mitochondrial long-chain fatty acid ß-oxidation to examine the bioenergetic roles of mitochondrial fatty acid metabolism in many tissues in multiple diverse disease states. Herein, we demonstrate that intact mitochondria robustly metabolize etomoxir to etomoxir-carnitine (ETO-carnitine) prior to nearly complete etomoxir-mediated inhibition of CPT1. The novel pharmaco-metabolite, ETO-carnitine, was conclusively identified by accurate mass, fragmentation patterns, and isotopic fine structure. On the basis of these data, ETO-carnitine was successfully differentiated from isobaric structures (e.g., 3-hydroxy-C18:0 carnitine and 3-hydroxy-C18:1 carnitine). Mechanistically, generation of ETO-carnitine from mitochondria required exogenous Mg2+, ATP or ADP, CoASH, and L-carnitine indicating that thioesterification by long-chain acyl-CoA synthetase to form ETO-CoA precedes its conversion to ETO-carnitine by CPT1. CPT1-dependent generation of ETO-carnitine was substantiated by an orthogonal approach using ST1326 (a CPT1 inhibitor) which effectively inhibits mitochondrial ETO-carnitine production. Surprisingly, purified ETO-carnitine potently inhibited calcium-independent PLA2γ and PLA2ß as well as mitochondrial respiration independent of CPT1. Robust production and release of ETO-carnitine from HepG2 cells incubated in the presence of ETO was also demonstrated. Collectively, this study identifies the chemical mechanism for the biosynthesis of a novel pharmaco-metabolite of etomoxir, ETO-carnitine, that is generated by CPT1 in mitochondria and likely impacts multiple downstream (non-CPT1 related) enzymes and processes in multiple subcellular compartments.

CPT1A-IL-10-mediated macrophage metabolic and phenotypic alterations ameliorate acute lung injury.

BACKGROUND: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate-limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)-induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin-10 (IL-10). METHODS: After nasal inhalation rIL-10 and/or LPS, wild type (WT), IL-10-/-, Cre-CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow-derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL-10 and/or LPS. The qRT-PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage. RESULTS: In in vivo experiments, we found that mice lacking CPT1A or IL-10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL-10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL-10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL-10-/- BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL-10 into macrophages showed reverse effect. CPT1A and IL-10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A-IL-10 axis is also involved in the process of maintaining mitochondrial homeostasis. CONCLUSIONS: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL-10/IL-10 receptor expression.

Screening primary carnitine deficiency in 10 million Chinese newborns: a systematic review and meta-analysis.

BACKGROUND: Primary carnitine deficiency (PCD) is a rare autosomal recessive fatty acid oxidation disorder caused by variants in SLC22A5, with its prevalence and SLC22A5 gene mutation spectrum varying across races and regions. This study aimed to systematically analyze the incidence of PCD in China and delineate regional differences in the prevalence of PCD and SLC22A5 gene variants. METHODS: PubMed, Embase, Web of Science, and Chinese databases were searched up to November 2023. Following quality assessment and data extraction, a meta-analysis was performed on screening results for PCD among Chinese newborns. RESULTS: After reviewing 1,889 articles, 22 studies involving 9,958,380 newborns and 476 PCD cases were included. Of the 476 patients with PCD, 469 underwent genetic diagnosis, revealing 890 variants of 934 alleles of SLC22A5, among which 107 different variants were detected. The meta-analysis showed that the prevalence of PCD in China was 0.05‰ [95%CI, (0.04‰, 0.06‰)] or 1/20 000 [95%CI, (1/16 667, 1/25 000)]. Subgroup analyses revealed a higher incidence in southern China [0.07‰, 95%CI, (0.05‰, 0.08‰)] than in northern China [0.02‰, 95%CI, (0.02‰, 0.03‰)] (P < 0.001). Furthermore, the result of the meta-analysis showed that the frequency of the variant with c.1400C > G, c.51C > G, c.760C > T, c.338G > A, and c.428C > T were 45% [95%CI, (34%, 59%)], 26% [95%CI, (22%, 31%)], 14% [95%CI, (10%, 20%)], 6% [95%CI, (4%, 8%)], and 5% [95%CI, (4%, 8%)], respectively. Among the subgroup analyses, the variant frequency of c.1400C > G in southern China [39%, 95%CI, (29%, 53%)] was significantly lower than that in northern China [79‰, 95%CI, (47‰, 135‰)] (P < 0.05). CONCLUSIONS: This study systematically analyzed PCD prevalence and identified common SLC22A5 gene variants in the Chinese population. The findings provide valuable epidemiological insights and guidance for future PCD screening effects in newborns.

S-1-Propenylcysteine Enhances Endurance Capacity of Mice by Stimulating Fatty Acid Metabolism via Muscle Isoform of Carnitine Acyltransferase-1.

BACKGROUND: Endurance is an important capacity to sustain healthy lifestyles. Aged garlic extract (AGE) has been reported to exert an endurance-enhancing effect in clinical and animal studies, although little is known about its active ingredients and mechanism of action. OBJECTIVES: This study investigated the potential effect of S-1-propenylcysteine (S1PC), a characteristic sulfur amino acid in AGE, on the swimming endurance of mice, and examined its mechanism of action by a metabolomics-based approach. METHODS: Male Institute of Cancer Research (ICR) mice (6 wk old) were orally administered either water (control) or S1PC (6.5 mg/kg/d) for 2 wk. The swimming duration to exhaustion was measured at 24 h after the final administration. Nontargeted metabolomic analysis was conducted on the plasma samples obtained from mice after 40-min submaximal swimming bouts. Subsequently, the enzyme activity of carnitine acyltransferase-1 (CPT-1) and the content of malonyl-coenzyme A (CoA), acetyl-CoA, and adenosine triphosphate (ATP) were quantified in heart, skeletal muscles, and liver of mice. RESULTS: The duration time of swimming was substantially increased in the S1PC-treated mice as compared with the control group. Metabolomic analysis revealed significant alterations in the plasma concentration of the metabolites involved in fatty acid metabolism, in particular medium- or long-chain acylcarnitines in the mice treated with S1PC. Moreover, the administration of S1PC significantly enhanced the CPT-1 activity with the concomitant decrease in the malonyl-CoA content in the heart and skeletal muscles. These effects of S1PC were accompanied by the elevation of the acetyl-CoA and ATP levels to enhance the energy production in those tissues. CONCLUSIONS: S1PC is a key constituent responsible for the endurance-enhancing effect of AGE. This study suggests that S1PC helps provide energy during endurance exercise by increasing fatty acid metabolism via CPT-1 activation in the heart and skeletal muscles.

Influence of incorporating L-carnitine or Moringa oleifera leaves extract into semen diluent on cryosurvival and in vitro fertilization competence of buck sperm.

This study aimed at scrutinizing efficiency of incorporating L-carnitine or M. oleifera leaves extract into semen diluent on improving cryopreservation capacity and in vitro fertilization ability of buck spermatozoa. Ejaculates (n=48) were collected by an artificial vagina from six adult Damascus bucks twice weekly during the breeding season (September-October). Following initial evaluation, ejaculates of each collection session from the same bucks were pooled, diluted (1:10) with glycerolized (3 % glycerol, v/v) tris-citric acid egg yolk diluent and were split into three aliquots. The first aliquot served as control, whereas the second and third aliquots were supplemented with 4 µL/mL L-carnitine and 400 µL/mL moringa leaves extract (v/v), respectively. Thereafter, all specimens were processed for cryopreservation and were stored in liquid nitrogen (-196 °C) for 12 months before post-thaw sperm criteria were analyzed by a computer-assisted sperm analysis (CASA) system. Integrity of sperm DNA post thawing was visualized in all semen groups by fluorescence imaging, and in vitro fertilization ability of spermatozoa was also determined. Inclusion of L-carnitine or moringa leaves extract into the diluent improved (P<0.05) post-thaw sperm physical, morphofunctional and kinematic attributes, whilst maintaining (P<0.05) integrity of sperm DNA throughout the freezing and thawing cycle. Consequently, both supplemented groups yielded higher (P<0.05) in vitro fertilization rates compared to control. These results accentuate the protective roles of these antioxidants on buck sperm against consequences of cryopreservation-induced oxidative stress, hence ameliorating post-thaw sperm quality and fertilization competence. This is crucial for successful application of AI and IVF in goat selective breeding programs.

A Rare Case Report of Hypoketotic Hypoglycemia Induced Seizures Due to Secondary Carnitine Deficiency in a 44-year-old Female.

Carnitine deficiency is a rare metabolic condition that can result in fasting hypoglycemia. Carnitine deficiency could be primary or secondary to other conditions. Among secondary causes, antiepileptics such as valproic acid have been incriminated. Valproic acid is known to deplete carnitine stores and inhibit the process of ß-oxidation. Herein we report the case of a 44-year-old female with epilepsy that presented with breakthrough seizures associated with hypoglycemia despite being on appropriate antiepileptic therapy. The patient was later found to have carnitine deficiency. Discontinuation of valproic acid and supplementation with l-carnitine resolved the patient's hypoglycemia and breakthrough seizures. With this case report, we hope to encourage clinicians to include carnitine deficiency in the differential diagnosis of unexplained hypoglycemia.

The YY1-CPT1C signaling axis modulates the proliferation and metabolism of pancreatic tumor cells under hypoxia.

Carnitine palmitoyltransferase 1C (CPT1C) is an enzyme that regulates tumor cell proliferation and metabolism by modulating mitochondrial function and lipid metabolism. Hypoxia, commonly observed in solid tumors, promotes the proliferation and progression of pancreatic cancer by regulating the metabolic reprogramming of tumor cells. So far, the metabolic regulation of hypoxic tumor cells by CPT1C and the upstream mechanisms of CPT1C remain poorly understood. Yin Yang 1 (YY1) is a crucial oncogene for pancreatic tumorigenesis and acts as a transcription factor that is involved in multiple metabolic processes. This study aimed to elucidate the relationship between YY1 and CPT1C under hypoxic conditions and explore their roles in hypoxia-induced proliferation and metabolic alterations of tumor cells. The results showed enhancements in the proliferation and metabolism of PANC-1 cells under hypoxia, as evidenced by increased cell growth, cellular ATP levels, up-regulation of mitochondrial membrane potential, and decreased lipid content. Interestingly, knockdown of YY1 or CPT1C inhibited hypoxia-induced rapid cell proliferation and vigorous cell metabolism. Importantly, for the first time, we reported that YY1 directly activated the transcription of CPT1C and clarified that CPT1C was a novel target gene of YY1. Moreover, the YY1 and CPT1C were found to synergistically regulate the proliferation and metabolism of hypoxic cells through transfection with YY1 siRNA to CRISPR/Cas9-CPT1C knockout PANC-1 cells. Taken together, these results indicated that the YY1-CPT1C axis could be a new target for the intervention of pancreatic cancer proliferation and metabolism.

Trajectory of Change in the Severity of Symptoms in Patients with Fibromyalgia over 24 Months: Exploratory Analyses of a Combination Pharmacological Intervention.

Symptoms of fibromyalgia (FM) fluctuate and vary in severity. The current study aimed to evaluate the efficacy of palmitoylethanolamide (PEA) and acetyl-L-carnitine (ALC) in FM patients over a 24-month period and to investigate the mediating function of pain catastrophizing subdomains in unfavorable relationships with disease severity levels in patients with FM. Patients were evaluated at baseline, after 12 months, and after 24 months, using different patient-reported measures (FIQR, FASmod, PSD, and PCS) to distinguish different levels of FM disease severity. A reduction of 30% or more from baseline was considered clinically important ("markedly improved"). A multivariate analysis was performed to identify the variables predictive of an FIQR reduction. Twenty-two patients (28.6%) were classified as "markedly improved", 16 patients (20.8%) as "slightly/moderately improved", and 39 patients (50.6%) as "not improved." The FIQR, FASmod, and PSD scores were significantly reduced at 24 months. The pain magnification domain score of the PCS was the only variable predictive of worse FIQR scores (Wald coefficient: -2.94; p = 0.047). These results suggest a potential long-term therapeutic role for the PEA + ALC combination, with pain magnification being the primary predictor of poor efficacy.