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Methylene cyclopropyl-glycine (MCPG) content in litchi seeds, semi-ripe and ripe fruit pulp
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... optimization of multiple reaction monitoring mass spectrometry conditions based on better baseline and sensitivity, the precursor ion product of m/z 128.0 82.0 was used for quantitation purpose. Table 1 shows the result of quantification of MCPG in the samples. Litchi seeds contain 1.8 g/g MCPG, while the ripe and semi-ripe pulp show a value of 0.187 and 0.566 g/g (fresh wt) MCPG respectively. ...Similar publications
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Fruits and vegetables are major sources of bioactive compounds included in human diet. The objective of the study was to evaluate the antioxidant activity and total phenolic compound content of lychee pulp. Hydroalcoholic extracts were obtained from the pulp (fresh, dried and freeze-dried), and analyzed by in vitro Folin-Ciocalteu, Fast Blue, ABTS+...
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Citations
... In absence of definite infectious aetiology, several alternate hypotheses have been proposed including pesticides, toxins, lychee fruit, and heat exposure for the outbreaks [2][3][4][5][6]. The 2014 outbreak investigation reported lychee toxins, methylene-cyclo-propyl-glycine (MCPG), and methylene-cyclo-propyl-acetic-acid (MCPA), as the potential causes [5][6][7]. The concentration of these encephalopathy cases in the Muzaffarpur district alone while lychee is cultivated in other districts doesn't satisfy the explanation. ...
... Urinary lychee metabolites detection may not correlate with fruit intake amount. In absence of the lethal dose (LD50) and effective dose (ED50) of lychee for humans, considering the doses for rats, about 300 lychees are to be consumed, which is difficult for young children [5,7,16,17]. Minimal involvement of children from upper socioeconomic strata does not support the lychee consumption hypothesis, as lychee is consumed by all. ...
Background: Periodic outbreaks of acute encephalopathy in children have been reported from Muzaffarpur, Bihar, India. No infectious cause has been identified for this. This study presents the clinical and metabolic profile of children hospitalized with acute encephalopathy and the potential role of ambient heat stress.
Methods: This cross-sectional study included children (<15 years) with acute encephalopathy admitted from April 4, 2019, to July 4, 2019. The clinical and laboratory investigations included infections, metabolic abnormalities, and muscle tissue analysis. The children who had metabolic derangements but no infectious cause were labeled as acute metabolic encephalopathy. The descriptive analysis summarized the clinical, laboratory, and histopathology findings, and their association with the ambient heat parameters was explored.
Results: Out of the 450 children hospitalized (median age, four years), 94 (20.9%) died. Children had early morning onset (89%), seizures (99%), fever (82%), hypoglycemia at admission (64%), raised aminotransferases (60%), and high blood urea (66%). Blood lactate (50%), lactate dehydrogenase (84%), pyruvate (100%), ammonia (32%), and creatinine phosphokinase (69%) were raised. Viral marker tests were negative. The patients had abnormal metabolic markers like decreased blood-free carnitine, elevated blood acylcarnitines, and elevated urinary lactate, oxalate, maleate, adipate, and fatty acid metabolites. Blood carnitine and acylcarnitine levels normalized in 75% of the patients treated with carnitine and coenzyme-Q. Muscle tissues showed megamitochondria on electron microscopy and reduced respiratory enzyme complex-I activity. A significant correlation between the number of admissions and ambient heat indices was observed.
Conclusions: The findings suggest secondary mitochondrial dysfunction as a possible mechanism for acute encephalopathy in children from Muzaffarpur, Bihar, and ambient heat stress as a possible risk factor.
... The role of infections has been nearly ruled out and pesticides were not isolated [5,8]. Litchi has been implicated as a causative factor due to overlap of the harvest season, more cases from areas around the orchards, history of visit to orchard and isolation of litchi toxin metabolites (hypoglycin A, methylene-cyclo-propyl-glycine [MCPG] and methylene-cyclo-propyl-acetic-acid) from the AES children [5,7,9]. AES in children of unknown aetiology coinciding with litchi harvesting has been reported from West Bengal, Bangladesh and Vietnam [10][11][12]. ...
Objectives
Despite periodic outbreaks, the causes and risk factors of acute encephalitis syndrome (AES) in children of Muzaffarpur, Bihar, India, remain unknown. We explored the correlation between AES caseload and the climate parameters.
Methods
Data for 1318 hospitalized children with AES during 2012–20 were used. The correlation between AES cases and daily climate parameters (temperature, sunshine, rainfall, humidity and wind speed) for the previous 24, 48 and 72 h were examined using Pearson’s and Spearman’s rank-order correlation and Poisson regression or negative binomial regression analyses.
Results
Most (91.8%) of the AES cases occurred during the summer season (May–July months), especially June month. Pearson’s and Spearman’s rank-order correlation analyses revealed that AES caseload had positive correlations with maximum (r = 0.275, ρ = 0.293) and minimum (r = 0.306, ρ = 0.306) temperatures during past 24 h and heat index (r = 0.325, ρ = 0.325) and negative correlation with humidity (r = −0.222, ρ = −0.222) and rainfall (r = −0.183, ρ = −0.183) (all p < 0.05). The correlation was consistent for the climate parameters for the past 24, 48 and 72 h. Regression analysis also documented a significant association of AES cases with daily maximum (β: 0.32–0.36) and minimum (β: 0.53–0.62) temperatures and heat index (β: 0.92–1.03) over past 24, 48 and 72 h (all p < 0.01). The number of AES cases exponentially increased when the daily maximum and minimum temperatures crossed 40°C and 31°C, respectively.
Conclusions
The climate parameters, especially temperature appears to be a risk factor for AES in children. The definite aetiological role of heat for AES in children needs further exploration.
... 12,19 The acute encephalopathy was associated with 2 major toxins: hypoglycin A and methylenecyclopropylglycine, 19 substances found naturally in lychee seeds and fruits, known to cause hypoglycemia in animals by inhibiting β-oxidation of fatty acids and gluconeogenesis. 4,12,14,15 The toxic principles of T. esculenta seeds are unknown. However, T. esculenta seeds contain talisin, a storage protein that has lectin-like activities characterized by inhibition of agglutination of human and animal erythrocytes in high concentrations (starting at 500 μg/mL). ...
An outbreak of acute encephalopathy occurred in pregnant ewes and their newborn lambs associated with consumption of Talisia esculenta fruits and bark. Clinical signs in 5 adult pregnant ewes included drooling, bloat, tachypnea, depression, ataxia, body shaking, difficulty in rising, and recumbency. Three neonatal lambs born to some of those ewes had similar clinical signs. No significant gross abnormalities were observed on autopsy. Histologically, neuronal necrosis, axonal and dendritic swelling, and loss of Purkinje neurons were observed in the cerebellum. The observation of similar neurologic clinical signs and lesions in pregnant ewes and their neonatal lambs suggests that the toxic principle of T. esculenta crosses the placenta and reaches the fetus.
... In humans, toxicity from both HGA and MCPrG was first described after the ingestion of unripened soapberry fruits (Isenberg et al., 2016), which are related to maple trees and belong to the family of Sapindaceae. It has long been recognized that ackee fruits (Scott, 1916) and litchi fruits can lead to death during harvesting, especially in children (Das et al., 2015;Gray & Fowden, 1962;Isenberg et al., 2015;John & Das, 2014;Shah & John, 2014;Shrivastava et al., 2017;Shrivastava et al., 2015). The intake of ackee and litchee fruits leads to the production of toxic metabolites and the detection of HGA (John & Das, 2014;Shah & John, 2014;Shrivastava et al., 2017;Shrivastava et al., 2015) and ...
... MCPrG (Isenberg et al., 2015;Das et al., 2015;Sander et al., 2017) in blood and urine samples from affected humans. The specific end products of the metabolism of HGA and MCPrG in serum and urine are methylenecyclopropylacetyl-glycine and -carnitine (MCPA-G and MCPA-C, respectively) and methylenecyclopropylformyl-glycine and -carnitine (MCPF-G and MCPF-C, respectively), which can only be detected in diseased humans (Isenberg et al., 2016) and horses (Bochnia et al., 2019). ...
Background
Hypoglycin A (HGA) and methylenecyclopropylglycine (MCPrG) from seeds/seedlings of Sycamore maple (SM, Acer pseudoplatanus) causes atypical myopathy (AM) in horses. AM was not known to occur in wild ruminants until several fatalities in milus (Elaphurus davidianus) following the ingestion of HGA in SM seeds. However, a role for MCPrG has not previously been evaluated.
Objectives
To test the hypothesis that MCPrG is also a major factor in AM in milus, three milus (M1, M2, M3) from the Zoo Dresden (aged 7–11 years, 2 females and 1 male, in good nutritional condition) that developed AM were studied.
Methods
Serum, urine and methanol extracts from the liver, kidney, rumen digesta and faeces were analysed by ultrahigh‐performance liquid chromatography‐tandem mass spectrometry for HGA, MCPrG and for conjugates of carnitine (C) and glycine (G): Methylenecyclopropylacetyl (MCPA)‐G, MCPA‐C, Methylenecyclopropylformyl (MCPF)‐G, MCPF‐C, butyryl‐C and isobutyryl‐C.
Results
HGA in serum was high (M2 480 nmol/L; M3 460 nmol/L), but MCPrG was not. HGA and MCPrG were found in rumen and faeces extracts, and MCPrG was also identified in the liver. Metabolites of HGA and MCPrG were high in serum, urine and liver, but not in the rumen or faeces.
Conclusions
This study shows that MCPrG is involved in the pathophysiology of AM in milus. The metabolism of MCPrG is considered to be faster because, after ingestion, the specific metabolites appear highly concentrated in the serum. The high toxin concentration in the liver suggests that a possible transfer into products for human consumption may pose a risk.
... MCPG was shown to exhibit strong hypoglycaemic activity and implicated to cause acute encephalopathy in animal models (Melde et al. 1991;Isenberg et al. 2015). It has been reported that the existence of MCPG also observed in litchi pulp (Das et al. 2015). ...
India has been blessed with a wide variety of wild and cultivated edible tropical fruits with unique taste and aroma/flavours. Fruits and vegetables are a rich reserve of nutritive fibres, vitamins, macronutrients and minerals, in addition to several phytochemicals. The Indian tropical fruits belong to diverse botanical groups, and some of the important edible fruits include mango, banana, papaya, citrus, guava, pineapple, litchi, sapota and pomegranate. Several minor and underutilized wild edible tropical fruits are also found throughout the country. Phenolic bioactive compounds, such as catechin, ellagic acid, epicatechin, epigallocatechin, anthocyanins, gallotannins, ellagitannins, gallic acid, sinapic acid, quercetin, resveratrol and kaempferol have been isolated from Indian tropical fruits, and these compounds are proven with medicinal and health-promoting properties. As a result, consumption of these fruits can be strongly allied to curtailed risk of various human diseases, including coronary heart diseases, diabetes and cancers. Antiproliferative activities, protection of cellular damage by free radicals, apoptosis and anti-inflammatory action are the main mechanisms by which fruits and vegetables are known to exhibit their chemoprevention and promote health.
... 1,[7][8][9][10] Litchi contains two naturally occurring compounds, methylenecyclopropylalanine, also known as hypoglycin A, and its analogue, methylenecyclopropylglycine (MCPG), which can indirectly contribute to hypoglycaemia and metabolic derangement that lead to encephalopathy and coma in malnourished children. 1,3,4,11 Despite convincing supportive evidence, the diagnosis and aetiopathogenesis are still not accepted by all, some of whom still insist on including this under the umbrella of acute encephalitis syndrome (AES) along with viral aetiologies (often regarded as encephalitis caused by an 'unknown virus'). 12 Hence, controversy continues to exist regarding the definition, nomenclature and treatment of this entity. ...
... Hence MCPG, an analogue of hypoglycin A, which was discovered to be present in litchi seeds in 1976, was hypothesized to be potentially associated somehow; but MCPG had not been investigated in litchi fruit arils (edible pulp). 11,[38][39][40] This was confirmed by a 2015 study that definitively detected MCPG in the edible arils of litchi fruit sampled from Muzaffarpur. 11 As reported by the researchers, the early-morning hypoglycaemia caused by skipping the evening meal, poor glucogenesis (through glycogenolysis) due to chronic malnutrition and the blocking of fatty acid β-oxidation on account of prior consumption of litchi containing MCPG, together led to the characteristic clinical features. ...
... 11,[38][39][40] This was confirmed by a 2015 study that definitively detected MCPG in the edible arils of litchi fruit sampled from Muzaffarpur. 11 As reported by the researchers, the early-morning hypoglycaemia caused by skipping the evening meal, poor glucogenesis (through glycogenolysis) due to chronic malnutrition and the blocking of fatty acid β-oxidation on account of prior consumption of litchi containing MCPG, together led to the characteristic clinical features. 1,3 Use of the term 'encephalopathy' instead of 'encephalitis' was recommended. ...
The acute encephalopathy occurring in children in Muzaffarpur, India, also recognised in other litchi-cultivating areas of India, Bangladesh, Vietnam and China, had previously been linked to litchi consumption. Recently, it has been identified as hypoglycaemic encephalopathy of an unusual aetiology with three key factors: undernutrition, prolonged fasting and litchi consumption. A second set of investigators has independently reconfirmed the diagnosis and the three-factor aetiology. Skipping the evening meal with an intake of large amounts of litchi in undernourished children is causative. Early-morning hypoglycaemia with an inadequate glycogen store leads to initiation of gluconeogenesis and fatty acid β-oxidation, but methylene cyclopropyl alanine and glycine present in the litchi aril block the fatty acid β-oxidation cycle. The outcomes are uncorrected hypoglycaemia and encephalopathy due to the entry of metabolic intermediates that cross the blood-brain barrier and affect neuronal function. Suggested measures include early 10% dextrose infusion. Awareness about the disease is of prime importance. The diagnosis and aetiopathogenesis are still under question from a part of the scientific community. This review was undertaken to present a comprehensive view of hypoglycaemic encephalopathy and to remove some of the lingering doubts.
... Meanwhile, the seed demonstrated a varied content of phenolic compounds with antitumor and cardioprotective action, although it was related to toxicity in the presence of methylene Cyclopropyl-Alanine (MCPA) and methylene cyclopropyl-glycine (MCPG) that are hypoglycemic substances (Das et al., 2015;Shrivastava et al., 2017). ...
Talisia esculenta (A. ST.-HIL.) Radlk is a Brazilian wild fruit, known as a pitomba, belonging to the Sapindaceae family. The objective of the present work was to perform a review of the literature in order to identify studies on its physico-chemical characterization, antioxidant activity and biological activity. The articles search was done in PubMed, SciELO, Science Direct and LILACS. We identified 90 publications, 8 in SciELO, 3 in LILACS, 67 in Science Direct and 12 in PubMed. Subsequently, duplication of the articles between the databases was verified, and the triage was done by reading the titles, abstracts and reading in full, to analyze which articles fit the study objective, and only 5 studies were included. The review exposes Talisia esculenta Radlk (A. ST.-HIL.) as a fruit that has a bioactive potential, but there is a shortage of studies that deal with its chemical composition and its biological activity.
... [2] Litchi fruit such as Ackee fruit in Jamaica and other African countries has potential to induce hypoglycemic encephalopathy which may be attributed to MCPG, depending on the other congenial factors. [3], [4] However, many experts in the last 5 years considered this encephalopathy to be a mystery and continue to disapprove or remain unconvinced with the findings of research and public health experts' viewpoint and have their own notions regarding these outbreaks. [5] The governments, both central and state, must accept that malnutrition is the cause. ...
... Subsequent studies clearly indicated that the disease is hypoglycemic encephalopathy causing death to undernourished children, and 10% dextrose infusion is beneficial to patients, thereafter showing good response in their health (Shah and John 2014). Though the presence of MCPG was known in litchi seeds (Gray and Fowden 1962), yet there was no direct detection method for MCPG in ripe and semi-ripe litchi fruit until 2015 (Das et al. 2015). The findings were subsequently reaffirmed by National Centre for Disease Control (NCDC) investigators in 2017 (Das and John 2017;Shrivastava et al. 2017). ...
Recently, the presence of methylenecyclopropylglycine (MCPG) found in litchi seeds and ripe and unripe litchi fruit pulp proved to be a breakthrough finding as it causes hypoglycemic encephalopathy leading to death of under nourished/starved children. Earlier methods of isolation and detection of MCPG in litchi fruit were tedious and time-consuming. To reduce the complexity, we developed a better and straightforward methodology using ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) and QuEChERS technique to quantify MCPG without derivatization in litchi samples. The UPLC system included a Thermo C8 column with a mobile phase 0.1% formic acid in acetonitrile and water (gradient flow) at a flow rate of 0.3 ml/min. MCPG levels were determined using an API 4000 mass spectrometer with electrospray ionization (ESI) source. Other parameters were also determined following the quantitation by multiple reaction monitoring mode. The method was validated for selectivity, specificity, linearity, limit of quantification (LOQ), limit of detection (LOD), intra-inter day precision and accuracy, stability, and ruggedness. Calibration curve ranged from 7.8 to1000 ng/ml linearly while the LOD value for MCPG was 0.66 ng/ml. The percent accuracy and precision ranged from 92.98 to 105% and 1.78 to 8.43%, respectively. Validated method was applied for the determination of MCPG in litchi samples which provided a better and novel method for the determination of MCPG.
... The lychee fruit contains both hypoglycin and methylenecyclopropylglycine (MCPG), which is metabolized to form the toxic coenzyme A ester methylenecyclopropylformyl-CoA [23]. As with ackee fruit, the concentration of the culpable amino acids diminishes as the lychee fruit ripens [22,[24][25][26][27]. Seed of lychee contain the highest levels of hypoglycin A and MCPG [22,26,27]. ...
... The lychee fruit contains both hypoglycin and methylenecyclopropylglycine (MCPG), which is metabolized to form the toxic coenzyme A ester methylenecyclopropylformyl-CoA [23]. As with ackee fruit, the concentration of the culpable amino acids diminishes as the lychee fruit ripens [22,[24][25][26][27]. Seed of lychee contain the highest levels of hypoglycin A and MCPG [22,26,27]. ...
The consumption by humans of plants with potential to induce neurological disorders is widespread, but overt disease surfaces only when the subject's toxic threshold is exceeded. Excessive intake arising from food dependency in the setting of hunger, chronic undernutrition, vitamin deficiency, inadequate detoxication, or other individual susceptibility, can trigger acute encephalopathy (lychee, ackee fruits), sub-acute spastic paraparesis (grasspea, cassava root/leaves) or ataxic neuropathy (cassava root flour). While these disorders are very rarely encountered in high-income countries, they are not only common among impoverished populations but also often occur as outbreaks that impact a significant proportion of an affected community. Unfamiliarity with the adverse effects of plant toxins has sometimes led to the mistaken attribution of nutritional neurotoxic disease to a neurotropic viral or synthetic pesticidal etiology. The combination of human population growth, food and water insecurity, poverty and, with climate change, increased dependency on environmentally tolerant plants with neurotoxic potential, predictably may result in an increased prevalence of nutritional neurotoxic disorders, especially in certain parts of Africa and Asia.
