Alpha-glucosidase Research Articles

In vitro antidiabetic evaluation of Bombax buonopozense methanol leaf extract

Diabetes mellitus (DM) is a major worldwide health burden that requires research into cost-effective treatment alternatives. It has been claimed that herbal medicines, have improved glucose metabolism in diabetics. It has been showed that several plant extracts are useful in preserving glucose homeostasis. Therefore, the present study aimed to evaluate the phytochemical and antidiabetic activities of Bombax buonopozense methanol leaf extracts. Standard methods were used for the identification of alkaloids, tannins, flavonoids, saponins, phenolics, cardiacglycosides and steroids. The enzyme inhibitory activities of the extracts of B. buonopozense was evaluated on α-amylase and α-glucosidase. The crude leaf extract of B. buonopozense exhibited a more effective inhibition on α-glucosidase with IC50 (Half maximal inhibitory concentration) values 888.20±35.06 μg/mL when compared to control (ascorbic acid) with values 1076±2.77 μg/mL. Fractions of ethyl acetate showed lower inhibitory property of alpha glucosidase with IC50 value 18.44±2.63 μg/mL compared to the control (ascorbic acid with IC50 value 16325±1318 μg/mL). This study showed the scientific basis for the traditional therapeutic usage of B. buonopozense by proven its antidiabetic activity in vitro. This is the first time that B. buonopozense’s antidiabetic efficacy and possible mechanisms have been documented.

First-in-Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease.

Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and Ctrough concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose-dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub-study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.

Cipaglucosidase alfa plus miglustat: linking mechanism of action to clinical outcomes in late-onset Pompe disease.

Enzyme replacement therapy (ERT) is the only approved disease-modifying treatment modality for Pompe disease, a rare, inherited metabolic disorder caused by a deficiency in the acid α-glucosidase (GAA) enzyme that catabolizes lysosomal glycogen. First-generation recombinant human GAA (rhGAA) ERT (alglucosidase alfa) can slow the progressive muscle degeneration characteristic of the disease. Still, most patients experience diminished efficacy over time, possibly because of poor uptake into target tissues. Next-generation ERTs aim to address this problem by increasing bis-phosphorylated high mannose (bis-M6P) N-glycans on rhGAA as these moieties have sufficiently high receptor binding affinity at the resultant low interstitial enzyme concentrations after dosing to drive uptake by the cation-independent mannose 6-phosphate receptor on target cells. However, some approaches introduce bis-M6P onto rhGAA via non-natural linkages that cannot be hydrolyzed by natural human enzymes and thus inhibit the endolysosomal glycan trimming necessary for complete enzyme activation after cell uptake. Furthermore, all rhGAA ERTs face potential inactivation during intravenous delivery (and subsequent non-productive clearance) as GAA is an acid hydrolase that is rapidly denatured in the near-neutral pH of the blood. One new therapy, cipaglucosidase alfa plus miglustat, is hypothesized to address these challenges by combining an enzyme enriched with naturally occurring bis-M6P N-glycans with a small-molecule stabilizer. Here, we investigate this hypothesis by analyzing published and new data related to the mechanism of action of the enzyme and stabilizer molecule. Based on an extensive collection of in vitro, preclinical, and clinical data, we conclude that cipaglucosidase alfa plus miglustat successfully addresses each of these challenges to offer meaningful advantages in terms of pharmacokinetic exposure, target-cell uptake, endolysosomal processing, and clinical benefit.

Screening of anti-diabetic potential of the siddha formulation sambirani poo kuligai by in-vitro alpha glucosidase enzyme inhibition assay

Background: Noninsulin-dependent diabetes mellitus (NIDDM) is a common disease of the endocrine system caused by the decreased secretion of insulin by the pancreatic Langerhans beta cell or by the lowering of insulin resistance due to excessive absorption of glucose. The Siddha system of medicine is a traditional medical system that uses a scientific and holistic approach to provide preventive, promotive, curative, rejuvenative and rehabilitative health care. According to Siddha literature, diabetes is known as Innippu Neer, Madhumegam and Neerizhivu. The various reasons for the cause of this disease are attributed to foodhabits and lifestyle changes and also due to hereditary causes. One of the therapeutic approaches is to decrease the postprandial hyperglycemia by retarding the absorption of glucose through the inhibition of carbohydrate-hydrolyzing enzymes, such as a-amylase and ?-glucosidase. ?-Glucosidase are enzyme that catalyze the absorption of digested glucose from dietary polysaccharides in the small intestine. Aim: The aim of the present study is to evaluate the anti-diabetic potential of the siddha formulation of Sambirani Poo Kuligai(SPK) by alpha glucosidase enzyme inhibition assay. Method: The spectrophotometric assay method was used to find alpha glucosidase inhibitory activity. Results: SPK showed presence of alpha glucosidase inhibitory potential with the maximum inhibition of about 41.74 ± 3.578 % and the corresponding IC50 is 606.5 ± 49.51?g/ml. Conclusion: This in-vitro study revealed the presence of the alpha glucosidase activity in the siddha formulation Sambirani Poo Kuligai possesses antidiabetic activity

VAL-1221 for the treatment of patients with Lafora disease: study protocol for a single-arm, open-label clinical trial

IntroductionLafora disease (LD) is an ultrarare fatal progressive myoclonic epilepsy, causing drug-resistant epilepsy, myoclonus and psychomotor deterioration. LD is caused by mutations in EPM2A or NHLRC1, which lead to the...

The combined effects of bisphenol S and hexavalent chromium on alpha-glucosidase: Intermolecular interaction, structural and functional changes

The co-contamination of heavy metal ions and organic pollutants has posed a threat to human health. Herein, this study investigated the intermolecular interactions of bisphenol S (BPS) and hexavalent chromium (Cr(VI)) under both individual and coexisting conditions, with alpha-glucosidase (AG), a key enzyme in carbohydrate metabolism, and the corresponding effects on the structure and function of AG. Multiple spectroscopic and molecular docking methods were employed to conduct the investigation in vitro and in silico. The results indicated that both BPS and Cr(VI) quenched the fluorescence of AG via a combined static and dynamic quenching processes. At 310 K, the binding constants of AG with BPS in the AG-BPS and (AG-Cr(VI))-BPS systems were 1.84 × 104 and 2.03 × 104 L mol−1, and the binding constants of AG with Cr(VI) in the AG-Cr(VI) and (AG-BPS)-Cr(VI) systems were 6.14 × 103 and 4.35 × 103 L mol−1. Cr(VI) could significantly affect the binding site of BPS in AG, while BPS had a minimal impact on the binding site of Cr(VI) in AG. BPS and Cr(VI) caused varied structural alterations of AG, and the impact of their coexistence on the structure of AG was related to the order in which they were added. Both BPS and Cr(VI) had a concentration-related effect on AG activity. This study provides valuable insights into the molecular mechanisms underlying the combined toxic effects of BPS and Cr(VI) on AG, highlighting the potential health risks associated with their environmental co-exposure.

Single stage bi-substrate transglycosylation reaction for the synthesis of ascorbic acid 2 glucoside using immobilized α-glucosidase

Alpha glucosidases are multifunctional glycoside hydrolases with hydrolysis and transglycosylation ability. It can be utilized for the glycosidic bond synthesis or glycosylation of Ascorbic acid/Vitamin C to its stable analogue, Ascorbic acid 2 glucoside (AA2G), a compound with wide applications in cosmetics and pharma. The application of α-glucosidases for industrial scale transglycosylation is limited due to the low transglycosylation yield of free enzymes. Enzyme immobilization techniques could enable the development of efficient, reusable catalysts. Only a few glycoside hydrolases have been studied in immobilized form for transglycosylation reactions, and α-glucosidases are probably the least explored in this form. Transglycosylation activity of immobilized α-glucosidase from Aspergillus carbonarius BTCF 5 was studied for AA2G synthesis, where different immobilization techniques like calcium alginate encapsulation, adsorption on chitosan beads, covalent cross-linking on magnetic nanoparticles, and cross-linked enzyme aggregates (CLEA) were employed for the immobilization. The immobilization yield of calcium alginate encapsulated enzyme, enzyme immobilized on Fe-MNP support, enzyme immobilized on chitosan beads and as CLEA were 107%, 99%, 46% and 486%, respectively. CLEA was identified as the best immobilization technique for this bi-substrate reaction due to the high immobilization yield and activity retention (30% activity retained after 5 consecutive cycles). Enzyme immobilization increased the transglycosylation activity by 38%, yielding 118 mM AA2G against 72 mM by the free enzyme. This indicates the potential of immobilized α-glucosidase as a catalyst for synthesizing AA2G at an industrial scale.

Brain glycogen build-up measured by magnetic resonance spectroscopy in classic infantile Pompe disease.

Classic infantile Pompe disease is caused by abnormal lysosomal glycogen accumulation in multiple tissues, including the brain due to a deficit in acid α-glucosidase. Although treatment with recombinant human acid α-glucosidase has dramatically improved survival, recombinant human acid α-glucosidase does not reach the brain, and surviving classic infantile Pompe patients develop progressive cognitive deficits and white matter lesions. We investigated the feasibility of measuring non-invasively glycogen build-up and other metabolic alterations in the brain of classic infantile Pompe patients. Four classic infantile patients (8-16 years old) and 4 age-matched healthy controls were scanned on a 7 T MRI scanner. We used T2-weighted MRI to assess the presence of white matter lesions as well as 1H magnetic resonance spectroscopy and magnetic resonance spectroscopy imaging to obtain the neurochemical profile and its spatial distribution, respectively. All patients had widespread white matter lesions on T2-weighted images. Magnetic resonance spectroscopy data from a single volume of interest positioned in the periventricular white matter showed a clear shift in the neurochemical profile, particularly a significant increase in glycogen (result of acid α-glucosidase deficiency) and decrease in N-acetyl-aspartate (marker of neuronal damage) in patients. Magnetic resonance spectroscopy imaging results were in line and showed a widespread accumulation of glycogen and a significant lower level of N-acetyl-aspartate in patients. Our results illustrate the unique potential of 1H magnetic resonance spectroscopy (imaging) to provide a non-invasive readout of the disease pathology in the brain. Further study will assess its potential to monitor disease progression and the correlation with cognitive decline.

Real-world data of in-hospital administration of alglucosidase alfa in French patients with Pompe disease: results from the National Claims Database.

Pompe disease is caused by a rare biallelic mutation in the GAA gene resulting in acid α-glucosidase deficiency and glycogen accumulation. We analyzed hospital admissions associated with the administration of Myozyme®, utilizing the French hospital discharge database, known in France as the Programme de Médicalisation des Systèmes d'Information (PMSI), which comprehensively captures all hospital activity within the country. In this observational study, we examined hospitalization records from April 4, 2012, to December 31, 2019, within the PMSI database, focusing on admissions where Myozyme® was administered. We particularly investigated the incidence of critical care admissions and adverse events (AEs) related to Myozyme®. From 2012 to 2019, approximately 26,714 hospital stays involving Myozyme® administration were recorded for 239 patients. Most (96.6%) of these were outpatient stays, with only 3.2% in critical care. Furthermore, hospitalizations without critical care needs increased from 96% in 2012 to 99% in 2019. Of the patients receiving at least one infusion, 997 critical care admissions were recorded, with 781 (78.3%) occurring concurrent with or the day after the Myozyme® treatment without directly correlating to adverse effects of enzyme therapy. The analysis of the French hospital discharge database indicated that Myozyme® was associated with a low incidence of AEs and complications in a hospital context, supporting the consideration of its safe use in home-infusion settings.

Clinical features and genetic analysis of 5 cases of infantile-type glycogen storage disease type II: Case reports.

Clinical and genetic mutation analysis was performed on 5 infantile glycogen storage disease type II children in Chinese mainland. Clinical data of 5 children with infantile-type glycogen storage disease type II due to the acidic α-glucosidase (GAA) gene variants diagnosed and treated at Hebei Provincial Children's Hospital from January 2018 to April 2020 were retrospectively analyzed. Among the 5 cases, 1 was female and 4 were male, and the age at first diagnosis was from 2 months to 7 months. The first symptoms of all 5 cases showed progressive muscle weakness, hypotonia, and motor developmental backwardness, and all of them had abnormally elevated creatine kinase, and the echocardiograms suggested different degrees of myocardial hypertrophy, with ejection fractions ranging from 44% to 67%. Analysis of GAA gene variations: all 5 cases were compound heterozygous, and a total of 12 variant loci were detected, of which c.2024_2026delACA, c.2853G > A, c.1124G > T, c.574G > A, c.2509C > T, and c.2013G > A were new mutations that had not been reported. All 5 children died before 1 year of age, and the age of death ranged from 7 months to 11.5 months, with a mean survival time of 9.8 months. Peripheral blood GAA gene testing and alpha-glucosidase enzyme activity testing is an effective method for diagnosing this disease.

Profiling of Antidiabetic Bioactive Flavonoid Compounds from an Edible Plant Kudzu (Pueraria lobata).

Pueraria lobata (Willd.) Ohwi, known as kudzu and used as a "longevity powder" in China, is an edible plant which is rich in flavonoids and believed to be useful for regulating blood sugar and treating diabetes, although the modes of action are unknown. Here, a total of 53 flavonoids including 6 novel compounds were isolated from kudzu using multidimensional preparative liquid chromatography. The flavonoid components were found to lower blood sugar levels, promote urine sugar levels in mice, and reduce the urine volume. Molecular docking and in vitro assays suggested that the antidiabetic effect of kudzu was attributed to at least three targets: sodium-dependent glucose transporter 2 (SGLT2), protein tyrosine phosphatase-1B (PTP1B), and alpha-glucosidase (AG). This study suggests a possible mechanism for the antidiabetic effect that may involve the synergistic action of multiple active compounds from kudzu.

Facile benzothiazole-triazole based thiazole derivatives as novel thymidine phosphorylase and α-glucosidase inhibitors: Experimental and computational approaches

The present study reports the new thiazole (A-L) derivatives based on benzothiazole fused triazole which were synthesized and assessed against thymidine phosphorylase and α-glucosidase enzymes. Several compounds with the same basic structure but different substituents were found to have high activity against the targeted enzymes, while others with the same basic skeleton but different substituents were found to have medium to low activity among the members of tested series. These analogs showed a varied range of inhibition in both case thymidine phosphorylase and alpha glucosidase, A (IC50 = 7.20 ± 0.30 µM and IC50 = 1.30 ± 0.70 µM), B (IC50 = 8.80 ± 0.10 µM and IC50 = 2.10 ± 0.30 µM), C (IC50 = 8.90 ± 0.40 µM and IC50 = 3.20 ± 0.20 µM) and thiazole containing analogs such as G (IC50 = 11.10 ± 0.20 µM and IC50 = 7.80 ± 0.20 µM) and H (IC50 = 12.30 ± 0.30 µM and IC50 = 6.30 ± 0.20 µM). When compared with standard drugs 7-Deazaxanthine, 7DX (IC50 = 10.60 ± 0.50 µM) and acarbose (IC50 = 4.30 ± 0.30 µM) respectively. These analogs were also subjected to molecular docking studies which indicated the binding interaction of molecules with active sites of the enzyme and strengthen the drug profile of these compounds. ADMET studies also predict the drug-like properties of these compounds, with no violations of drug likeness rules.

The glycogenolytic enzyme acid α-glucosidase is expressed in the bovine uterine endometrium.

Progesterone has been shown to stimulate glycogen catabolism in uterine epithelial cells. Acid α-glucosidase (GAA) is an enzyme that breaks down glycogen within lysosomes. We hypothesized that progesterone may stimulate glycogenolysis in the uterine epithelium via GAA. We found that GAA was more highly expressed in the stroma on Day 1 than on Day 11. However, GAA did not appear to differ in the epithelium on Days 1 and 11. Progesterone (0-10 μM) had no effect on the levels of the full-length inactive protein (110 kDa) or the cleaved (active) peptides present inside the lysosome (70 and 76 kDa) in immortalized bovine uterine epithelial (BUTE) cells. Furthermore, the activity of GAA did not differ between the BUTE cells treated with 10 μM progesterone or control. Overall, we confirmed that GAA is present in the cow endometrium and BUTE cells. However, progesterone did not affect protein levels or enzyme activity.

P.064 A case of late onset Pompe Disease presenting in 6th decade

Background: Late onset Pompe disease (LOPD), rare autosomal recessive lysosomal storage disease, resulting from mutation in alpha glucosidase enzyme (GAA) can present even in 6th decade of life. Slowly progressive, subtle, limb girdle pattern of weakness (LGPW), with auxiliary features such as ptosis, enlarged tongue, axial rigidity, facial diplegia, variable degree of respiratory weakness is not uncommon. Hypertrophic and electrical cardiac abnormalities are well described in LOPD. Methods: We present a case of 67-year-old male presenting with proximal weakness, subtle ptosis, bilateral quadriceps and shoulder girdle atrophy, and left toe numbness. PMHx: CABG, NSTEMI. Statin use. FMHx: noncontributory. Results: EMG: L5 radiculopathy, with unexpected myopathic units in hip/pelvic/ shoulder girdle muscles with active denervation and muscle irritability. CK, CRP, SPEP, ANA, LFTs, HMG-CoA reductase: normal. GAA enzymatic activity=0.96µmol/L/hr (low), genetics: pathogenic variants in GAA gene: c.-32-13T>G and c.1194+3G>C. ECHO: severe diastolic dysfunction, restrictive left ventricular filling. PFTs: normal. Diagnosed with LOPD, started on therapy. Conclusions: LOPD remains a differential for LGPW especially in older patient population with history of cardiopulmonary features. Age-appropriate conconminant pathologies may confound the diagnostic process.Symptoms may preceed diagnosis for years.GAA enzymatic activity followed by genetic testing remains readily available and can confirm diagnosis, preventing delay of approved therapy.

Failure of Autophagy in Pompe Disease.

Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective elimination of worn-out or damaged proteins and organelles. The autophagic pathway is largely responsible for the delivery of cytosolic glycogen to the lysosome where it is degraded to glucose via acid α-glucosidase. Although the physiological role of lysosomal glycogenolysis is not fully understood, its significance is highlighted by the manifestations of Pompe disease, which is caused by a deficiency of this lysosomal enzyme. Pompe disease is a severe lysosomal glycogen storage disorder that affects skeletal and cardiac muscles most. In this review, we discuss the basics of autophagy and describe its involvement in the pathogenesis of muscle damage in Pompe disease. Finally, we outline how autophagic pathology in the diseased muscles can be used as a tool to fast track the efficacy of therapeutic interventions.

Comparative Study on Anti-Diabetic Activity of Momordica charantia and Psidium guajava

Diabetes is a metabolic disease characterised by decreased insulin signalling and persistent hyperglycaemia. The most frequent progression of diabetes is known as diabetes mellitus which is defined as persistent hyperglycaemia brought on by either peripheral insulin resistance or impaired pancreatic β cell production of insulin. This condition is caused by the disruptions in the digestion of carbohydrates, fats and proteins which are caused by defects in the production, release and regulation of insulin. The breakdown of carbohydrates is significantly aided by the intestinal digestive enzymes α-glucosidase and α-amylase. One type of antidiabetic treatment is to lower the blood glucose levels after a meal by blocking the enzymes α-glucosidase and α-amylase. This could be a key tactic in blood glucose control. When compared to other commercial pharmaceuticals used to treat diabetes, herbal treatments are thought to be more in harmony with the human body and to have less harmful side effects. This herbal remedy is reasonably priced as well. The aim of the current study is to compare the anti- diabetic activity of the methanolic extracts of Momordica charantia and Psidium guajava. The methods used in the determination of invitro antidiabetic activity are alpha amylase and alpha glucosidase inhibitory assays. In the current study, when compared the individual inhibition activity of Momordica charantia and Psidium guajava on the intestinal enzymes (alpha amylase and alpha glucosidase), Momordica charantia has the highest inhibition that is 79.83% at 0.8 mL concentration while the Psidium guajava has shown only 70.58% inhibition at 0.8 mL concentration. Which suggests that the presence of bio active compounds may be responsible for the plants many medicinal uses, including the treatment of diabetes.

AAV-GAA Gene Therapy Clears Long Chain Length Neuronal Glycogen in a Pompe Disease Rat Model

Pompe disease is due to mutations in the acid a-glucosidase (GAA) gene. GAA protein degrades lysosomal glycogen and dysfunctional or absent protein leads to cellular glycogen accumulation. In recent years, it has become clear that glycogen accumulation in the central nervous system (CNS) needs to be targeted in Pompe disease. However, the standard of care — intravenous enzyme replacement therapy using recombinant GAA does not effectively target the CNS. Here, we investigated the ability of neonatal AAV-GAA therapy to clear neuronal glycogen in the Pompe ( Gaa−/−) rat. On post-natal day one, male Gaa−/− rats received an administration of AAV9-DES-hGAA (1x1014 vector genomes/kg) via the temporal vein injection or sham injection (1xPBS). Rats were euthanized at age 9 months, and spinal cords and the diaphragm muscle were harvested and glycogen biochemistry was evaluated by matrix-assisted laser desorption/ionization mass spectrometry glycogen imaging (MALDI) and immunohistochemistry (GAA antibody). MALDI imaging reveal significant reduction in glycogen accumulation in the cervical spinal cord, and AAV9-DES-hGAA selectively targeting longer glucose chains within glycogen. Immunohistochemistry verified GAA expression in spinal cord neurons of rats treated with AAV-GAA. In the diaphragm muscle, MALDI revealed that the expected increase glycogen in the untreated Pompe diaphragm was associated with a decrease in n-linked glycans, a potential biomarker of the disease. Strikingly, glycogen content and glycans in the AAV-GAA treated diaphragm were indistinguishable from wild type. We conclude the neonatal gene therapy with AAV9-DES-hGAA can drive functionally relevant GAA expression in the adult rat CNS, and also effectively targets the diaphragm. R01HD052682 (DDF and BJB), R01AG066653 (RCS), R01CA266004 (RCS), R01AG078702 (RCS), RM1NS133593 (RCS), R35NS116824 (MSG). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Respiration and Cough in Pompe Disease: Results from a neuromechanical computational model of the respiratory control system

Late Onset Pompe Disease (LOPD) is an incurable, rare progressive genetic disease. It is characterized by glycogen build-up, due to mutations in the gene encoding the lysosomal enzyme acid alpha glucosidase, throughout muscle and neural regions. This accumulation is associated with cell death and muscle fiber swelling, eventually leading to respiratory insuffciency and airway clearance (i.e. cough) deficiency. Impairments in effective airway clearance result from the inability to clear normal pulmonary volume. Emerging evidence indicates significant respiratory neuron dysfunction, altering pulmonary function in humans and animal models. It has been suggested that respiratory and airway clearance insuffciency observed in LOPD may be attributed to medullary motoneurons potentially associated with the respiratory and cough pattern generators (Fuller et al., 2013; DeRuisseau et al., 2009). However, the precise neural mechanisms that suppress breathing and cough are not fully understood. One possible target for LOPD respiratory insuffciencies may be reduced medullary inspiratory neuron activity within this network, which could result in decreased phrenic motoneuron output. Using a stochastic neural network simulator that consisted of discrete “integrate and fire” populations, we simulated a systematic decrease in three medullary inspiratory neuron populations: inspiratory driver (I-Driver), inspiratory decrementing (I-Dec), or inspiratory augmenting (I-Aug) neurons. We simulated breathing and three cough trials. By targeting these populations, we expected global decreased neural bursts, suppressed inspiratory motor drive, and/or suppressed expiratory motoneuron output. Simulations indicated that when the I-Dec motoneuron population decreased by 25%, it resulted in apnea and abolished cough. Reducing the I-Aug motoneuron population by 20% resulted in longer inspiratory phase durations (TI) and a decreased respiratory rate. During cough, there was a decrease in the duration and amplitudes of the expiratory motoneuronal activity associated with decreased cough receptor and pulmonary stretch receptor afferent feedback. When the I-Driver motoneuron population was reduced by 25%, TI decreased and I amplitude increased during respiration. During cough, lumbar and phrenic motoneuron discharge duration and amplitude decreased. These results are consistent with previously reported in vivo data. Overall, our simulation data support the plausibility of glycogen storage dysfunction impairing medullary neuronal and premotoneuronal excitability within the inspiratory network. Our results also suggest that some neurons may be more sensitive to glycogen storage than others within the brainstem inspiratory network. Supported by NHLBI L30HL165496, NIH T32 HL 134621 and 3OT2OD023854. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Alpha-Amylase and Alpha-Glucosidase Inhibitory Potential of Overnight Soaked Aqueous Extract of Abelmoschus esculentus

Phytochemicals are secondary metabolites which act as antioxidants and possess various protective role.Alpha Amylase and Alpha Glucosidase enzymes catalyse hydrolysis of starch to simple sugars. Abelmoschus esculentus is a flowering plant of the Malvaceae family and is valued for its green seed pods. It naturally possesses anti-diabetic property, acts as a starch blocker as it prevents the absorption of starch in the body. Abelmoschus esculentus was cut vertically to open and added to 50ml of water. Soaked overnight and the aqueous extract was decanted and used for the phytochemical screening test followed by the evaluation of antioxidant and antidiabetic potential. The data were analysed statistically by a one-way analysis of variance (ANOVA) followed by Duncan’s multiple range test. Overnight soaked extract of Abelmoschus esculentus exhibited a significant antioxidant potential (IC50=280 µg/ml) and compared with standard vitamin C. Alpha amylase and alpha glucosidase inhibitory potential of Abelmoschus esculentus was analysed (IC50=380µg/ml and 320µg/ml respectively) and compared with standard acarbose. Though Abelmoschus esculentus is a common vegetable, its efficiency increases when soaking overnight.

Acid α-glucosidase (GAA) activity and glycogen content in muscle biopsy specimens of patients with Pompe disease: A systematic review

Pompe disease is a rare genetic disorder characterized by a deficiency of acid α-glucosidase (GAA), leading to the accumulation of glycogen in various tissues, especially in skeletal muscles. The disease manifests as a large spectrum of phenotypes from infantile-onset Pompe disease (IOPD) to late-onset Pompe disease (LOPD), depending on the age of symptoms onset. Quantifying GAA activity and glycogen content in skeletal muscle provides important information about the disease severity. However, the distribution of GAA and glycogen levels in skeletal muscles from healthy individuals and those impacted by Pompe disease remains poorly understood, and there is currently no universally accepted standard assay for GAA activity measurement. This systematic literature review aims to provide an overview of the available information on GAA activity and glycogen content levels in skeletal muscle biopsies from patients with Pompe disease.A structured review of PubMed and Google Scholar literature (with the latter used to check that no additional publications were identified) was conducted to identify peer-reviewed publications on glycogen storage disease type II [MeSH term] + GAA, protein human (supplementary concept), Pompe, muscle; and muscle, acid alpha-glucosidase. A limit of English language was applied. Results were grouped by methodologies used to quantify GAA activity and glycogen content in skeletal muscle. The search and selection strategy were devised and carried out in line with Preferred Reporting of Items in Systematic Reviews and Meta-Analysis guidelines and documented using a flowchart. Bibliographies of papers included in the analysis were reviewed and applicable publications not already identified in the search were included.Of the 158 articles retrieved, 24 (comprising >100 muscle biopsies from >100 patients) were included in the analysis, with four different assays. Analysis revealed that patients with IOPD exhibited markedly lower GAA activity in skeletal muscles than those with LOPD, regardless of the measurement method employed. Additionally, patients with IOPD had notably higher glycogen content levels in skeletal muscles than those with LOPD. In general, however, it was difficult to fully characterize GAA activity because of the different methods used. The findings underscore the challenges in the interpretation and comparison of the results across studies because of the substantial methodological variations. There is a need to establish standardized reference ranges of GAA activity and glycogen content in healthy individuals and in Pompe disease patients based on globally standardized methods to improve comparability and reliability in assessing this rare disease.