bims-glecem 2022-04-24 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–04–24
sixteen papers selected by
Dipsikha Biswas, Københavns Universitet

Two Diseases-One Preclinical Treatment Targeting Glycogen Synthesis.
Mechanochemical Promoted Heterocycles: A Solvent-Free Route to Triazole Carbohydrates as Glycogen Phosphorylase Inhibitors.
Skeletal muscle cell-specific differences in type 2 diabetes.
Determination of Glucan Chain Length Distribution of Glycogen using the Fluorophore-Assisted Carbohydrate Electrophoresis (FACE) Method.
Glycogen storage disease type IIIa in pregnant women: A guide to management.
GSK-3β and its Inhibitors in Alzheimer's Disease: A Recent Update.
Molecular mechanisms of aberrant neutrophil differentiation in glycogen storage disease type Ib.
Sodium-glucose cotransporter type 2 channel inhibitor: Breakthrough in the treatment of neutropenia in patients with glycogen storage disease type 1b?
Korean naked waxy barley (saechalssal) extract reduces blood glucose in diabetic mice by modulating the PI3K-Akt-GSK3β pathway.
Premise and peril of Wnt signaling activation through GSK-3β inhibition.
McArdle disease and pregnancy: A case report and scoping review of pregnancy outcomes.
Role of aluminum exposure on Alzheimer's disease and related glycogen synthase kinase pathway.
Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases.
Late-Onset Pompe Disease Presenting with Isolated Tongue Involvement.
Discovery of Azaindolin-2-One as a Dual Inhibitor of GSK3β and Tau Aggregation with Potential Neuroprotective Activity.
Nitrogen removal pathways during simultaneous nitrification, denitrification, and phosphorus removal under low temperature and dissolved oxygen conditions.

Neurotherapeutics. 2022 Apr 22.

Two Diseases-One Preclinical Treatment Targeting Glycogen Synthesis.

Matthew S Gentry, Kia H Markussen, Katherine J Donohue.



Keywords:  AAV9; Adult polyglucosan body disease; Glycogen; Glycogen storage disease; Lafora disease; Neurodegeneration

DOI:  https://doi.org/10.1007/s13311-022-01240-9
Curr Org Synth. 2022 Apr 20.

Mechanochemical Promoted Heterocycles: A Solvent-Free Route to Triazole Carbohydrates as Glycogen Phosphorylase Inhibitors.

Ahlem Guesmi, Wesam Abdulfattah, Manel Ben Ticha, Faisal K Algathami, Kaiss Aouadi, Ammar Houasf, Lotfi Khezami, Naoufel Ben Hamadi.

   AIMS: This study aimed to recommend a novel way for the preparation of carbohydrates containing triazole derivatives.
BACKGROUND: Triazoles containing derivatives have numerous biological activities. Ball milling is a fast, modest, green process with massive potential. One of the greatest interesting applications of this technique is in the arena of heterocycles.
OBJECTIVE: Solvent-free click reactions are facilitated via the activation of copper powder using a ball milling mechanochemical procedure. An optimization study of parameters affecting the reaction rate, such as reaction time, size, and milling ball number, has been conducted. Different substrates have been tested using this adopted procedure considering in all cases, in high yields and purity, the corresponding chiral optically pure five-membered glycoconjugates containing 1,2,3-triazole.
METHOD: Three milling balls of 10 mm in diameter were placed in the milling jar (50 mL; stainless steel). 1 mmol of alkyne, 2 mmol of azide, and 1 mmol of Cu powder (63 mg) were added, respectively, in the presented order. Milling was assured for 25 min at 650 rpm deprived of solvent.
RESULT: The cycloaddition results and the deprotection of the cycloadducts were affected by the selection of the protective groups. Cleavage of the acetyl protecting groups provided water-soluble triazoles. The four 1,4-di-substituted 1,2,3-triazoles synthesized via deacetylation were tested against glycogen phosphorylase. The best inhibitor of rabbit muscle glycogen phosphorylase was 2-Amino-3-{2-[1-(3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-propionic acid b (Ki = 40.8 ±3.2 μM). This novel procedure affords an eco-friendly reaction profile (catalyst-free) affording high yields and short reaction times.
CONCLUSION: In this work, acetyl protective groups were used to the corresponding deprotected water-soluble triazole analogous to recognizing glycogen phosphorylase inhibitors. Triazole 6a was the most effective inhibitor of RMGPb with a Ki value of 40.8 μM.

Keywords:  Mechanochemical synthesis; carbohydrate; glycogen phosphorylase; high-speed vibration milling; hydrolysis; solvent-free reaction

DOI:  https://doi.org/10.2174/1570179419666220420133644
Cell Mol Life Sci. 2022 Apr 23. 79(5): 256

Skeletal muscle cell-specific differences in type 2 diabetes.

Noni T Frankenberg, Shaun A Mason, Glenn D Wadley, Robyn M Murphy.

  Major stores of glucose are found as glycogen in skeletal muscle and liver. Skeletal muscle is a heterogenous tissue, with cellular metabolic and contractile distinctions dependent on whether the cell (fibre) is slow-twitch (Type I) or fast-twitch (Type II). We hypothesised that proteins important for glycogen metabolism would be differentially abundant between these diverse fibres. We further hypothesised that the cellular location of these proteins would be different in muscle samples between control (CON) and individuals with type 2 diabetes (T2D). We dissected individual muscle fibre segments from vastus lateralis skeletal muscle biopsy samples from CON and T2D and used cell-type-specific approaches to address muscle heterogeneity. We measured glycogen and glycogen-related proteins by immunoblotting techniques. A lower proportion of Type I fibres was found in muscle in T2D compared with CON. AMPK-β2, glycogen branching enzyme (GBE), glycogen debranching enzyme (GDE), and glycogen phosphorylase (GP) were differentially localized between fibre types and in fibres from CON and T2D individuals. A key novel finding was that the majority of glycogen is loosely bound or cytosolic in location in human skeletal muscle. The proportion of this diffusible pool of glycogen was significantly lower in Type I fibres in T2D compared to CON. A hyperinsulinaemic, euglycaemic clamp in people with type 2 diabetes had no effect on the proportion of diffusible glycogen. We identify cell-type as an important consideration when assessing glycogen metabolism in muscle. Our findings demonstrate varying glucose handling abilities in specific muscle fibre types in type 2 diabetes. A model is presented to provide an overview of the cell-specific differences in glycogen metabolism in type 2 diabetes.

Keywords:  Glucose regulation; Glycogen; Hyperinsulinaemic euglycaemic clamp; Single fibres

DOI:  https://doi.org/10.1007/s00018-022-04265-7
J Vis Exp. 2022 Mar 31.

Determination of Glucan Chain Length Distribution of Glycogen using the Fluorophore-Assisted Carbohydrate Electrophoresis (FACE) Method.

Léa Fermont, Nicolas Szydlowski, Christophe Colleoni.

Glycogen particles are branched polysaccharides composed of linear chains of glucosyl units linked by α-1,4 glucoside bonds. The latter are attached to each other by α-1,6 glucoside linkages, referred to as branch points. Among the different forms of carbon storage (i.e., starch, β-glucan), glycogen is probably one of the oldest and most successful storage polysaccharides found across the living world. Glucan chains are organized so that a large amount of glucose can quickly be stored or fueled in a cell when needed. Numerous complementary techniques have been developed over the last decades to solve the fine structure of glycogen particles. This article describes Fluorophore-Assisted Carbohydrate Electrophoresis (FACE). This method quantifies the population of glucan chains that compose a glycogen particle. Also known as chain length distribution (CLD), this parameter mirrors the particle size and the percentage of branching. It is also an essential requirement for the mathematical modeling of glycogen biosynthesis.

DOI: https://doi.org/10.3791/63392
JIMD Rep. 2022 May;63(3): 216-220

Glycogen storage disease type IIIa in pregnant women: A guide to management.

Demi Beneru, Michel C Tchan, Kate Billmore, Roshini Nayyar.

  Glycogen storage disease type IIIa (GSD-IIIa) is an autosomal recessive disorder that impairs glycogenolysis, producing ketotic hypoglycaemia, hepatomegaly, cardiac and skeletal myopathy. During pregnancy, increased metabolic demand requires careful management. There are few case reports about pregnancy in GSD-IIIa, however none detail management during caesarean section. This case describes a 25-year-old women with GSD-IIIa diagnosed at 5 months of age. She had modest metabolic control with complications including hepatomegaly, mild skeletal myopathy and poor enteral function requiring multiple operative interventions. She had a planned pregnancy managed by a multidisciplinary team, which included a metabolic geneticist, maternal-fetal medicine specialist and metabolic dietitian. Nocturnal cornstarch was provided to meet basal carbohydrate requirements and a high protein diet with regular carbohydrates was consumed throughout the day. The woman remained well during the antenatal period and had an induction of labour at 38 weeks gestation. She had an emergency caesarean section in early labour due to an abnormal cardiotocography (CTG). The intraoperative and postoperative period were uncomplicated. A live baby boy was born in good condition, weighing 2440 g with APGARs of 9 and 9 at 1 and 5 min. She was managed in labour with glucose 10% IV at 3.5 mg/kg/min, hourly blood sugar level (BSL) monitoring and early epidural anaesthetic. The aim of the first 24-h post-partum was prevention of hypoglycaemia, which required strict management with dextrose 10% IV at 3.5 mg/kg/min, oral carbohydrate supplementation and BSL monitoring. This case highlights the complexity of GSD-IIIa as well as provides a proposed plan for management during pregnancy.

Keywords:  glycogen storage disease type 3; metabolic; obstetric; pregnancy

DOI:  https://doi.org/10.1002/jmd2.12282
Mini Rev Med Chem. 2022 Apr 20.

GSK-3β and its Inhibitors in Alzheimer's Disease: A Recent Update.

Neha Chauhan, Swati Paliwal, Smita Jain, Kanika Verma, Sarvesh Paliwal, Swapnil Sharma.

  Alzheimer's disease (AD) is an emerging major health and socioeconomic burden worldwide. It is characterized by neuronal loss, memory loss and cognitive impairment in the aging population. Despite several scientific advancements over the past five decades, the underlying molecular mechanism of the disease progression is yet unknown. Glycogen synthase kinase-3β (GSK-3β) has huge implications on brain function causing molecular pathologies, neuronal damage and impairment of brain performance in AD. It is one of the key players in signaling pathways for normal brain functioning and a critical molecular link between amyloid beta (Aβ) and tau neurofibrillary tangles (NFTs). GSK-3β activation is driven by phosphorylation of tau(τ) protein which results in disruption of neuronal synaptic activities and formation of neuronal plaques. Although, the accumulation of Aβ plaques and intracellular tangles of hyperphosphorylated tau protein have been well established as neuropathological hallmarks of disease but the molecular mechanism has not been unraveled. This review focuses on the role of GSK-3β in the molecular mechanisms participating in manifestation and progression of AD. h.

Keywords:  Alzheimer’s disease; glycogen synthase kinase-3; neurodegenerative diseases; neurofibrillary tangles; tau protein.

DOI:  https://doi.org/10.2174/1389557522666220420094317
Cell Mol Life Sci. 2022 Apr 18. 79(5): 246

Molecular mechanisms of aberrant neutrophil differentiation in glycogen storage disease type Ib.

Sang Wan Sim, Yuyeon Jang, Tae Sub Park, Byung-Chul Park, Young Mok Lee, Hyun Sik Jun.

  Glycogen storage disease type Ib (GSD-Ib), characterized by impaired glucose homeostasis, neutropenia, and neutrophil dysfunction, is caused by a deficiency in glucose-6-phosphate transporter (G6PT). Neutropenia in GSD-Ib has been known to result from enhanced apoptosis of neutrophils. However, it has also been raised that neutrophil maturation arrest in the bone marrow would contribute to neutropenia. We now show that G6pt-/- mice exhibit severe neutropenia and impaired neutrophil differentiation in the bone marrow. To investigate the role of G6PT in myeloid progenitor cells, the G6PT gene was mutated using CRISPR/Cas9 system, and single cell-derived G6PT-/- human promyelocyte HL-60 cell lines were established. The G6PT-/- HL-60s exhibited impaired neutrophil differentiation, which is associated with two mechanisms: (i) abnormal lipid metabolism causing a delayed metabolic reprogramming and (ii) reduced nuclear transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ) in G6PT-/- HL-60s. In this study, we demonstrated that G6PT is essential for neutrophil differentiation of myeloid progenitor cells and regulates PPARγ activity.

Keywords:  CRISPR/Cas9; Glucose-6-phosphate transporter; Myeloid progenitor cells; Peroxisome proliferator-activated receptor-γ

DOI:  https://doi.org/10.1007/s00018-022-04267-5
JIMD Rep. 2022 May;63(3): 199-206

Sodium-glucose cotransporter type 2 channel inhibitor: Breakthrough in the treatment of neutropenia in patients with glycogen storage disease type 1b?

Magdalena Kaczor, Milena Greczan, Karolina Kierus, Ewa Ehmke Vel Emczyńska-Seliga, Elżbieta Ciara, Barbara Piątosa, Dariusz Rokicki, Janusz Książyk, Dorota Wesół-Kucharska.

  Glycogen storage disease type 1b (GSD 1b) is an inherited metabolic defect caused by biallelic mutations in the SLC37A4 gene encoding microsomal glucose-6-phosphate (G6P) transporter in the endoplasmic reticulum (ER) membrane. Ineffective G6P transport into the ER leads to hypoglycaemia, hyperlactatemia, hyperuricemia, hypertriglyceridemia, hepato- and/or nephromegaly. Clinical manifestations of the disease include recurrent, severe infections and inflammatory bowel (Crohn-like) caused by neutropenia and diminished bactericidal and fungicidal activity of neutrophils. Granulocyte colony-stimulating factor (G-CSF) administration is currently a standard therapy to prevent adverse effects of neutropenia, but the treatment is associated with a high risk of severe side effects. On the other hand, short-treatment with sodium-glucose cotransporter type 2 inhibitor - empagliflozin (EMPA) was reported to act directly on the mechanism of neutropenia and neutrophil dysfunction in GSD 1b. We observed significant improvement in clinical and laboratory parameters after introducing EMPA to treatment, that is reduced frequency of infections, lower number of bowel movements, and improved postoperative wound healing. EMPA is effective in the treatment of neutropenia in our GSD 1b patients, which allows for dose reduction and even withdrawal of G-CSF. We did not observe any significant side effects of EMPA treatment in our patients.

Keywords:  GSD 1b; G‐CSF; SGLT2 inhibitor; empagliflozin; neutropenia

DOI:  https://doi.org/10.1002/jmd2.12278
Biomed Pharmacother. 2022 Apr 18. pii: S0753-3322(22)00365-1. [Epub ahead of print]150 112976

Korean naked waxy barley (saechalssal) extract reduces blood glucose in diabetic mice by modulating the PI3K-Akt-GSK3β pathway.

Ju Ri Ham, Young-Jin Son, Yongjin Lee, Hyun-Jin Lee, Jiyoung Yeo, Mi Ja Lee, Mi-Kyung Lee.

  Saechalssal barley is Korea's representative naked waxy barley. This study investigated the anti-diabetic effect of the extract derived from saechalssal and its mechanism. The prethanol extract of saechalssal (SPE) showed greater α-glucosidase inhibitory activity in vitro and a more significant lowering of the postprandial blood glucose levels in normal mice compared to its water extract (SWE). When mice with type 2 diabetes (T2DM) induced by a high-fat diet and streptozotocin were fed SPE (200 mg/kg/day) for six weeks, the fasting blood glucose and serum free fatty acid levels were significantly lower than those of the control group. SPE significantly elevated the hepatic glycogen accumulation with increasing glycogen synthesis-related gene (GYS2 and UGP2) levels compared to the control group. SPE stimulated the expression of the hepatic glycolysis-related genes (GK, PFK1, and PK) and suppressed the gluconeogenesis-related genes (G6Pase, FBP1, and PEPCK). SPE up-regulated the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), whereas it down-regulated the phosphorylation of glycogen synthase kinase 3 beta (GSK3β) compared to the control. The major flavonoids of SPE were naringin, prunin, and catechin, while its phenolic acids were ferulic acid and vanillic acid. These phytochemical compounds may contribute to the anti-hyperglycemic effects of SPE in diabetes. Overall, these results suggest that SPE has potential anti-diabetic activity through the regulating the PI3K/Akt/GSK3β pathway.

Keywords:  Phytochemical compound; Saechalssal; Type 2 diabetes; Waxy barley; α-glucosidase

DOI:  https://doi.org/10.1016/j.biopha.2022.112976
iScience. 2022 Apr 15. 25(4): 104159

Premise and peril of Wnt signaling activation through GSK-3β inhibition.

Samuel M Law, Jie J Zheng.

  Wnt signaling pathways have been extensively studied in the context of several diseases, including cancer, coronary artery disease, and age-related disorders. β-Catenin plays a central role in the most studied Wnt pathways, the Wnt/β-catenin signaling pathway, commonly referred to as the canonical Wnt signaling pathway. β-catenin is a substrate of glycogen synthase kinase 3β (GSK-3β), and the phosphorylated β-catenin by GSK-3β can be degraded by the proteasome through ubiquitination. Thus, GSK-3β inhibitors have become a widely used chemical biology tool to study the canonical Wnt signaling pathway. Among the varied GSK-3β inhibitors, a compound known as CHIR-99021 is one of the most widely used. Although these inhibitors contribute greatly to our understanding of the canonical Wnt pathway, certain pitfalls associated with such an approach may have been overlooked. In many published studies, micromolar concentrations of CHIR-99021 are used to activate the canonical Wnt pathway. Although CHIR-99021 is a specific GSK-3β inhibitor, it specifically inhibits the kinase at the nanomolar level. Therefore, caution is required when micromolar levels of CHIR-99021 are used for the purpose of activating the canonical Wnt signaling pathway.

Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2022.104159
Obstet Med. 2022 Mar;15(1): 40-44

McArdle disease and pregnancy: A case report and scoping review of pregnancy outcomes.

Christopher M Nash, Nabha Shetty, Ashley Miller, Kyle McCoy.

  McArdle disease is an autosomal recessive disorder affecting skeletal muscle glycogen metabolism. Limited data are available regarding pregnancy outcomes with this genetic condition. We present a recent case of a woman with McArdle disease, along with a scoping review of all published literature regarding pregnancy and delivery outcomes for women with McArdle disease. A total of 35 cases are summarised. Overall, pregnancy does not worsen or increase the risk for disease flare. Women can successfully deliver vaginally, with consideration of an assisted second stage recommended to reduce the risk of postpartum rhabdomyolysis.

Keywords:  McArdle disease; glycogen storage disease type V; pregnancy

DOI:  https://doi.org/10.1177/1753495X211016159
Drug Chem Toxicol. 2022 Apr 21. 1-13

Role of aluminum exposure on Alzheimer's disease and related glycogen synthase kinase pathway.

Sonia Sanajou, Pınar Erkekoğlu, Gönül Şahin, Terken Baydar.

  Aluminum (Al) is an environmentally abundant metal that is not essential for life. There is considerable evidence that Al as a neurotoxic xenobiotic may play a role in the pathogenesis of neurodegenerative diseases like Alzheimer's disease (AD). Exposure to aluminum has been shown to cause neuronal damage that resembles the symptoms of AD. In this review, we will summarize recent data about Al as the possible risk of incidence of AD. Then glycogen synthase kinase-3 beta (GSK3β) contributes to the hyperphosphorylation of Tau protein, the main component of neurofibrillary tangles, one of the hallmarks of AD as one of the mechanisms behind Al neurotoxicity will be covered. Overall, there is still a need for epidemiological studies and more in vivo and in vitro studies to determine the exact mechanisms of its neurotoxicity and the role of GSK3β in both Al toxic effect and AD.

Keywords:  Aluminum; Alzheimer’s disease; GSK3β; neurotoxicity; tau

DOI:  https://doi.org/10.1080/01480545.2022.2065291
Int J Mol Sci. 2022 Apr 16. pii: 4413. [Epub ahead of print]23(8):

Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases.

Mate Marosi, Parsa Arman, Giuseppe Aceto, Marcello D'Ascenzo, Fernanda Laezza.

  Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na+ channels (Nav1.2 and Nav1.6) and voltage-gated K+ channels (Kv4 and Kv7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.

Keywords:  GSK3β-mediated phosphorylation; intracellular fibroblast growth factors (iFGF); neuronal excitability; neuronal plasticity; neuropsychiatric disorders; protein–protein interaction; sodium- and potassium-current; voltage-gated ion channels

DOI:  https://doi.org/10.3390/ijms23084413
Case Rep Neurol. 2022 Jan-Apr;14(1):14(1): 98-103

Late-Onset Pompe Disease Presenting with Isolated Tongue Involvement.

Jasem Al-Hashel, Ismail Ismail.

  Late-onset Pompe disease (LOPD) is a rare autosomal recessive metabolic disorder that is caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), which is responsible for glycogen breakdown. It has a wide clinical spectrum but usually presents with limb girdle and respiratory muscles weakness. Tongue involvement has been rarely reported as the sole initial symptom of LOPD. A 65-year-old male presented with difficulty in speech and eating for a 4-year duration. He started to notice speech difficulty with production of particular speech sounds such as /l/, /d/, and /t/. Within 1 year, he developed difficulties in manipulating food with the tongue and oral residue in lateral sulci requiring digital manipulation, which was suggestive of tongue muscles weakness. Clinical examination showed tongue fasciculations, mild atrophic changes, and mild tongue weakness. Investigations showed mildly elevated creatine kinase levels, and electromyography of the tongue muscles revealed moderate spontaneous activity, denervation, chronic reinnervation with high-amplitude motor unit potentials, and positive sharp waves, with preserved recruitment. Given the diagnostic uncertainty, a screening for LOPD was performed using a dried blood spot, and GAA enzyme activity levels were found to be low; 1.06 μmol/L/h (reference values in adults: 2.10-29.00 μmol/L/h). Next-generation sequencing showed pathogenic variant in GAA gene, confirming the diagnosis of LOPD. This rare report of LOPD presenting with isolated tongue involvement adds to the expanding phenotypic variability of this disease. Tongue involvement is an important and early clinical sign of LOPD that needs careful evaluation and can aid in early diagnosis of this rare and treatable disease.

Keywords:  Acid maltase deficiency; Glycogen storage disease type II; Late-onset Pompe disease; Pompe disease; Tongue weakness

DOI:  https://doi.org/10.1159/000521524
Pharmaceuticals (Basel). 2022 Mar 31. pii: 426. [Epub ahead of print]15(4):

Discovery of Azaindolin-2-One as a Dual Inhibitor of GSK3β and Tau Aggregation with Potential Neuroprotective Activity.

Taha F S Ali, Halil I Ciftci, Mohamed O Radwan, Eslam Roshdy, Ahmed M Shawky, Mohammed A S Abourehab, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita.

  The inhibition of glycogen synthase kinase 3β (GSK3β) activity through pharmacological intervention represents a promising approach for treating challenging neurodegenerative disorders like Alzheimer's disease. Similarly, abnormal tau aggregate accumulation in neurons is a hallmark of various neurodegenerative diseases. We introduced new dual GSK3β/tau aggregation inhibitors due to the excellent clinical outcome of multitarget drugs. Compound (E)-2f stands out among the synthesized inhibitors as a promising GSK3β inhibitor (IC50 1.7 µM) with a pronounced tau anti-aggregation effect in a cell-based model of tauopathy. Concurrently, (E)-2f was demonstrated to be non-toxic to normal cells, making it a promising neuroprotective lead compound that needs further investigation.

Keywords:  Alzheimer’s disease; GSK3β; Tau; azaindolin-2-one; neurofibrillary tangles; neuroprotective; protein aggregation

DOI:  https://doi.org/10.3390/ph15040426
Bioresour Technol. 2022 Apr 16. pii: S0960-8524(22)00506-5. [Epub ahead of print] 127177

Nitrogen removal pathways during simultaneous nitrification, denitrification, and phosphorus removal under low temperature and dissolved oxygen conditions.

Xuanye Bai, Michelle M McKnight, Josh D Neufeld, Wayne J Parker.

  Nitrogen removal pathways of simultaneous nitrification, denitrification, and phosphorus removal (SNDPR) at low dissolved oxygen (0.3 mg/L) and temperature (10℃) were explored to understand nitrogen removal mechanisms. Biological nitrogen and phosphorus removal was sustained with total inorganic nitrogen removal, phosphorus removal, and simultaneous nitrification and denitrification (SND) efficiencies of 62.6%, 97.3%, and 31.2%, respectively. The SND was observed in the first 2 h of the aerobic phase and was attributed to denitrifying ordinary heterotrophic organisms using readily biodegradable chemical oxygen demand and denitrifying phosphorus accumulating organisms (DPAOs), which removed 15.1% and 12.2% of influent nitrogen, respectively. A phosphorus accumulating organism (PAO)-rich community was indicated by stoichiometric ratios and supported by 16S rRNA gene analysis, with Dechloromonas, Zoogloea, and Paracoccus as DPAOs, and Ca. Accumulibacter and Tetrasphaera as PAOs. Even though Ca. Competibacter (10.4%) was detected, limited denitrifying glycogen accumulating organism denitrification was observed.

Keywords:  16S rRNA gene analysis; Functional annotation of prokaryotic taxa; Glycogen accumulating organism; Nutrient removal; Phosphorus accumulating organism

DOI:  https://doi.org/10.1016/j.biortech.2022.127177