Glucose metabolism is a mechanism by which energy is produced in form of adenosine triphosphate (ATP) by mitochondria and precursor metabolites are supplied to enable the ultimate enrichment of ...mature metabolites in the cell. Recently, glycolytic enzymes have been shown to have unconventional but important functions. Among these enzymes, pyruvate kinase M2 (PKM2) plays several roles including having conventional metabolic enzyme activity, and also being a transcriptional regulator and a protein kinase. Compared with the closely related PKM1, PKM2 is highly expressed in cancer cells and embryos, whereas PKM1 is dominant in mature, differentiated cells. Posttranslational modifications such as phosphorylation and acetylation of PKM2 change its cellular functions. In particular, PKM2 can translocate to the nucleus, where it regulates the transcription of many target genes. It is notable that PKM2 also acts as a protein kinase to phosphorylate several substrate proteins. Besides cancer cells and embryonic cells, astrocytes also highly express PKM2, which is crucial for lactate production via expression of lactate dehydrogenase A (LDHA), while mature neurons predominantly express PKM1. The lactate produced in cancer cells promotes tumor progress and that in astrocytes can be supplied to neurons and may act as a major source for neuronal ATP energy production. Thereby, we propose that PKM2 along with its different posttranslational modifications has specific purposes for a variety of cell types, performing unique functions.
Pyruvate kinase M2 (PKM2) is crucial for cell proliferation in embryonic and cancer cells. PKM2 has a novel function as protein kinase and transcription factor. In nucleus, PKM2 has a variety of binding proteins to regulate the expression of specific genes.
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons located in the substantia nigra pars compacta and the presence of proteinaceous inclusions called Lewy bodies and Lewy ...neurites in numerous brain regions. Increasing evidence indicates that Lewy pathology progressively involves additional regions of the nervous system as the disease advances, and the prion‐like propagation of α‐synuclein (α‐syn) pathology promotes PD progression. Accordingly, the modulation of α‐syn transmission may be important for the development of disease‐modifying therapies in patients with PD. Here, we demonstrate that α‐syn fibrils induce c‐src activation in neurons, which depends on the FcγRIIb‐SHP‐1/‐2‐c‐src pathway and enhances signals for the uptake of α‐syn into neurons. Blockade of c‐src activation inhibits the uptake of α‐syn and the formation of Lewy body‐like inclusions. Furthermore, the blockade of c‐src activation also inhibits the release of α‐syn via activation of autophagy. The brain‐permeable c‐src inhibitor, saracatinib, efficiently reduces α‐syn propagation into neighboring regions in an in vivo model system. These results suggest a new therapeutic target against progressive PD.
Synopsis
This study reveals that c‐src promotes the release and uptake of α‐syn and that c‐src inhibition attenuates α‐syn cell‐to‐cell transmission, suggesting that c‐src‐targeting drugs might be repurposed for the development of Parkinson's therapeutics.
Inhibition of c‐src activation inhibits the uptake of α‐syn and LB‐like inclusion body formations.
Abrogation of c‐src activation inhibits the release of α‐syn via activation of autophagy.
A brain permeable c‐src inhibitor, saracatinib, efficiently ameliorates α‐syn propagation in an in vivo model system.
This study reveals that c‐src promotes the release and uptake of α‐syn and that c‐src inhibition attenuates α‐syn cell‐to‐cell transmission, suggesting that c‐src‐targeting drugs might be repurposed for the development of Parkinson's therapeutics.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, with aging being considered the greatest risk factor for developing PD. Caveolin-1 (Cav-1) is known to participate in ...the aging process. Recent evidence indicates that prion-like propagation of misfolded α-synuclein (α-syn) released from neurons to neighboring neurons plays an important role in PD progression. In the present study, we demonstrated that cav-1 expression in the brain increased with age, and considerably increased in the brain of A53T α-syn transgenic mice. Cav-1 overexpression facilitated the uptake of α-syn into neurons and formation of additional Lewy body-like inclusion bodies, phosphorylation of cav-1 at tyrosine 14 was found to be crucial for this process. This study demonstrates the relationship between age and α-syn spread and will facilitate our understanding of the molecular mechanism of the cell-to-cell transmission of α-syn.
This study examined the microstructure and friction/wear behavior of (TiB+TiC) particulate-reinforced titanium matrix composites (TMCs) fabricated by in situ synthesis. Boron carbide (B4C) particles ...with 1500μm (1500 μmB4C) or 150μm (150μm B4C) diameter were added to a titanium matrix during vacuum induction melting to provide in situ synthesized (TiB+TiC) particulate reinforcement. The reinforcements prepared with 150μm B4C were finer than those prepared with 1500μm B4C. The size of the reinforcement particles affected their tendency to fragment under the applied load and thus produce more wear of the TMCs. Therefore, the friction and wear behavior of the TMCs is discussed on the basis of the coefficient of friction, hardness, and reinforcement fragmentation during sliding wear. The fine TMC reinforcements prepared with 150μm B4C were more easily fragmented from the Ti matrix than the coarse reinforcements, and this debris further decreased the wear resistance. An adherent transfer layer on the worn surface was formed from hardened particles of oxide debris, reinforcements, and base material. Its presence produced two-body abrasion.
•B4C was added to Ti melts to produce reinforcements by the in situ reaction of 5Ti+B4C=4TiB+TiC.•in situ reinforcements are composed of needle-like TiB and spherical TiC particulates.•Shear stress was insufficient to deform the Ti and TMCs under an applied load in the elastic region.•Wear resistance of the TMCs was improved according to increased reinforcement size and content.•Fine reinforcements of TMCs were more easily fragmented from the Ti matrix than coarse reinforcements.
Background
Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors are a novel class of anti‐hyperglycaemic agents.
Objective
This study aimed to evaluate the safety and the adjuvant glycaemic control ...effect of an SGLT2 inhibitor, DWP16001, in diabetic dogs receiving insulin treatment.
Methods
Nineteen diabetic dogs receiving insulin treatment (NPH, porcine lente and glargine insulin) were divided into two groups according to dosing frequency: DWP TOD group (n = 10) and DWP SID group (n = 9). In the DWP TOD group, 0.025 mg/kg of DWP16001 was administered once every 3 days, whereas, in the DWP SID group, 0.025 mg/kg of DWP16001 was administered once a day. Food intake was maintained during the trial period. Hypoglycaemia, ketoacidosis or unexpected life‐threatening reactions were assessed as adverse effects before and after DWP16001 administration. We compared insulin requirement reduction and blood glucose level control between two groups.
Results
No specific adverse effects were observed during the clinical trial, and haematological parameter remained unchanged. Moreover, the fasting glucose levels and daily insulin dose in the DWP TOD group were lower than the pre‐administration values, but not significantly different for 8 weeks. Systolic blood pressure, fructosamine and insulin dose decreased significantly in the DWP SID group compared to the DWP TOD group at 8 weeks (p < 0.05) without affecting food consumption. Among these patients, 10 patients were monitored while receiving DWP16001 for 12 months (DWP TOD group n = 5, DWP SID group n = 5). The fasting glucose and fructosamine levels and daily insulin dose were reduced in both groups at 12 months compared with those before receiving DWP16001.
Conclusion
When DWP16001, an SGLT2 inhibitor, was supplied to dogs with type 1 diabetes, no adverse effects were observed, and it was confirmed that the administered insulin dose can be reduced in controlling blood glucose.
Administration of the SGLT2 inhibitor, DWP16001, can be an adjunctive method for managing diabetes in terms of glycaemic control without adverse effects in diabetic dogs receiving insulin therapy. This study will serve as the primary basis for the application of SGLT2 inhibitors in dogs with insulin‐dependent diabetes mellitus.
Recent evidence of prion-like propagation of α-synuclein (α-syn) into neighboring neurons set up a paradigm to elucidate the mechanism of progression of Parkinson’s disease (PD) and to develop ...therapeutic strategies. Here, we show that FcγRIIB expressed in neurons functions as a receptor for α-syn fibrils and mediates cell-to-cell transmission of α-syn. SHP-1 and 2 are activated downstream by α-syn fibrils through FcγRIIB and play an important role in cell-to-cell transmission of α-syn. Also, taking advantage of a co-culture system, we show that cell-to-cell transmission of α-syn induces intracellular Lewy body-like inclusion body formation and that the FcγRIIB/SHP-1/2 signaling pathway is involved in it. Therefore, the FcγRIIB-SHP-1/-2 signaling pathway may be a therapeutic target for the progression of PD. The in vitro system is an efficient tool for further high-throughput screening that can be used for developing a therapeutic intervention in PD.
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•α-Syn fibrils bind to FcγRIIB expressed in neurons•FcγRIIB mediates cell-to-cell transmission of α-syn as a receptor, transmitting signals to enhance it•SHP-1/2 activation by FcγRIIB is essential for cell-to-cell transmission of α-syn•Blocking this signaling pathway attenuates Lewy body-like inclusion body formation
Prion-like propagation of α-synuclein (α-syn) may contribute to the progression of Parkinson’s disease. Choi et al. demonstrate that FcγRIIB functions as a receptor for α-syn fibrils and that the FcγRIIB-SHP-1/2 signaling pathway mediates cell-to-cell transmission of α-syn. Blocking this signaling pathway attenuates transmission, suppressing Lewy body-like inclusion body formation.
Parkinson's disease (PD) is a complex neurodegenerative disorder with an unclear etiology. Despite significant research efforts, developing disease-modifying treatments for PD remains a major unmet ...medical need. Notably, drug repositioning is becoming an increasingly attractive direction in drug discovery, and computational approaches offer a relatively quick and resource-saving method for identifying testable hypotheses that promote drug repositioning. We used an artificial intelligence (AI)-based drug repositioning strategy to screen an extensive compound library and identify potential therapeutic agents for PD. Our AI-driven analysis revealed that efavirenz and nevirapine, approved for treating human immunodeficiency virus infection, had distinct profiles, suggesting their potential effects on PD pathophysiology. Among these, efavirenz attenuated α-synuclein (α-syn) propagation and associated neuroinflammation in the brain of preformed α-syn fibrils-injected A53T α-syn Tg mice and α-syn propagation and associated behavioral changes in the C. elegans BiFC model. Through in-depth molecular investigations, we found that efavirenz can modulate cholesterol metabolism and mitigate α-syn propagation, a key pathological feature implicated in PD progression by regulating CYP46A1. This study opens new avenues for further investigation into the mechanisms underlying PD pathology and the exploration of additional drug candidates using advanced computational methodologies.
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•Our AI analysis shows that efavirenz and nevirapine, used in HIV treatment, may impact PD pathophysiology.•In vivo and in vitro, efavirenz attenuates α-syn propagation, micro/astrogliosis, and inhibits α-syn release and uptake.•RNA-seq analysis shows efavirenz modulates cholesterol metabolism, mitigating α-syn propagation in PD via CYP46A1 regulation.
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