Relationship between fatigue caused by type 2 diabetes mellitus and 5-HT degradation in skeletal muscle / 药学学报

Fatigue is a common complication of type 2 diabetes mellitus (T2DM). We examined the relationship between T2DM fatigue and the skeletal muscle 5-hydroxytryptamine (5-HT) system. In animal experiments, a T2DM model was established in mice by feeding a high-fat diet with intraperitoneal injection of streptozotocin. The mice were treated with the 5-HT2A receptor antagonist sarpogrelate hydrochloride (SH) and the 5-HT synthesis inhibitor carbidopa (CDP) (separately and in combination). In cell culture experiments, C2C12 cells were stimulated with D-glucose, palmitic acid or 5-HT. 5-HT2AR, 5-HT synthesis and 5-HT degradation were inhibited by SH, CDP, or monoamine oxidase A (MAO-A) inhibitor. The animal experiments were in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University. The results showed that 5-HT2AR, 5-HT synthase and MAO-A were expressed in mouse skeletal muscle and C2C12 cells. The expression of these proteins was significantly up-regulated in T2DM mice or when C2C12 cells were exposed to palmitic acid and D-glucose; palmitic acid was a stronger stimulant of their expression than D-glucose. Rotating rod experiments and biochemical index tests have shown that T2DM fatigue is associated with an increase in skeletal muscle 5-HT2AR, 5-HT synthesis and 5-HT degradation. 5-HT2AR mediates the expression of MAO-A and the synthesis of 5-HT, which indirectly regulates the degradation of 5-HT. MAO-A regulates cell inflammation, mitochondrial ROS production and membrane potential depolarization by mediating 5-HT degradation. MAO-A also inhibits the expression of peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1), carnitine palmitoyltransferase-1 (CPT1) and ATP synthase-6 (ATP6), thus inhibiting mitochondrial functions such as fatty acid β oxidation and ATP synthesis. SH and CDP can effectively treat T2DM fatigue, and can also reduce blood glucose and blood lipid, and the combination of SH and CDP has a clear synergistic effect.

Aprendizagem através de role-playing games: uma abordagem para a educação ativa / Learning through role-playing games: an approach for active learning and teaching

This study evaluates the use of role-playing games (RPGs) as a methodological approach for teaching cellular biology, assessing student satisfaction, learning outcomes, and retention of acquired knowledge. First-year undergraduate medical students at two Brazilian public universities attended either an RPG-based class (RPG group) or a lecture (lecture-based group) on topics related to cellular biology. Pre- and post-RPG-based class questionnaires were compared to scores in regular exams and in an unannounced test one year later to assess students' attitudes and learning. From the 230 students that attended the RPG classes, 78.4% responded that the RPG-based classes were an effective tool for learning; 55.4% thought that such classes were better than lectures but did not replace them; and 81% responded that they would use this method. The lecture-based group achieved a higher grade in 1 of 14 regular exam questions. In the medium-term evaluation (one year later), the RPG group scored higher in 2 of 12 questions. RPG classes are thus quantitatively as effective as formal lectures, are well accepted by students, and may serve as educational tools, giving students the chance to learn actively and potentially retain the acquired knowledge more efficiently.

Avaliamos o uso dos role-plying games (RPGs) como uma metodologia de ensino e aprendizagem em Biologia Celular. Alunos do primeiro ano de Medicina participaram de aula expositiva tradicional (grupo referência) ou de aula com RPG (grupo RPG). Comparações foram feitas pela análise de questionários pré- e pós-aula com RPG, das notas nas provas regulares, e das notas obtidas em um teste aplicado um ano após a conclusão da disciplina. Dos 230 alunos que participaram das aulas com RPG, 78,4% responderam que o RPG é uma ferramenta eficaz na aprendizagem; 55,4% acharam que essas aulas são melhores que as aulas tradicionais, mas não as substituem; e 81% responderam que usariam essa metodologia. Os alunos do grupo referência tiveram nota maior em uma de 14 questões das provas regulares; os alunos do grupo RPG tiveram notas maiores em duas de 12 questões aplicadas um ano depois. Portanto, aulas com RPG foram tão eficientes quanto as aulas tradicionais (quantitativamente), são bem aceitas pelos estudantes, e podem ser uma metodologia que lhes dá a chance de aprender ativamente e, potencialmente, levar a uma melhor retenção do conhecimento aprendido.

New paradigm for ATP synthesis and consumption.

A central postulate of the chemiosmotic theory of ATP synthesis (Mitchell 1966) in mitochondria is the presence of a delocalized electrical potential of about 200 mV (Δφ) across the energy-transducing membrane between two bulk aqueous compartments. This Δφ forms the major component of the driving force for ATP synthesis, according to this theory. Experimental techniques to measure this electrical potential difference can be classified into two categories. The first method is to use ions that are permeant to the inner mitochondrial membrane or to introduce non-physiological substances that are charged and membrane-permeant. By achieving transmembrane diffusion of these ions or substances, Δφ can be calculated using the assumption of equilibrium and the Nernst equation (Mitchell 1966). The second method is to employ microelectrodes to penetrate the inner mitochondrial membrane and make direct measurements of the potential across it (Tedeschi 1980). Each method has its own protagonists. The long-standing paradox in bioenergetics is that while the former method produces results favouring the chemiosmotic theory, the latter method finds results, such as a zero Δφ, which cannot be reconciled with the chemiosmotic theory. A large amount of experimental and analytical research and scientific debate has taken place over several decades in an attempt to resolve the paradox. However, this has led to a polarization of scientific opinion, with each group claiming the correctness of their experimental technique. Even after such a large body of work, the paradox could not be resolved. Accordingly, all previous mechanisms, including the chemiosmotic theory, are also polarized and explain only data recorded from one set of experimental techniques. However, no one considered that both sets of experimental data could be correct and reflect some important aspect of the overall process of oxidative phosphorylation and could evolve a mechanism that could explain both poles. In view of these facts, the emergence of Nath’s torsional mechanism of energy transduction and ATP synthesis can be considered to be a milestone in the understanding of the process. The mechanism had its 10th anniversary recently (Nath 2010a, b). One key aspect of the mechanism is its ability to explain both the sets of experimental data on a rational basis. The following is a brief description of the mechanism in the membrane as per the understanding of this author. Consider a sequence of movement of ions through the energy-transducing membrane. Assuming that there are specific access channels for themovement of anions and protons, only one type of access channel is open at a given time (or both may be closed). Now, let us assume that an anion has moved through an open access channel through the membrane. This movement closes the open anion access channel and opens an adjacent proton access channel. The local electrical potential (Δψ) thus created is used or stored by themolecular motor. Then, the proton moves through its open access channel along its electrochemical gradient and a reciprocal process takes place. In each movement half the energy is transferred to the molecular motor. The process is akin to the principle of alternating current motors. The torque produced by the molecular motor is finally used in the synthesis of ATP. It should be noted that the time average charge in the transport cycle is zero. How can this mechanism explain the two poles of experimental data? In the first method, an external charged agent is introduced. This dissipates the Δψ created in the access channel during the first half-cycle and the same (that is the local potential created by the primary translocation) is measured. In the second method of measurement, the microelectrode measures an average potential after completion of a cycle, which is zero. The proposed torsional mechanism thus explains both experimental data sets without any ambiguity. Thus, the long-standing paradox of the contradictory but correct experimental results is resolved. This is an important achievement of the torsional mechanism (Nath 2010b).