Current research in physiology最新文献

Synaptic vesicles specific to inhibitory GABA-releasing neurons are critical for regulating neuronal excitability. To study the specific molecular composition, architecture, and function of inhibitory synaptic vesicles, we have developed a new method to isolate and purify GABA synaptic vesicles from mouse brains. GABA synaptic vesicles were immunoisolated from mouse brain tissue using an engineered fragment antigen-binding region (Fab) against the vesicular GABA transporter (vGAT) and purified. Western blot analysis confirmed that the GABA synaptic vesicles were specifically enriched for vGAT and largely depleted of contaminants from other synaptic vesicle types, such as vesicular glutamate transporter (vGLUT1), and other cellular organelles. This degree of purity was achieved despite the relatively low abundance of vGAT vesicles compared to the total synaptic vesicle pool in mammalian brains. Cryo-electron microscopy images of these isolated GABA synaptic vesicles revealed intact morphology with circular shape and protruding proteinaceous densities. The GABA synaptic vesicles are functional, as assessed by a hybrid (ex vivo/in vitro) vesicle fusion assay, and they undergo synchronized fusion with synthetic plasma membrane mimic vesicles in response to Ca²⁺-triggering, but, as a negative control, not to Mg²⁺-triggering. Our immunoisolation method could also be applied to other types of vesicles.

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Human monoamine transporters (MATs) are critical to regulating monoaminergic neurotransmission by translocating their substrates from the synaptic space back into the presynaptic neurons. As such, their primary substrate binding site S1 has been targeted by a wide range of compounds for treating neuropsychiatric and neurodegenerative disorders including depression, ADHD, neuropathic pain, and anxiety disorders. We present here a comparative study of the structural dynamics and ligand-binding properties of two MATs, dopamine transporter (DAT) and serotonin transporter (SERT), with focus on the allosteric modulation of their transport function by drugs or substrates that consistently bind a secondary site S2, proposed to serve as an allosteric site. Our systematic analysis of the conformational space and dynamics of a dataset of 50 structures resolved for DAT and SERT in the presence of one or more ligands/drugs reveals the specific residues playing a consistent role in coordinating the small molecules bound to subsites S2–I and S2-II within S2, such as R476 and Y481 in dDAT and E494, P561, and F556 in hSERT. Further analysis reveals how DAT and SERT differ in their two principal modes of structural changes, PC1 and PC2. Notably, PC1 underlies the transition between outward- and inward-facing states of the transporters as well as their gating; whereas PC2 supports the rearrangements of TM helices near the S2 site. Finally, the examination of cross-correlations between structural elements lining the respective sites S1 and S2 point to the crucial role of coupled motions between TM6a and TM10. In particular, we note the involvement of hSERT residues F335 and G338, and E493-E494-T497 belonging to these two respective helices, in establishing the allosteric communication between S1 and S2. These results help understand the molecular basis of the action of drugs that bind to the S2 site of DAT or SERT. They also provide a basis for designing allosteric modulators that may provide better control of specific interactions and cellular pathways, rather than indiscriminately inhibiting the transporter by targeting its orthosteric site.

This paper describes how lentils (Lens culinaris species) can positively affect health by reducing inflammation, providing antioxidants, and displaying antimicrobial properties. Lentils are rich in proteins, essential amino acids, minerals, and fibers, making them a valuable source of nutrition, particularly in low and middle-income countries. Lentils have many health benefits, including positive effects on diabetes management, support for cardiovascular health, and antioxidative properties. The antioxidative properties of lentils, attributed to their phenolic content, and their ability to inhibit inflammation-related enzymes are also discussed. We discuss the potential of lentils as a dietary tool in promoting immunity, reducing disease burdens, and preventing nutritional deficiencies. Overall, lentils are a highly nutritious food with various health benefits, including anti-inflammatory and antimicrobial effects. The fiber and protein content in lentils make them beneficial for weight management, blood sugar regulation, and supporting overall gut health. Furthermore, the slow rate at which lentils affect blood sugar levels, due to their low glycemic index, can be advantageous for individuals with diabetes.

Cosmos caudatus leaves are one of around 7500 types of plants that are known to have herbal or medicinal plant properties in Indonesia. This research determines the effectiveness of Cosmos caudatus as an antioxidant agent against cells, biomolecules, and bone density. Forty-three male rat aged 3–4 months were divided into four groups.Group P0 was only given distilled water. Group P1 was given kenikir leaf extract at a dose of 0.91 mg/kg. Group P2 was given kenikir leaf extract at a dose of 1.82 mg/kg. And group P3 was given kenikir leaf extract at 3.64 mg/kg ad libitum once a day for 28 days. The highest average SOD level was in the 1.82 mg/bb P2 conversion dose group (1.09 ± 1.76). The lowest mean CTX level was in the P2 group (8.30 ± 1.10). There was a significant increase in mean trabecular bone in the P2 group (43.33 ± 5.32). The number of osteoblast cells increased significantly at P2 (103.94 (SD 38.14)). The number of osteoclasts decreased from the control group (P0) to 0.60 (SD 0.43) at P2. Indicate that the Cosmos caudatus extract may have advantages as an antioxidant support agent for bone metabolism.

Serotonin (5-hydroxytryptamine, 5-HT) signaling plays an important role in dynamic control of peripheral and central nervous system physiology, with altered 5-HT homeostasis implicated in a significant number of disorders, ranging from pulmonary, bowel, and metabolic disease to depression, obsessive-compulsive disorder, and autism spectrum disorder (ASD). The presynaptic, 5-HT transporter (SERT) has a well-established role in regulating 5-HT signaling and is a target of widely prescribed psychotherapeutics, the 5-HT selective reuptake inhibitors (SSRIs). Although SSRI therapy provides symptom relief for many suffering from mood and anxiety disorders, response to these medications is slow (weeks), and too many receive modest or no benefit. At present, all prescribed SSRIs act as competitive SERT antagonists. Although non-serotonergic therapeutics for mood disorders deserve aggressive investigation, the development of agents that target SERT regulatory pathways have yet to be considered for their possible utility and may possibly offer improved efficacy and more rapid onset. Here, we focus attention on a significant body of evidence that SERT transport activity can be rapidly elevated by protein kinase G (PKG) and p38α mitogen activated protein kinase (MAPK) linked pathways, mechanisms that are impacted by disease-associated genetic variation. Here, we provide a brief overview of kinase-linked, posttranslational regulation of SERT, with a particular focus on evidence from pharmacological and genetic studies that the transporter's regulation by PKG/p38α MAPK associated pathways offers an opportunity to more subtly adjust, rather than eliminate, SERT function as a therapeutic strategy.

Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such as diabetes mellitus, hypertension, and glomerulonephritis. Affecting over 10% of the global population, CKD stands as a significant cause of morbidity and mortality. Despite substantial advances in understanding CKD pathophysiology and management, there is still a need to explore novel mechanisms and potential therapeutic targets. Urotensin II (UII), a potent vasoactive peptide, has garnered attention for its possible role in the development and progression of CKD. The UII system consists of endogenous ligands UII and UII-related peptide (URP) and their receptor, UT. URP pathophysiology is understudied, but alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been linked to cardiovascular and kidney dysfunctions, including systemic hypertension, chronic heart failure, glomerulonephritis, and diabetes. UII gene polymorphisms are associated with increased risk of diabetes. Pharmacological inhibition or genetic ablation of UT mitigated kidney and cardiovascular disease in rodents, making the UII system a potential target for slowing CKD progression. However, a deeper understanding of the UII system's cellular mechanisms in renal and extrarenal organs is essential for comprehending its role in CKD pathophysiology. This review explores the evolving connections between the UII system and CKD, addressing potential mechanisms, therapeutic implications, controversies, and unexplored concepts.

The autonomic nervous system (ANS) regulates involuntary bodily functions such as blood pressure, heart rate, breathing, and digestion, in addition to controlling motivation and behavior. In older adults, the ANS is dysregulated, which changes the ability of the ANS to respond to physiological signals, regulate cardiovascular autonomic functionality, diminish gastric motility, and exacerbate sleep problems. For example, a decrease in heart rate variability, or the variation in the interval between heartbeats, is one of the most well-known alterations in the ANS associated with health issues, including cardiovascular diseases and cognitive decline. The inability to perform fundamental activities of daily living and compromising the physiological reactivity or motivational responses of older adults to moving toward or away from specific environmental stimuli are significant negative consequences of chronic and geriatric conditions that pose grave threats to autonomy, health, and well-being. The most updated research has investigated the associations between the action responsiveness of older adults and the maintenance of their physiological and physical health or the development of mental and physical health problems. Once autonomic dysfunction may significantly influence the development of different age-related diseases, including ischemic stroke, cardiovascular disease, and autoimmune diseases, this review aimed to assess the relationship between aging and autonomic functions. The review explored how motivational responses, physiological reactivity, cognitive processes, and lifelong developmental changes associated with aging impact the ANS and contribute to the emergence of health problems.