生理学报最新文献

The present study aims to investigate the effect of cathepsin K (CatK) on ischemic angiogenesis in high-fat diet fed mice. The mice were subjected to unilateral hindlimb ischemic surgery, and the ischemic blood flow was measured with a laser Doppler blood flow imager. Immunohistochemical staining was used to observe the quantity of new capillaries in the ischemic lower extremity, and Western blot was used to detect the expression of insulin receptor substrate-1 (IRS-1), p-Akt, Akt and vascular endothelial growth factor (VEGF). Firstly, the effect of high-fat diet on ischemic angiogenesis was observed in wild-type mice, which were randomly divided into control group and high-fat diet group and were fed with normal diet or 60% high-fat diet respectively for 16 weeks. The results showed the body weight and the plasma CatK concentration of the high-fat diet group was significantly increased compared with the control group (P < 0.05), and the blood flow recovery of the high-fat diet group was significantly lower than control group (P < 0.05). Then, wild-type and CatK knock out (CatK^-/-) mice were both fed with high-fat diet to further observe the effect and mechanism of CatK on ischemic angiogenesis under high-fat diet. The results showed that the blood flow recovery in the CatK^-/- group was significantly greater than the wild-type group, and the number of CD31 positive cells was significantly increased (P < 0.05). At the same time, the protein expression levels of IRS-1, p-Akt and VEGF in the ischemic skeletal muscle were significantly increased in the CatK^-/- group compared with the wild-type group (P < 0.05). These results suggest that the deficiency of CatK improves ischemic angiogenesis in high-fat diet fed mice through IRS-1-Akt-VEGF signaling pathway.

Trace amine-associated receptor 1 (TAAR1) is a classical type of G-protein-coupled receptor, which is widely distributed in the brain of mammals, especially in the limbic system and the region rich in monoaminergic neurons, and it is a highly conserved TAAR subtype in all species. TAAR1 can specifically respond to endogenous trace amines in the central nervous system and peripheral tissues, and plays an important role in the pathophysiological mechanisms involving the dysregulation of monoamine system and glutamate system leading to mental disorders. In addition, TAAR1 modulator can act on inwardly rectifying potassium channels and regulate synaptic transmission and neuronal activity. According to the latest research findings, TAAR1 exerts a series of functions by regulating signal pathways and substrate phosphorylation, which is related to emotion, cognition, fear and addiction. Therefore, we conducted a detailed review of relevant studies on the TAAR1 signaling pathways, aiming at revealing the great potential of TAAR1 as a new target for drug treatment of neuropsychiatric disorders.

The depolarization-activated current of intercalated cells in the distal nephron was detected for the first time, and the type of ion channel mediating the current was identified based on electrophysiological and pharmacological properties. The whole-cell current of distal nephron in kidney of C57BL/6J mice was recorded by Axon MultiClamp 700B patch-clamp system, and the effects of several K⁺ channel inhibitors on the depolarization-activated current in intercalated cells were observed. In addition, the immunofluorescence technique was used to investigate the localization of the channel in intercalated cells. The results showed that when K⁺ concentration of the bath solution was equal to intracellular fluid (140 mmol/L K⁺), the depolarization-activated current could be recorded in intercalated cells, but this current was not observed in the principal cells. The depolarization-activated current detected in the intercalated cells could be blocked by Kv4.1 inhibitors. The immunofluorescence experiment showed that the fluorescence of Kv4.1 protein was only present in intercalated cells and not observed in principal cells. Kv4.1 protein immunofluorescence was observed in the luminal and basolateral membrane of intercalated cells, but the fluorescence intensity of luminal membrane was higher than that of basolateral membrane. We conclude that the depolarization-activated current detected in intercalated cells is mediated by Kv4.1 and this channel is mainly expressed in the luminal membrane of intercalated cells.

Prostaglandin E₂ (PGE2) is an important lipid molecule derived from arachidonic acid, which regulates a variety of physiological and pathological activities. Based on the inhibition of inflammatory PGE₂ production, non-steroidal anti-inflammatory drugs (NSAIDs) are considered as the most commonly used drugs to treat inflammatory diseases and to relieve fever and pain symptoms. PGE₂ mediates its functions via four different G protein-coupled receptors, named EP1-EP4. Though the limited distribution and low PGE₂ affinity of EP1, it plays important roles in the maintenance of many physiological functions and homeostasis. Moreover, EP1 is widely involved in the inflammatory response, pain perception and multisystem pathological function regulation. In this review, we will briefly summarize the recent advances on the physiological and pathophysiological function of EP1 and its targeted drugs development.

Spinocerebellar ataxias (SCAs) are a group of autosomal dominant neurodegenerative diseases that have been currently identified with numerous subtypes exhibiting genetic heterogeneity and clinical variability. Purkinje neuronal degeneration and cerebellar atrophy are common pathological features among most SCA subtypes. The physiological functions of Purkinje cells are regulated by multiple factors, and their dysfunction in signal transduction may lead to abnormal cerebellar motor control. This review summarizes the abnormalities in voltage-gated ionic channels, intracellular calcium signaling, and glutamate signaling transduction of Purkinje cells in SCAs, aiming to provide a theoretical basis for further understanding the common pathogenesis of SCAs and developing specific treatments.

Mitochondria are dynamically changing organelles that maintain stable mitochondrial morphology, number, and function through constant fusion and division, a process known as mitochondrial dynamics, which is an important mechanism for mitochondrial quality control. Excessive fusion and division of mitochondria can lead to a homeostatic imbalance in mitochondrial dynamics, causing mitochondrial dysfunction, leading to cellular damage, and even death. The physiological functions of the kidney are mainly powered by mitochondria, and homeostatic imbalance in mitochondrial dynamics affects mitochondrial function and is closely related to renal diseases such as acute kidney injury and diabetic nephropathy. This article reviews the regulation of mitochondrial kinetics, how imbalances in mitochondrial kinetic homeostasis affect mitochondrial injury, and the impact of mitochondrial injury on renal pathophysiology, in order to improve understanding and knowledge of the role of mitochondria in renal disease.

Mitophagy is a process that selectively removes excess or damaged mitochondria and plays an important role in regulating intracellular mitochondrial mass and maintaining mitochondrial energy metabolism. TANK-binding kinase 1 (TBK1) is a multifunctional serine/threonine protein kinase, which is involved in the regulation of PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent and -independent mitophagy. Recent studies have shown that TBK1 phosphorylates the autophagy related proteins, such as optineurin (OPTN), p62/sequestosome-1, Ras-related GTP binding protein 7 (Rab7), and mediates the binding of nuclear dot protein 52 (NDP52) to UNC-51 like autophagy activating kinase 1 (ULK1) complex, as well as the binding of TAX1-binding protein 1 (TAX1BP1) to microtubule-associated protein 1 light chain 3 (LC3), thereby enhancing PINK1/Parkin-dependent mitophagy. In addition, TBK1 is a direct substrate of AMP-activated protein kinase (AMPK)/ULK1 pathway, and its activation phosphorylates dynamin-related protein 1 (Drp1) and Rab7 to promote PINK1/Parkin-independent mitophagy. This article reviews the role and mechanism of TBK1 in regulating PINK1/Parkin-dependent and -independent mitophagy.

Cardiovascular complications are the leading cause of death in diabetic patients. Among them, diabetic cardiomyopathy (DCM) is a type of specific cardiomyopathy excluding myocardial damage caused by hypertension and coronary heart disease. It is characterized by abnormal metabolism of cardiomyocytes and gradual decline of cardiac function. The clinical manifestations of DCM are impaired diastolic function in early stage and impaired systolic function in late stage. Eventually it developed into heart failure. Mitochondria are the main organelles that provide energy in cardiomyocytes. Mitochondrial dynamics refers to the dynamic process of mitochondrial fusion and fission, which is an important approach for mitochondrial quality control. Mitochondrial dynamics plays a crucial role in maintaining mitochondrial homeostasis and cardiac function. The proteins that regulate mitochondrial fission are mainly Drp1 and its receptors, Fis1, MFF, MiD49 and MiD51. The protein that performs mitochondrial outer membrane fusion is Mfn1/2, and the inner membrane fusion protein is Opa1. This paper reviews recent progress on mitochondrial dynamics in DCM. The main contents are as follows: mitochondrial dynamics imbalance in both type 1 and 2 DCM is manifested as increased fission and inhibited fusion. The molecular mechanism of the former is mainly associated with up-regulated Drp1 and down-regulated Opa1, while the molecular mechanism of the latter is mainly associated with up-regulated Drp1 and down-regulated Mfn1/2. Increased mitochondrial fission and inhibited fusion can lead to mitochondrial dysfunction and promote the development of DCM. The active ingredients of the traditional Chinese medicine such as punicalagin, paeonol and endogenous substance melatonin can improve mitochondrial function and alleviate the symptoms of DCM by inhibiting mitochondrial fission or promoting mitochondrial fusion. This article is helpful to further understand the role and mechanism of mitochondrial dynamics in DCM, and provide new treatment methods and intervention strategies for clinical DCM patients based on mitochondrial dynamics.

The present study aimed to investigate the alterations in functional interaction between hippocampal CA1 and medial entorhinal cortex (MEC) after moderate traumatic brain injury (TBI) in C57BL/6J mice, and the possible beneficial effects of comprehensive exercise (CE). Following TBI, two microelectrodes were implanted into CA1 and MEC for extracellular recording. We found a clear synchronization of neuronal firing in CA1 and MEC, particularly within 100 Hz and peaked at 20-30 Hz range. TBI induced a significant reduction (P < 0.001) of the coherences of firing between 20-40 Hz frequency band. The mean power spectral densities (PSD) of all group mice in MEC were steadily larger than the values in CA1 in both 20-40 Hz and 56-100 Hz ranges. TBI induced significant and consistent increases of averaged 20-40 Hz or 56-100 Hz PSD (P < 0.001 or P < 0.01) in both CA1 and MEC. Injured mice displayed more varied firing patterns, and showed increased burst frequency (BF), burst duration (BD), inter-spike intervals (ISI) and inter-burst interval (IBI). Injured mice also showed worsened neurological function, sleep, gait performance, and working memory. CE facilitated the restoration of aforementioned electrophysiological characteristics and functional deficits in TBI mice. These results suggest that the beneficial effects of CE on TBI functional deficits may be partly attributed to improved neuronal network interaction between CA1 and MEC.

Perineuronal nets (PNNs) are specialized extracellular matrix (ECM) structures present in the central nervous system (CNS) and have been identified as significant regulators of developmental plasticity in the developing cortex. PNNs are particularly enriched in the cortex surrounding parvalbumin-expressing (PV⁺) cells. A growing body of evidence suggests that the abnormalities in PV⁺ neurons and PNNs are associated with various neurological disorders, including schizophrenia, which is a neurodevelopmental defect disease. The N-methyl-D-aspartate receptor (NMDAR) selective antagonist is frequently employed to establish animal models of schizophrenia in laboratory settings. The crucial involvement of GluN2B-containing NMDARs in the development of CNS has been extensively established. However, the role of GluN2B in the pathophysiology of schizophrenia has yet to be thoroughly investigated. The present study inhibited GluN2B function through intraperitoneal infusion of the GluN2B selective antagonist ifenprodil into juvenile mice aged 3-4 weeks, followed by the administration of social stress when these mice reached 9 weeks of age. Then, immunofluorescence staining was employed to examine the changes in the PNNs and PV⁺ cells, an acoustic startle and prepulse inhibition test was used to detect activities of the PV⁺ cells, and Western blot was used to quantify the protein expression levels of GluN2A and GluN2B in the prefrontal cortex (PFC). The study revealed that in the PFC of mice subjected to GluN2B antagonist treatment in early life and social stress in adulthood, there was an increase in the number of PV⁺ cells wrapped by PNNs, and a decrease in the activation of PV⁺ cells during the prepulse inhibition test, which is an indicator of sensory gating functions, as well as changes in the protein expression levels of GluN2A and GluN2B, which resulted in an increase in the ratio of GluN2A to GluN2B. These aberrations in the mice are comparable to those observed in animal models and patients with schizophrenia. The findings suggest that even a transient hypofunction of GluN2B in early life poses a significant risk for the emergence of schizophrenia symptoms in adulthood.