Physiological research最新文献

Orthostatic intolerance (OI) is defined as the development of characteristic symptoms while standing, which significantly improve by recumbency. The most common forms are vasovagal syncope (VVS), orthostatic hypotension, and postural orthostatic tachycardia syndrome (POTS). Lately, there has been a growing body of evidence that autoimmunity may play a role in the pathophysiology of orthostatic intolerance syndromes. The aim was to compare the presence and levels of autoimmune autoantibodies in patients with POTS, VVS syncope, and the control group. Altogether, 61 patients with symptoms of orthostatic intolerance were evaluated in this study - 19 POTS patients and 42 VVS patients. The control group contained 22 patients with no signs of orthostatic intolerance. We evaluated levels of autoantibodies against three subtypes of G-protein coupled adrenergic receptor (alpha-1 and beta-1,2 adrenergic receptors), type 4 of muscarinic acetylcholine receptor, and angiotensin II type 1 receptor. We compared the levels between the three patient groups. Significantly higher levels of angiotensin II type 1 receptor (AT1R) autoantibodies were found in the POTS group compared with controls (0.67± 0.35 ng/ml vs. 0.38±0.32 ng/ml, p=0.008). There was no significant difference in AT1R antibodies between the VVS and control groups (0.46±0.34 ng/ml vs 0.38±0.32 ng/ml, p= 0.38). Autoantibody concentration against ADRA1, ADRB1, ADRB2, and M4R were not significantly different between the groups. Autoimmune mechanisms may lead to abnormal regulation of the renin-angiotensin-aldosterone system and may contribute to the pathophysiology of POTS.

Subarachnoid hemorrhage (SAH) is a critical neurological emergency and one of the leading causes of stroke. Neuronal demise serves as the primary factor contributing to early brain injury (EBI) following SAH. This study aims to investigate the molecular mechanism underlying Hirudin's impact on EBI after SAH, with a particular focus on pyroptosis. The SAH rat model was established by performing intravascular puncture, followed by the administration of Hirudin and Nod-like receptor protein 3 (NLRP3) agonist Nigericin into the lateral ventricle. The SAH grading, neurological score, brain water content, blood-brain barrier (BBB) permeability, neuronal damage, inflammatory reaction, neuronal death, distribution of microglia marker Iba-1 and expression levels of NLRP3 inflammasomal-related proteins were evaluated at 72 h post-SAH. Hirudin treatment significantly ameliorated neurological scores and attenuated brain edema, BBB permeability, inflammatory response, microglia activation, and pyroptosis in SAH rats. Additionally, Hirudin treatment downregulated the expression levels of NLRP3 inflammasomal- related proteins, such as NLRP3, apoptosis- associated speck-like protein (ASC) and cleaved caspsase-1. However, Nigericin partially counteracted the aforementioned effects of Hirudin, indicating that Hirudin exerted its inhibitory effect on pyroptosis by modulating the NLRP3 inflammasome pathway. The neuroprotective effect of Hirudin on EBI following SAH is attributed its ability to inhibit pyroptosis mediated by NLRP3 inflammasome, suggesting its potential as a promising therapeutic approach for SAH. Keywords: Subarachnoid hemorrhage, Early brain injury, Hirudin, pyroptosis, Nod-like receptor protein 3 (NLRP3) inflammasome.

Fanconi anemia (FA) and ferroptosis both affect tumor-related processes. However, few studies have reported on genetic associations between FA and ferroptosis. Our study evaluated the usefulness of genes related to ferroptosis in predicting and diagnosing FA. Transcriptome sequencing data were collected from 11 normal participants and 21 patients with FA. Differential gene analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) analysis, gene correlation analysis, protein-protein interaction network analysis, qRT-PCR, and pan-cancer analysis were performed. The pan-cancer analysis was carried out based on data obtained from the GTEx and TCGA databases. Two hundred ninety-eight differentially expressed genes were detected based on the comparison of FA patients and normal participants, among which four critical non-FA genes, MAD2L1, ASPM, PCNA, and TOP2A, were identified. Among the ferroptosis-related genes, five genes, including CDKN1A, EMC2, FDFT1, HSPB1, and MT1G, were identified as being associated with FA, and the areas under the curve (AUC) of these five ferroptosis-related genes were 0.907, 0.640, 0.902, 0.840, and 0.929, respectively. The AUC for the diagnosis of FA reached 1.000 when the five ferroptosis-related genes were used in combination. In addition, the expressions of CDKN1A, EMC2, FDFT1, and HSPB1 were associated with the prognosis of multiple cancers (P<0.05). The five ferroptosis-related genes CDKN1A, EMC2, FDFT1, HSPB1, and MT1G exhibited excellent predictive effects for the diagnosis of FA.

Transmembrane Protein 138 (TMEM138) is a transmembrane protein belonging to the superfamily of transmembrane proteins. Recent research has unveiled its involvement in various biological processes such as cell proliferation, differentiation, and apoptosis. Furthermore, abnormal expression of TMEM138 has been linked to a range of diseases, particularly neurodege-nerative diseases and tumors. This review provides an overview of TMEM138, focusing on its molecular characteristics, biological functions, and potential roles in disease pathogenesis. The aim is to offer a valuable reference for future research and clinical applications.

Oligodendrocytes are vital for the functioning of the nervous system. Oligodendrocyte-created myelin sheaths work as dynamic partners which play a substantial role in the myelination of axons. In addition to its well-known functions of providing insulation and enhancing conduction velocity, myelination controls axons' maturity, longevity, and regenerative ability via trophic support and signalling molecules. Myelination also regulates ion concentration and offers neuroprotection. Myelin is generated via complex procedures including cell differentiation, specialised lipids, and protein synthesis. Understanding the physiology of myelin sheath formation is required to understand various neurological disorders associated with myelin sheath damage. This review focuses on our growing understanding of the intricate actions and changes in oligodendrocytes during the course of evolution and in Alzheimer's disease.

Bruton's tyrosine kinase (BTK) is a crucial part of the B-cell receptor signaling pathway that has been extensively studied in various types of malignancies. Recent studies have extended our knowledge on its role in metabolism as well as neurological disorders. It may play an important role in the pathophysiology of neurological diseases, such as multiple sclerosis, Alzheimer's disease, brain injury, and several others. Activation of inflammasomes, mainly NLRP3, is one of the core mechanisms by which it promotes inflammation in the brain related to aging and diseases. In this paper, we provide an overview of the less explored roles of BTK in several brain diseases and discuss the potential of its inhibition to become a therapeutic target for neurological diseases.

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of cirrhosis and liver cancer. Its global prevalence increases annually, significantly affecting quality of life. Only a few patients manage to alleviate NAFLD through lifestyle modifications. The pathogenic mechanisms and therapeutic targets of this disease remain inadequately explored. In recent years, many studies highlighted a close relationship between the thyroid-stimulating hormone (TSH) and NAFLD. TSH has been shown to promote fat accumulation in the liver by participating in the ab initio synthesis, uptake and secretion of lipids. Moreover, TSH exacerbates hepatocyte inflammation and fibrosis by inducing endoplasmic reticulum stress and promoting the release of inflammatory factors. Although some of the conclusions remain controversial and are subject to debate, exploring the connection and possible pathways between TSH and NAFLD is crucial. Such research could advance early clinical prevention and intervention strategies, thereby reducing the incidence of severe NAFLD-associated comorbidities. Therefore, this review aims to summarize currently available evidence on the association between TSH and NAFLD focusing on the following objectives: elucidating the relationship between TSH and NAFLD; TSH may be a potential target for NAFLD prevention; exploring potential molecular targets that could block TSH-mediated promotion of NAFLD.

Berberine (BBR), a small molecule protoberberine isoquinoline alkaloid, is easy to cross the blood-brain barrier and is a potential drug for neurodegenerative diseases. Here, we explored the role and molecular mechanism of BBR in Alzheimer's disease (AD) progression. Weighted gene co-expression network analysis (WGCNA) was conducted to determine AD pathology-associated gene modules and differentially expressed genes (DEGs) were also identified. GO and KEGG analyses were performed for gene function and signaling pathway annotation. Cell counting kit-8 (CCK8) assay was applied to analyze cell viability. Immunofluorescence (IF) staining assay was conducted to measure the levels of polarization markers. The production of inflammatory cytokines was analyzed by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) were detected using a ROS detection kit and a MMP Detection Kit (JC-1), respectively. AD pathology-associated DEGs were applied for GO function annotation and KEGG enrichment analysis, and the results uncovered that AD pathology was related to immune and inflammation. Lipopolysaccharide (LPS) exposure induced the M1 phenotype of microglia, and BBR suppressed LPS-induced M1 polarization and induced microglia toward M2 polarization. Through co-culture of microglia and neuronal cells, we found that BBR exerted a neuro-protective role by attenuating the injury of LPS-induced HMC3 on SH-SY5Y cells. Mechanically, BBR switched the M1/M2 phenotypes of microglia by activating PI3K-AKT signaling. In summary, BBR protected neuronal cells from activated microglia-mediated neuro-inflammation by switching the M1/M2 polarization in LPS-induced microglia via activating PI3K-AKT signaling. Key words Alzheimer's Disease, Berberine, Microglia polarization, Neuroinflammation, PI3K-AKT signaling.

To explore the effects and underlying mechanisms of Mdivi-1 on three common clinical models of acute kidney injury (AKI). Three common AKI cell models were constructed, classified into the control group (human renal tubular epithelial cells [HK-2] cells), the Iohexol group (HK-2 cells treated with Iohexol), the Genta group (HK-2 cells treated with Gentamicin), and the Cis group (HK-2 cells treated with Cisplatin). To explore the optimal protective concentration of Mdivi-1 for each AKI cell model, the experimental design consisted of the following seven groups: the control group (HK-2 cells cultured in medium), three injury groups (HK-2 cells subjected to Iohexol, Gentamicin, or Cisplatin), and the corresponding protection groups (with a certain concentration of Mdivi-1 added to each injury group). Cellular survival and apoptosis, reactive oxygen species (ROS) levels, and the expression of recombinant Sirtuin 3 (SIRT3) in each group were measured. Mitochondrial fission and fusion dynamics in cells were observed under an electron microscope. To explore relevant pathways, the changes in relevant pathway proteins were analyzed through Western blotting. The half maximal inhibitory concentration (IC50) values were 150.06 mgI/ml at 6 h in the Iohexol group, 37.88 mg/ml at 24 h in the Gentamicin group, and 13.48 microM at 24 h in the Cisplatin group. Compared with the control group, the three injury groups showed increased cell apoptosis rates and higher expressions of apoptotic proteins in HK-2 cells, with an accompanying decrease in cell migration. After the addition of corresponding concentrations of Mdivi-1, the optimal concentrations were 3 µM in the Iohexo-3 group, 1 microM in the Genta-1 group, and 5 µM in the Cis-5 group, HK-2 cells showed the highest survival rate, reduced apoptosis, decreased mitochondrial ROS and SIRT3 expression, and reduced mitochondrial fission and autophagy when compared with each injury group. Further verification with Western blot analysis after the addition of Mdivi-1 revealed a reduction in the expressions of mitochondrial fission proteins DRP1, Nrf2, SIRT3, Caspase-3, Jun N-terminal Kinase (JNK)/P-JNK, NF-kappaB, Bcl2, and autophagic protein P62, as well as reduced ROS levels. Mdivi-1 had protective effects on the three common AKI cell models by potentially reducing mitochondrial fission in cells and inhibiting the production of ROS through the mediation of the NF- B/JNK/SIRT3 signaling pathway, thereby exerting protective effects. Key words AKI, Cisplatin, Gentamicin, Iohexol, Mdivi-1.

To investigate the impact of hyperbaric oxygen therapy (HBOT) on the cognitive function of mice with Alzheimer's disease (AD), while also identifying the cellular pathways associated with autophagy involved in the treatment. Twenty-four APP/PSl double transgenic mice were randomly assigned to either Group A or Group B, while another 24 C57 mice were randomly allocated to Group C or Group D. HBOT was administered to mice in Group B and Group D, and the Morris water maze test was used to assess changes in mice behavior. Histological examination using hematoxylin and eosin staining was conducted to observe pathological alterations in the hippocampus of the mice brain tissue. Polymerase chain reaction (PCR) was employed to analyze autophagy-related gene pathways in the hippocampus of the mice. Following HBOT, mice in Group B exhibited a significant reduction in escape latency and a notable increase in residence time within the target quadrant compared with Group A (P<0.05), as well as Group C and Group D (P<0.01). The hippocampal neurons in Group A and Group B mice exhibited disorganized arrangements, characterized by pyknosis and margination. Conversely, neurons in Group C displayed orderly arrangements, retaining intact structures with round nuclei demonstrating clear nuclear staining and normal morphology. The cellular morphology of mice in Group D remained unaffected. PCR analysis revealed no notable disparity in autophagy-related gene expression between Group A and Group C. However, the expression levels of five genes including Tgfb1, Mapk14, Bid, Atg7, and Akt1, were significantly elevated in Group B compared to Group A. HBOT has the potential to improve the cognitive function in mice modeled with AD. This improvement of cognitive function appears to be mediated by the up-regulation of autophagy-related genes, specifically Tgfb1, Mapk14, Bid, Atg7, and Akt1. These results indicate that HBOT may offer a therapeutic strategy for treating AD by enhancing autophagy mechanisms. Key words Alzheimer's disease, Autophagy, Hyperbaric oxygen, Morris water maze, PCR.