Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Alzheimer’s disease (AD) is a chronic, progressive, and irreversible neurodegenerative disorder that typically begins with a subtle onset and progresses slowly. Pathologically, it is characterized by two hallmark features: the extracellular accumulation of amyloid β-protein (Aβ), forming senile plaques, and the intracellular hyperphosphorylation of tau protein, resulting in neurofibrillary tangles (NFTs). These pathological changes are accompanied by substantial neuronal and synaptic loss, particularly in critical brain regions such as the cerebral cortex and hippocampus. Clinically, AD presents as a gradual decline in memory, language abilities, and spatial orientation, significantly impairing the quality of life of affected individuals. With the aging population steadily increasing in China, the incidence of AD is rising, making it a major public health concern that requires urgent attention. The growing societal and economic burden of AD underscores the pressing need to identify effective diagnostic biomarkers and develop novel therapeutic strategies. Among the various molecular signaling pathways involved in neurological disorders, the Notch signaling pathway is especially noteworthy due to its evolutionary conservation and regulatory roles in cell proliferation, differentiation, development, and apoptosis. In the central nervous system, Notch signaling is essential for neurodevelopment and synaptic plasticity and has been implicated in several neurodegenerative processes. Although some studies suggest that Notch signaling may influence AD-related pathology, its precise role in AD remains poorly understood. In particular, the interaction between Notch signaling and non-coding RNAs (ncRNAs)—key regulators of gene expression—has received limited attention. NcRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are known to exert extensive regulatory functions at both transcriptional and post-transcriptional levels. Dysregulation of these molecules has been widely associated with various diseases, including cancers, cardiovascular conditions, and neurodegenerative disorders. Notably, interactions between ncRNAs and major signaling pathways such as Notch can produce widespread biological effects. While such interactions have been increasingly reported in several disease models, comprehensive studies investigating the regulatory relationship between Notch signaling and ncRNAs in the context of AD remain scarce. Given the capacity of ncRNAs to modulate signaling cascades and form complex regulatory networks, a deeper understanding of their crosstalk with the Notch pathway could provide novel insights into AD pathogenesis and reveal potential targets for diagnosis and treatment. In this study, we investigated the regulatory landscape involving the Notch signaling pathway and associated ncRNAs in AD using bioinformatics approaches. By integrating data from multiple public databases, we systematically identified significantly dysregulated Notch pathway-related genes and their interacting ncRNAs in AD. Based on this analysis, we constructed a lncRNA-miRNA-mRNA regulatory network to elucidate the potential mechanisms linking Notch signaling to ncRNA-mediated gene regulation in AD pathogenesis. Furthermore, we explored the internal relationships and molecular mechanisms within this network and assessed the feasibility and clinical relevance of these molecules as early diagnostic biomarkers and potential therapeutic targets for AD. This study aims to deepen our understanding of the molecular basis of AD and offer novel strategies for its diagnosis and treatment.

Aim To investigate the mechanism of ligu aged 2 months of the same strain were used as the constilide (LIG) in delaying the senescence of auditory trol (Ctrl) group. Auditory brainstem response test was cortex and treating central presbycusis. Methods used to detect the auditory threshold of mice before and Forty C57BL/6J mice aged 13 months were randomly di after treatment. Levels of serum MDA and activity of vided into ligustilide low-dose(L-LIG) group, ligustil serum SOD were detected to display the level of oxidative ide medium-dose (M-LIG) group, ligustilide high-dose stress. The pathological changes of auditory cortex were (H-LIG) group and aging (Age) group, and 10 mice observed by HE staining. Ferroptosis was observed by

Aim To screen and study the expression of long non-coding RNA (IncRNA) in rats with middle cerebral artery occlusion (MCAO) with MCAO treated with Tao Hong Si Wu decoction (THSWD) and determine the possible molecular mechanism of THSWD in treating MCAO rats. Methods Three cerebral hemisphere tissue were obtained from the control group, MCAO group and MCAO + THSWD group. RNA sequencing technology was used to identify IncRNA gene expression in the three groups. THSWD-regulated IncRNA genes were identified, and then a THSWD-regu-lated IncRNA-mRNA network was constructed. MCODE plug-in units were used to identify the modules of IncRNA-mRNA networks. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) were used to analyze the enriched biological functions and signaling pathways. Cis- and trans-regulatory genes for THSWD-regulated IncRNAs were identified. Reverse transcription real-time quantitative pol-ymerase chain reaction (RT-qPCR) was used to verify IncRNAs. Molecular docking was used to identify IncRNA-mRNA network targets and pathway-associated proteins. Results In MCAO rats, THSWD regulated a total of 302 IncRNAs. Bioinformatics analysis suggested that some core IncRNAs might play an important role in the treatment of MCAO rats with THSWD, and we further found that THSWD might also treat MCAO rats through multiple pathways such as IncRNA-mRNA network and network-enriched complement and coagulation cascades. The results of molecular docking showed that the active compounds gallic acid and a-mygdalin of THSWD had a certain binding ability to protein targets. Conclusions THSWD can protect the brain injury of MCAO rats through IncRNA, which may provide new insights for the treatment of ischemic stroke with THSWD.

Objective:To explore the rehabilitation effect of multi-factor intervention based on the Finnish model of prevention of cognitive impairment in the elderly on patients with cognitive impairment after first-episode stroke, and to provide reference for rehabilitation nursing of cognitive impairment after stroke.Methods:The quasi-experiment research scheme was adopted and convenience sampling method was used to select participants with first-episode stroke cognitive impairment hospitalized in the General Hospital of Tianjin Medical University Airport Site. The 50 patients admitted from January to June 2022 were selected as the control group, and 50 patients admitted from July to December 2022 were selected as the intervention group. The control group received routine rehabilitation nursing and health education, and the intervention group received the Finnish model of prevention of cognitive impairment in the elderly on patients before discharge on the basis of the control group. The Mini-Mental State Examination (MMSE) and Health Education Compliance Assessment Scale for Stroke Patients were used to evaluate the changes of overall cognitive function and rehabilitation compliance before intervention, 3 and 6 months after intervention.Results:The final control group included 49 cases, including 35 males and 14 females, aged (64.67 ± 7.47) years old; the intervention group included 50 cases, 32 males and 18 females, aged (66.68 ± 8.75) years old. Before intervention, there were no significant differences in overall cognitive function and compliance of rehabilitation score ( P>0.05). At 3 and 6 months after intervention, the overall cognitive function score, the total score on compliance of rehabilitation, dimension scores of diet compliance, exercise rehabilitation compliance and health behavior compliance of the intervention group were (26.36±2.36) , (125.96 ± 13.80) , (23.30 ± 5.26) , (27.72 ± 4.46) , (43.66 ± 6.80) and (27.26 ± 3.71) , (152.44 ± 9.06) , (30.12 ± 6.42) , (33.32 ± 3.02) , (52.36 ± 4.70) , respectively. They were higher than the control group (24.04 ± 4.50) , (116.67 ± 10.26) , (19.31 ± 3.95) , (25.29 ± 3.45) , (40.59 ± 4.33) and (24.27 ± 4.33) , (138.92 ± 16.71) , (24.20 ± 4.48) , (30.00 ± 5.53) , (47.65 ± 8.03) , and the differences had statistical significance ( t values were -5.31- -2.67, all P<0.05). According to the variance analysis of repeated measurement, intergroup and time factor, the interaction between groups and time had significant impact on general cognitive function score, the total score of rehabilitation compliance, the dimension scores of diet, exercise rehabilitation and health behavior compliance ( Fgroup values were 8.33-18.08, Ftime values were 135.71-944.69, Finteraction values were 5.46-27.30, all P<0.05) . Time factor had significant impact on patient medication adherence score ( Ftime=206.23, P<0.05) . Conclusions:Multi-factor intervention based on the Finnish model of prevention of cognitive impairment in the elderly can improve the overall cognitive function and rehabilitation compliance of patients with cognitive impairment after first-episode stroke.

The main characteristics of neurodegenerative diseases represented by Alzheimer’s disease (AD) and Parkinson’s disease (PD) is the progressive irreversible loss of neurons, leading to varying degrees of pathological changes and loss of cognitive function. There is still no effective treatment. With the acceleration of global aging society, the incidence of neurodegenerative diseases is rapidly increasing, becoming a serious global public health concern that urgently requires the development of effective therapeutic strategies. The Hippo signaling pathway, a highly evolutionarily conserved pathway, consists of the core components MST1/2, LATS1/2, and downstream effectors, transcriptional co-activators YAP and TAZ. It plays a crucial role in the regulation of various biological processes such as cell proliferation, differentiation, development, and apoptosis. Dysregulation of the Hippo pathway contributes to the development of many diseases, including cancer, cardiovascular diseases, immune disorders, etc. Therefore, targeting the dysregulated components of the Hippo pathway may be an effective strategy for treating various diseases. Increasing evidence indicates that the Hippo pathway is excessively activated in the development of neurodegenerative diseases, manifested by increased expression of MST1 and downregulation of YAP. Stabilizing the Hippo pathway levels has shown improvements in AD and PD. However, most studies on the Hippo pathway in AD and PD focus on changes in the expression levels of Hippo pathway components, and research in other neurodegenerative diseases is still lacking. Therefore, further investigation is needed to fully understand the mechanistic role of the Hippo pathway in neurodegenerative diseases. Meanwhile, miRNA, similarly dysregulated in neurodegenerative diseases and serving as biomarkers, is a primary target for miRNA therapy in neurodegenerative diseases, including AD and PD. Activating or inhibiting dysregulated miRNAs is the main strategy of miRNA therapy during the neurodegenerative disease development. Evidence suggests that the interaction between the Hippo pathway and miRNA can result in widespread biological effects and crosstalk in the occurrence of different types of diseases. However, studies on the interplay between the Hippo pathway and miRNA in neurodegenerative diseases are relatively scarce. In this paper, we predicted the miRNAs related to Hippo pathway through bioinformatics database, and further screened the miRNAs with crosstalk relationship with Hippo signaling pathway through experiments in combination with PubMed. Then, the mechanism of action of Hippo signaling pathway related miRNAs in AD and PD is further elucidated. It is reported that the Hippo pathway and its related miRNA may exert neuroprotective effects by reducing oxidative stress, improving neuroinflammation, stabilizing autophagy levels, maintaining neuronal mitochondrial function, and ameliorating blood-brain barrier dysfunction, thereby delaying the progression of AD and PD. However, research on miRNA directly regulating the Hippo pathway to improve AD and PD is limited, and observations of the Hippo pathway and its related miRNA in other neurodegenerative diseases are scarce. However, considering the regulatory relationship between the Hippo pathway and miRNA in multiple diseases and their respective roles in key mechanisms of neurodegenerative diseases, such as oxidative stress and neuroinflammation, the crosstalk between miRNA and the Hippo pathway holds a crucial regulatory role in the development of neurodegenerative diseases. Thus, the interaction pathways of the Hippo pathway and its related miRNA may be a pivotal avenue for exploring effective therapeutic strategies for neurodegenerative diseases in the future.

AIM To investigate the effects of Ginkgo biloba extract on hearing function,cochlear morphology and autophagy-related protein expression in a rat model of presbycusis.METHODS Forty-five rats were randomly divided into the control group,the model group and the low,medium and high dose G.biloba extract groups(10,20 and 30 mg/kg),with 9 rats in each group.The rat model of presbycusis was established by intraperitoneal injection of 500 mg/kg D-galactose(D-gal).Eight weeks after the corresponding administration,the rats had their changes of hearing threshold detected by the auditory brainstem evoked potential(ABR);their morphological changes of cochlear hair cells,stria vascularis(SV)and spiral ganglion cells observed by HE staining;their number of hair cells inside and outside the cochlea detected by immunofluorescence staining;their ultrastructure changes of cochlear hair cells observed by transmission electron microscopy;and their expression of autophagy-related proteins in cochlea tissue detected by Western blot.RESULTS Compared with the control group,the model group displayed increased ABR threshold(P<0.01);more severely damaged inner and outer hair cells,spiral ganglion cells and SV,decreased SV thickness and numbers of spiral ganglion cells,inner and outer hair cells and autophagosomes(P<0.01);decreased protein expressions of Beclin1 and LC3 Ⅱ and ratio of LC3 Ⅱ/LC3 Ⅰ in cochlear tissue(P<0.01),and higher P62 protein expression(P<0.01).Compared with the model group,the medium and high dose G.biloba extract groups shared decreased ABR thresholds(P<0.01);improved morphology of inner and outer hair cells and SV in the cochlea,normalized,morphology of spiral ganglion cells,and increased SV thickness and the numbers of spiral ganglion cells,inner and outer hair cells and autophagosomes(P<0.05,P<0.01);increased protein expressions of Beclin1 and LC3 Ⅱ and the ratio of LC3 Ⅱ/LC3 Ⅰ in the cochlea(P<0.01),and decreased P62 protein expression(P<0.01).CONCLUSION The protective effects G.biloba extract on hearing function and cochlear cells in the rat model of presbycusis may be associated with the up-regulated expression of Beclin1 and LC3 Ⅱ proteins and down-regulated P62 protein expression in cochlear tissues.