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Raspberry ketone accounts for the characteristic aroma of the raspberry fruit. In order to explore the genes involved in raspberry ketone synthesis, the transcriptome in fruit tissues of two red raspberry varieties "Polka" and "Orange legend", were sequenced and 24213 single genes were obtained. As the red raspberry fruit ripening, genes involved in flavonoid and anthocyanin synthesis were up-regulated, while those associated with lignin synthesis were down-regulated. A gene (RinPKS4) highly related to raspberry ketone synthesis was identified by transcriptome analysis, and RinPKS4 gene was over-expressed in raspberry in order to further understand the function of RinPKS4 gene in raspberry ketone synthesis. The results showed that the gene expression level of RinPKS4 in the leaf tissues of a transgenic lines increased by about 4-fold and the content of raspberry ketone increased by 42.64% compared with the wide type. This study lays a theoretical foundation for further study on the synthesis and regulation of raspberry ketone in red raspberry.
Subject(s)
Butanones , Gene Expression Profiling , Gene Expression Regulation, Plant , Plant Proteins , Rubus , Rubus/genetics , Rubus/metabolism , Rubus/chemistry , Butanones/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Fruit/genetics , Fruit/metabolism , Transcriptome , Plants, Genetically Modified/genetics , Plants, Genetically Modified/metabolism , Genes, PlantABSTRACT
Nicotiana tabacum L. (tobacco) has extremely high economic value, medicinal value, scientific research value and some other uses. Though it has been widely cultivated throughout the world, classification and change of its suitable habitats is not that clear, especially in the context of global warming. In order to achieve rational cultivation and sustainable development of tobacco, current (average from 1970-2000) and future (2070, average from 2061-2080) potential suitable habitats of Nicotiana tabacum L. were forecasted with MaxEnt model and ArcGIS platform based on 854 occurrence data and 22 environmental factors in this study. The results revealed that mean temperature of warmest quarter (bio10), annual precipitation (bio12), solar radiation in September (Srad9), and clay content (CLAY) were the four decisive environment variables for the distribution of Nicotiana tabacum L. Under current climate conditions, suitable habitats of Nicotiana tabacum L. were mainly distributed in south-central Europe, south-central North America, most parts of South America, central Africa, south and southeast Asia, and southeast coast of Australia, and only 13.7% of these areas were highly suitable. By the year 2070, suitable habitats under SSP1-2.6, SSP3-7.0, and SSP5-8.5 climate scenarios would all increase with the largest increase found under SSP3-7.0 scenario, while suitable habitats would reduce under SSP2-4.5 climate scenario. Globally, the center of mass of suitable habitats would migrate to southeast to varying degrees within Libya under four different climate scenarios. The emergence of new habitats and the disappearance of old habitats would all occur simultaneously under each climate scenario, and the specific changes in each area, combined with the prediction results under current climate conditions, will provide an important reference for the adjustment of agronomic practices and rational cultivation of Nicotiana tabacum L. both currently and in the future.
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BACKGROUND General paresis of the insane (GPI) is characterized by cognitive impairment, neuropsychiatric symptoms, and brain structural abnormalities, mimicking many neuropsychiatric diseases. Olfactory dysfunction has been linked to cognitive decline and neuropsychiatric symptoms in numerous neuropsychiatric diseases. Nevertheless, it remains unclear whether patients with GPI experience olfactory dysfunction and whether olfactory dysfunction is associated with their clinical manifestations. MATERIAL AND METHODS Forty patients with GPI and 37 healthy controls (HCs) underwent the "Sniffin Sticks" test battery, Mini-Mental State Examination, and Neuropsychiatric Inventory to measure olfactory function, cognitive function, and neuropsychiatric symptoms, respectively. Brain structural abnormalities were evaluated using visual assessment scales including the medial temporal lobe atrophy (MTA) visual rating scale and Fazekas scale. RESULTS Compared with HCs, patients with GPI exhibited significant olfactory dysfunction, as indicated by deficits in the odor threshold (OT) (P=0.001), odor discrimination (OD) (P<0.001), and odor identification (OI) (P<0.001). In patients with GPI, the OI was positively correlated with cognitive function (r=0.57, P<0.001), but no significant correlation was found between olfactory function and neuropsychiatric symptoms, blood, or cerebrospinal fluid biomarkers (rapid plasma reagin circle card test and Treponema pallidum particle agglutination test), or brain structural abnormalities (MTA and Fazekas scale scores). Mediation analysis indicated that the impaired OI in patients with GPI was mediated by cognitive impairment and impaired OT respectively. CONCLUSIONS Patients with GPI exhibited overall olfactory dysfunction. OI is correlated with cognitive function and the impaired OI is mediated by cognitive impairment in patients with GPI. Thus, OI may serve as a marker for reflecting cognitive function in patients with GPI.
Subject(s)
Cognitive Dysfunction , Olfaction Disorders , Humans , Male , Cognitive Dysfunction/physiopathology , Female , Middle Aged , Olfaction Disorders/physiopathology , Olfaction Disorders/diagnosis , Aged , Neuropsychological Tests , Adult , Biomarkers , Cognition/physiology , Case-Control Studies , Smell/physiology , Paresis/physiopathologyABSTRACT
Tobacco, a crop of significant economic importance, was greatly influenced in leaf quality by protein content. However, current processing parameters fail to adequately meet the requirements for protein degradation. Microorganisms possess potential advantages for degrading proteins and enhancing the quality of tobacco leaves, and hold substantial potential in the process of curing. To effectively reduce the protein content in tobacco leaves, thereby improving the quality and safety of the tobacco leaves. In this study, tobacco leaf were used as experimental material. From these, the BSP1 strain capable of effectively degrading proteins was isolated and identified as Bacillus subtilis by 16S rDNA analysis. Furthermore, the mechanisms were analyzed by integrating microbiome, transcriptome, and metabolome. Before curing, BSP1 was applied to the surface of tobacco leaves. The results indicated that BSP1 effectively improves the activity of key enzymes and the content of related substances, thereby enhancing protein degradation. Additionally, protein degradation was achieved by regulating the diversity of the microbial community on the surface of the tobacco leaves and the ubiquitin-proteasome pathway. This study provided new strategies for extracting and utilizing functional strains from tobacco leaves, opening new avenues for enhancing the quality of tobacco leaves.
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Background: Late-life depression (LLD) is characterized by disrupted brain networks. Resting-state networks in the brain are composed of both stable and transient topological structures known as microstates, which reflect the dynamics of the neural activities. However, the specific pattern of EEG microstate in LLD remains unclear. Methods: Resting-state EEG were recorded for 31 patients with episodic LLD (eLLD), 20 patients with remitted LLD (rLLD) and 32 healthy controls (HCs) using a 64-channel cap. The clinical data of the patients were collected and the 17-Item Hamilton Rating Scale for Depression (HAMD) was used for symptom assessment. Duration, occurrence, time coverage and syntax of the four microstate classes (A-D) were calculated. Group differences in EEG microstates and the relationship between microstates parameters and clinical features were analyzed. Results: Compared with NC and patients with rLLD, patients with eLLD showed increased duration and time coverage of microstate class D. Besides, a decrease in occurrence of microstate C and transition probability between microstate B and C was observed. In addition, the time coverage of microstate D was positively correlated with the total score of HAMD, core symptoms, and miscellaneous items. Conclusion: These findings suggest that disrupted EEG microstates may be associated with the pathophysiology of LLD and may serve as potential state markers for the monitoring of the disease.
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AIM: This study investigates the molecular mechanisms through which Panax ginseng and Panax notoginseng saponin (PNS) mitigate neuroinflammatory damage and promote neural repair postischemic stroke, utilizing bioinformatics, and experimental approaches. BACKGROUND: Cerebral infarction significantly contributes to disability worldwide, with chronic neuroinflammation worsening cognitive impairments and leading to neurodegenerative diseases. Addressing neuroimmune interactions is crucial for slowing disease progression and enhancing patient recovery, highlighting the need for advanced research in neuroimmune regulatory mechanisms and therapeutic strategies. OBJECTIVE: To elucidate the effects of the traditional Chinese medicine components Panax ginseng and PNS on neuroinflammatory damage following ischemic stroke, focusing on the molecular pathways involved in mitigating inflammation and facilitating neural repair. METHODS: The study employs single-cell sequencing and transcriptomic analysis to investigate gene expression changes associated with cerebral infarction. Gene set enrichment analysis and weighted gene co-expression network analysis are used to identify key molecular markers and core genes. Furthermore, pharmacological profiling, including functional assays, assesses the impact of Ginsenoside-Rc, a PNS derivative, on microglial cell viability, cytokine production, and reactive oxygen species (ROS) levels. RESULTS: Our analysis revealed that MAPK14 is a critical mediator in the neuroinflammatory response to ischemic stroke. Ginsenoside-Rc potentially targets and modulates MAPK14 activity to suppress inflammation. Experimental validation showed that Ginsenoside-Rc treatment, combined with MAPK14 silencing, significantly alters MAPK14 expression and mitigates neuroinflammatory damage, evidenced by reduced microglial cell death, inflammatory factor secretion, and ROS production. CONCLUSION: Ginsenoside-Rc's modulation of MAPK14 offers a promising therapeutic strategy for reducing neuroinflammation and potentially improving cognitive recovery post-ischemic stroke. This supports the therapeutic application of the traditional Chinese medicine Sanqi in ischemic stroke care, providing a theoretical and experimental foundation for its use. OTHERS: Future work will focus on extending these findings through clinical trials to evaluate the efficacy and safety of Ginsenoside-Rc in human subjects, aiming to translate these promising preclinical results into practical therapeutic interventions for ischemic stroke recovery.
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[This retracts the article DOI: 10.1021/acsomega.3c01296.].
ABSTRACT
Rheumatoid arthritis (RA) is the predominant manifestation of inflammatory arthritis, distinguished by an increasing burden of morbidity and mortality. The intricate interplay of genes and signalling pathways involved in synovial inflammation in patients with RA remains inadequately comprehended. This study aimed to ascertain the role of necroptosis in RA, as along with their associations with immune cell infiltration. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify central genes for RA. In this study, identified total of 28 differentially expressed genes (DEGs) were identified in RA. Utilising WGCNA, two co-expression modules were generated, with one module demonstrating the strongest correlation with RA. Through the integration of differential gene expression analysis, a total of 5 intersecting genes were discovered. These 5 hub genes, namely fused in sarcoma (FUS), transformer 2 beta homolog (TRA2B), eukaryotic translation elongation factor 2 (EEF2), cleavage and polyadenylation specific factor 6 (CPSF6) and signal transducer and activator of transcription 3 (STAT3) were found to possess significant diagnostic value as determined by receiver operating characteristic (ROC) curve analysis. The close association between the concentrations of various immune cells is anticipated to contribute to the diagnosis and treatment of RA. Furthermore, the infiltration of immune cells mentioned earlier is likely to exert a substantial influence on the initiation of this disease.
Subject(s)
Arthritis, Rheumatoid , Gene Regulatory Networks , Necroptosis , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Arthritis, Rheumatoid/genetics , Humans , Necroptosis/immunology , Gene Expression Profiling , Transcriptome , Computational Biology/methods , Gene Expression Regulation , Signal Transduction/immunology , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Biomarkers , ROC CurveABSTRACT
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent glocal cause of chronic hepatic disease, with incidence rates that continue to rise steadily. Treatment options for affected patients are currently limited to dietary changes and exercise interventions, with no drugs having been licensed for the treatment of this disease. There is thus a pressing need for the development of novel therapeutic strategies. Work from our group suggests that the primary bioactive ingredient in green tea, epigallocatechin gallate (EGCG), may help reduce liver fat content and protect against hepatic injury through the inhibition of dipeptidyl peptidase 4 (DPP4) expression and activity. The study investigated the potential pathways by which EGCG may improve NAFLD, identified the sites of interaction between EGCG and DPP4, and proposed novel clinical treatment strategies. METHODS: A clinical randomized controlled trial was conducted to investigate the potential efficacy of EGCG in NAFLD patients. The study compared relevant indices before and after EGCG administration. Animal models of NAFLD were constructed using male C57BL/6J mice fed a high-fat diet to observe the ameliorative effects of EGCG on the livers of the model mice and to investigate the potential pathways by which EGCG alleviates NAFLD. The interaction mechanism between EGCG and DPP4 was investigated using oleic acid and palmitic acid-treated HepG2 cell lines. Plasmids in which different sites had been disrupted were used to identify the effective interaction sites. RESULTS: ECGC was found to suppress the accumulation of lipids, inhibit inflammation, remediate dysregulated lipid metabolism, and improve the pathogenesis of NAFLD via the inhibition of the expression and activity of DPP4. CONCLUSIONS: The study results indicate that EGCG has a positive impact on improving NAFLD. These results highlight promising new opportunities to safely and effectively treat NAFLD in the clinic. STUDY ID NUMBER: ChiCTR2300076741; https://www.chictr.org.cn/.
Subject(s)
Catechin , Dipeptidyl Peptidase 4 , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease , Catechin/analogs & derivatives , Catechin/pharmacology , Non-alcoholic Fatty Liver Disease/drug therapy , Animals , Male , Humans , Mice , Dipeptidyl Peptidase 4/metabolism , Liver/drug effects , Liver/metabolism , Diet, High-Fat/adverse effects , Middle Aged , Female , Disease Models, Animal , Adult , Hep G2 CellsABSTRACT
[This corrects the article DOI: 10.3389/fncel.2022.878673.].
ABSTRACT
Recent studies have explored the association between primary aldosteronism and cardiovascular disease incidence. The association between specific primary aldosteronism treatments and differential improvement in cardiovascular event rates is yet to be established. This study was designed to compare the relative effects of spironolactone therapy and surgical intervention on cardiovascular outcomes among primary aldosteronism patients. This retrospective observational study included 853 primary aldosteronism patients from the First Affiliated Hospital of China Medical University between 2014 and 2022. Patients who had completed abdominal computed tomography (CT) examinations with similar metabolic characteristics and 6-month follow-up analyses were included in this study. These patients were separated into a surgical treatment group (n = 33) and a spironolactone treatment group (n = 51). Demographic data, biochemical analysis results, liver/spleen (L/S) X-ray attenuation ratio, hospitalization frequency, and cardiovascular events were compared between the two groups. The spironolactone group demonstrated significantly improved metabolic characteristics compared to the surgical group, shown by lower BMI, blood pressure, total cholesterol (TC), insulin resistance index (IRI), and reduced non-alcoholic fatty liver disease prevalence. Metabolic parameters did not differ significantly within the surgical treatment group when comparing pre- and postoperative values. The incidence of cardiovascular events was lower in the spironolactone group compared to the surgery group (23/33 vs. 20/51, P < 0.001) despite higher hospitalization rates(37/31 vs. 61/53, P < 0.001). In patients with primary aldosteronism, spironolactone treatment is more effective than surgical intervention in remediating abnormal lipid and glucose metabolism while improving cardiovascular outcomes. Chinese clinical trial registry registration number: ChiCTR2300074574.
Subject(s)
Cardiovascular Diseases , Hyperaldosteronism , Spironolactone , Humans , Hyperaldosteronism/complications , Hyperaldosteronism/drug therapy , Hyperaldosteronism/therapy , Male , Female , Middle Aged , Retrospective Studies , Adult , Cardiovascular Diseases/etiology , Spironolactone/therapeutic use , Glycolipids/metabolism , Mineralocorticoid Receptor Antagonists/therapeutic use , Treatment Outcome , Adrenalectomy , China/epidemiologyABSTRACT
BACKGROUND: Suicide is one of the most lethal complications of late-life depression (LLD), and habenular dysfunction may be involved in depression-related suicidality and may serve as a potential target for alleviating suicidal ideation. This study aimed to investigate abnormal functional connectivity of the habenula in LLD patients with suicidal ideation. METHODS: One hundred twenty-seven patients with LLD (51 with suicidal ideation (LLD-S) and 76 without suicidal ideation (LLD-NS)) and 75 healthy controls (HCs) were recruited. The static functional connectivity (sFC) and dynamic functional connectivity (dFC) between the habenula and the whole brain were compared among the three groups, and correlation and moderation analyses were applied to investigate whether suicidal ideation moderated the relationships of habenular FC with depressive symptoms and cognitive impairment. RESULTS: The dFC between the right habenula and the left orbitofrontal cortex (OFC) increased in the following order: LLD-S > LLD-NS > control. No significant difference in the habenular sFC was found among the LLD-S, LLD-NS and control groups. The dFC between the right habenula and the left OFC was positively associated with global cognitive function and visuospatial skills, and the association between this dFC and visuospatial skills was moderated by suicidal ideation in patients with LLD. CONCLUSION: The increased variability in dFC between the right habenula and left OFC was more pronounced in the LLD-S group than in the LLD-NS group, and the association between habenular-OFC dFC and visuospatial skills was moderated by suicidal ideation in patients with LLD.
Subject(s)
Habenula , Magnetic Resonance Imaging , Suicidal Ideation , Humans , Habenula/physiopathology , Female , Male , Aged , Middle Aged , Prefrontal Cortex/physiopathology , Prefrontal Cortex/diagnostic imaging , Depression/physiopathology , Depression/psychology , Case-Control Studies , Depressive Disorder/physiopathology , Depressive Disorder/psychologyABSTRACT
BACKGROUND: Functional abnormalities of the habenula in patients with depression have been demonstrated in an increasing number of studies, and the habenula is involved in cognitive processing. However, whether patients with late-life depression (LLD) exhibit disrupted habenular functional connectivity (FC) and whether habenular FC mediates the relationship between depressive symptoms and cognitive impairment remain unclear. METHODS: Overall, 127 patients with LLD and 75 healthy controls were recruited. The static and dynamic FC between the habenula and the whole brain was compared between LLD patients and healthy controls, and the relationships of habenular FC with depressive symptoms and cognitive impairment were explored by correlation and mediation analyses. RESULTS: Compared with the controls, patients with LLD exhibited decreased static FC between the right habenula and bilateral inferior frontal gyrus (IFG); there was no significant difference in dynamic FC of the habenula between the two groups. Additionally, the decreased static FC between the right habenula and IFG was associated with more severe depressive symptoms (especially psychomotor retardation) and cognitive impairment (language, memory, and visuospatial skills). Last, static FC between the right habenula and left IFG partially mediated the relationship between depressive symptoms (especially psychomotor retardation) and cognitive impairment (verbal fluency and working memory). CONCLUSIONS: Patients with LLD exhibited decreased static FC between the habenula and IFG but intact dynamic FC of the habenula. This decreased static FC mediated the relationship between depressive symptoms and cognitive impairment.
Subject(s)
Cognitive Dysfunction , Habenula , Humans , Memory, Short-Term , Depression , Cognitive Dysfunction/psychology , Language , Magnetic Resonance ImagingABSTRACT
OBJECTIVE: Cognitive impairments are prevalent in late-life depression (LLD). However, it remains unclear whether there are concurrent brain oscillation alterations in resting condition across varying level of depression severity. This cross-sectional study aims to investigate the characteristics of altered resting-state oscillations, including power spectrum and functional connectivity, and their association with the cognitive impairments in LLD with different depression severity. METHODS: A total of 65 patients with LLD and 40 elder participants without depression were recruited. Global cognition and subtle cognitive domains were evaluated. A five-minute resting-state electroencephalography (EEG) was conducted under eyes-closed conditions. Measurements included the ln-transformed absolute power for power spectrum analysis and the weighted phase lag index (wPLI) for functional connectivity analysis. RESULTS: Attentional and executive dysfunction were exhibited in Moderate-Severe LLD group. Enhanced posterior upper gamma power was observed in both LLD groups. Additionally, enhanced parietal and fronto-parietal/occipital theta connectivity were observed in Moderate-Severe LLD group, which were associated with the attentional impairment. LIMITATIONS: Limitations include a small sample size, concomitant medication use, and a relatively higher proportion of females. CONCLUSIONS: Current study observed aberrant brain activity patterns in LLD across different levels of depression severity, which were linked to cognitive impairments. The altered posterior brain oscillations may be trait marker of LLD. Moreover, cognitive impairments and associated connectivity alterations were exhibited in moderate-severe group, which may be a state-like marker of moderate-to severe LLD. The study deepens understanding of cognitive impairments with the associated oscillation changes, carrying implications for neuromodulation targets in LLD.
Subject(s)
Cognitive Dysfunction , Depression , Female , Humans , Aged , Depression/psychology , Cross-Sectional Studies , Magnetic Resonance Imaging , Brain/diagnostic imaging , ElectroencephalographyABSTRACT
Osteoarthritis (OA) is a degenerative joint disease commonly found in middle-aged and older people. Chondrocytes are the only cells in joint cartilage that are difficult to heal after pyroptosis, and they will aggravate the wear and tear of joint cartilage and affect the progression of OA. Pyroptosis is a novel form of programmed cell death, and the classical pyroptosis pathway is a programmed cell death pattern mediated by inflammatory cysteine protease-1. Activation of NLRP3 leads to activation and cleavage of caspase-1 precursors, which in turn leads to activation and cleavage of GSDMD proteins and the release of proinflammatory factors. Resolvin D1 (RvD1) is a specialized pro-resolving mediator (SPM) derived from omega-3 unsaturated fatty acids that reduces inflammation and catabolic responses in OA chondrocytes. However, it is unclear whether RvD1 promotes OA chondrocyte proliferation and thus joint cartilage repair. Our results show that RvD1 regulates the NLRP3/caspase-1 signaling pathway by inhibiting the expression of caspase-1, promoting the proliferation of OA chondrocytes, promoting the repair of articular cartilage in rats and delaying the progression of osteoarthritis.
Subject(s)
NLR Family, Pyrin Domain-Containing 3 Protein , Osteoarthritis , Humans , Middle Aged , Rats , Animals , Aged , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Chondrocytes/metabolism , Caspase 1/metabolism , Osteoarthritis/metabolism , Signal Transduction , Cell ProliferationABSTRACT
The pathogenesis of rheumatoid arthritis (RA) is heavily impacted by the inflammation and activation of fibroblast-like synoviocytes (FLS). The objective of this investigation is to clarify the involvement of exosomes derived from FLS stimulated by tumour necrosis factor α (TNF-α) in angiogenesis and the underlying mechanisms. FLS cells were obtained from synovial fluid of RA patients and exosomes were obtained from FLS cell supernatant with TNF-α stimulation by ultracentrifugation. Exosomes were subsequently analysed using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. The functional effects of exosomes with TNF-α stimulation on human umbilical vein endothelial cells (HUVEC) migration, invasion, and angiogenesis was evaluated using wound scratch healing test, transwell invasion assay, and tube formation assay. DNA nanoball-seq (DNBSEQ) sequencing platform was utilised to analysis different expression miRNA from exosomes, miRNA and mRNA from HUVEC. The expression level of miR-200a-3p was determined through quantitative real-time polymerase chain reaction (qRT-PCR). The quantification of KLF6 and VEGFA expression levels were performed by qRT-PCR and western blot analysis. The validation of the association between miR-200a-3p and KLF6 was established through a fluorescence enzyme reporting assay. In comparison to exosome induced by PBS, exosome induced by TNF-α exhibited a substantial exacerbation of invasion, migration, and angiogenesis in HUVEC. 4 miRNAs in exosomes and HUVEC cells, namely miR-1246, miR-200a-3p, miR-30a-3p, and miR-99b-3p was obtained. MiR-200a-3p maintained high consistency with the sequencing results. We obtained 5 gene symbols, and KLF6 was chose for further investigation. The expression of miR-200a-3p in exosomes induced by TNF-α and in HUVEC treated with these exosomes demonstrated a significantly increase. Additionally, HUVEC cells displayed a notable decrease in KLF6 expression and a significant elevation in VEGFA expression. This was further confirmed by the fluorescence enzyme report assay, which provided evidence of the direct targeting of KLF6 by miR-200a-3p. Exosomes induced by TNF-α have the ability to enhance the migration, invasion, and angiogenesis of HUVEC cells via the miR-200a-3p/KLF6/VEGFA axis.
Subject(s)
Arthritis, Rheumatoid , Exosomes , MicroRNAs , Synoviocytes , Humans , Arthritis, Rheumatoid/metabolism , Cell Proliferation , Exosomes/genetics , Exosomes/metabolism , Exosomes/pathology , Fibroblasts/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/pathology , Kruppel-Like Factor 6/metabolism , Kruppel-Like Factor 6/pharmacology , MicroRNAs/genetics , MicroRNAs/metabolism , Synoviocytes/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/pharmacologyABSTRACT
Stroke has been associated with devastating clinical outcomes, with current treatment strategies proving largely ineffective. Therefore, there is a need to explore alternative treatment options for addressing post-stroke functional deficits. Gene therapy utilizing adeno-associated viruses (AAVs) as a critical gene vector delivering genes to the central nervous system (CNS) gene delivery has emerged as a promising approach for treating various CNS diseases. This review aims to provide an overview of the biological characteristics of AAV vectors and the therapeutic advancements observed in preclinical models of ischemic stroke. The study further investigates the potential of manipulating AAV vectors in preclinical applications, emphasizing the challenges and prospects in the selection of viral vectors, drug delivery strategies, immune reactions, and clinical translation.
Subject(s)
Ischemic Stroke , Stroke , Humans , Dependovirus/genetics , Genetic Therapy , Gene Transfer Techniques , Genetic Vectors , Stroke/genetics , Stroke/therapyABSTRACT
Polygonum cuspidatum polyketide synthase 1 (PcPKS1) has the catalytic activity of chalcone synthase (CHS) and benzylidene acetone synthase (BAS), which can catalyze the production of polyketides naringenin chalcone and benzylidene acetone, and then catalyze the synthesis of flavonoids or benzylidene acetone. In this study, three amino acid sites (Thr133, Ser134, Ser33) that may affect the function of PcPKS1 were identified by analyzing the sequences of PcPKS1, the BAS from Rheum palmatum and the CHS from Arabidopsis thaliana, as well as the conformation of the catalytic site of the enzyme. Molecular modification of PcPKS1 was carried out by site-directed mutagenesis, and two mutants were successfully obtained. The in vitro enzymatic reactions were carried out, and the differences in activity were detected by high performance liquid chromatography (HPLC). Finally, mutants T133LS134A and S339V with bifunctional activity were obtained. In addition to bifunctional activities of BAS and CHS, the modified PcPKS1 had much higher BAS activity than that of the wild type PcPKS1 under the conditions of pH 7.0 and pH 9.0, respectively. It provides a theoretical basis for future use of PcPKS1 in genetic engineering to regulate the biosynthesis of flavonoids and raspberry ketones.
Subject(s)
Fallopia japonica , Amino Acid Sequence , Fallopia japonica/genetics , Fallopia japonica/metabolism , Polyketide Synthases/chemistry , Acetone , Mutagenesis, Site-Directed , Flavonoids/chemistry , Flavonoids/metabolism , Acyltransferases/metabolismABSTRACT
Objective: This retrospective analysis was to assess the role of Janus kinases (JAK) inhibitors compared with conventional disease modifying anti-rheumatic drugs (DMRADs) in the treatment of polymyalgia rheumatica (PMR) with glucocorticoids (GCs) reduction. Methods: Clinical information was collected from PMR patients in the JAK inhibitor group and the DMARDs group from January 2020 to August 2021 at Jiaxing first Hospital. Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin (Hb), albumin and dose of GCs before and after treatment were compared between two groups. Results: Thirty female patients with PMR were included into this study. The dose of GCs in the JAK inhibitor group was significantly lower than in the DMARDs group at baseline and at 3 and 6 months after treatment. There were no significant differences in various laboratory parameters (including CRP, ESR, Hb and albumin) between two groups (P > 0.05) except that Hb in the DMARDs group was significantly higher than in the JAK inhibitor group at 3 and 6 months after treatment (P<0.05). One patient in the JAK inhibitor group developed herpes zoster, and received tofacitinib treatment after herpes zoster was relieved. Conclusion: Our study indicates that JAK inhibitors in the treatment of PMR are as effective as DMRADs and are also helpful for the reduction of GCs dose.