The role of natural flavonoids on neuroinflammation as a therapeutic target for Alzheimer's disease: a narrative review.

Alzheimer's disease is a neurodegenerative disease that affects a large proportion of older adult people and is characterized by memory loss, progressive cognitive impairment, and various behavioral disturbances. Although the pathological mechanisms underlying Alzheimer's disease are complex and remain unclear, previous research has identified two widely accepted pathological characteristics: extracellular neuritic plaques containing amyloid beta peptide, and intracellular neurofibrillary tangles containing tau. Furthermore, research has revealed the significant role played by neuroinflammation over recent years. The inflammatory microenvironment mainly consists of microglia, astrocytes, the complement system, chemokines, cytokines, and reactive oxygen intermediates; collectively, these factors can promote the pathological process and aggravate the severity of Alzheimer's disease. Therefore, the development of new drugs that can target neuroinflammation will be a significant step forward for the treatment of Alzheimer's disease. Flavonoids are plant-derived secondary metabolites that possess various bioactivities. Previous research found that multiple natural flavonoids could exert satisfactory treatment effects on the neuroinflammation associated with Alzheimer's disease. In this review, we describe the pathogenesis and neuroinflammatory processes of Alzheimer's disease, and summarize the effects and mechanisms of 13 natural flavonoids (apigenin, luteolin, naringenin, quercetin, morin, kaempferol, fisetin, isoquercitrin, astragalin, rutin, icariin, mangiferin, and anthocyanin) derived from plants or medicinal herbs on neuroinflammation in Alzheimer's disease. As an important resource for the development of novel compounds for the treatment of critical diseases, it is essential that we focus on the exploitation of natural products. In particular, it is vital that we investigate the effects of flavonoids on the neuroinflammation associated with Alzheimer's disease in greater detail.

Aberrant dentato-rubro-thalamic pathway in action tremor but not rest tremor: A multi-modality magnetic resonance imaging study.

AIMS: The purpose of this study was to clarify the dentato-rubro-thalamic (DRT) pathway in action tremor in comparison to normal controls (NC) and disease controls (i.e., rest tremor) by using multi-modality magnetic resonance imaging (MRI). METHODS: This study included 40 essential tremor (ET) patients, 57 Parkinson's disease (PD) patients (29 with rest tremor, 28 without rest tremor), and 41 NC. We used multi-modality MRI to comprehensively assess major nuclei and fiber tracts of the DRT pathway, which included decussating DRT tract (d-DRTT) and non-decussating DRT tract (nd-DRTT), and compared the differences in DRT pathway components between action and rest tremor. RESULTS: Bilateral dentate nucleus (DN) in the ET group had excessive iron deposition compared with the NC group. Compared with the NC group, significantly decreased mean diffusivity and radial diffusivity were observed in the left nd-DRTT in the ET group, which were negatively correlated with tremor severity. No significant difference in each component of the DRT pathway was observed between the PD subgroup or the PD and NC. CONCLUSION: Aberrant changes in the DRT pathway may be specific to action tremor and were indicating that action tremor may be related to pathological overactivation of the DRT pathway.

Sesamin Attenuates Obesity-Associated Nonalcoholic Steatohepatitis in High-Fat and High-Fructose Diet-Fed Mice.

This study explored the effects of sesamin on nonalcoholic steatohepatitis (NASH). High-fat and high-fructose diet-fed mice supplemented with or without sesamin. The results suggested that sesamin-treated mice lost body weight and fat tissue weight, had lower levels of serum metabolic parameters, and insulin resistance was mitigated. Histological examinations showed that sesamin treatment mitigated the progression of hepatic steatosis, and inflammation. In addition, sesamin enhanced hepatic antioxidant capacity, and decreased the activations of hepatic c-jun N-terminal kinase, inhibitor of kappa B kinase α, and insulin receptor substrate 1 as well as hepatic interleukin-6 and tumor necrosis factor-alpha levels. Further experiments indicated that sesamin treatment downregulated GRP78 and phospho-inositol-requiring enzyme 1 (IRE1) expression, and upregulated x-box binding protein 1 (XBP1) expression in hepatic tissue. The aforementioned results suggest that sesamin alleviates obesity-associated NASH, which might be linked to the effect of sesamin on the regulation of the hepatic endoplasmic reticulum stress-IRE1/XBP1 pathway. Thus, sesamin may be a good food functional ingredient in the treatment of obesity-associated NASH.

A LAMP-Based Toolbox Developed for Detecting the Major Pathogens Affecting the Production and Quality of the Chinese Medicinal Crop Aconitum carmichaelii.

Aconitum carmichaelii Debeaux is a traditional Chinese medicinal herb that has been utilized for approximately 2,000 years. However, as cultivation has increased, there have been more reports of A. carmichaelii infections caused by four major pathogenic fungal species, Fusarium oxysporum, F. solani, Mucor circinelloides, and Sclerotium rolfsii, resulting in increased disease incidences and limited production and quality. To detect these infections, we developed a LAMP-based toolbox in this study. The cytochrome c oxidase subunit 1 (cox1) gene, translation elongation factor-1α (EF-1α), internal transcribed spacer (ITS) regions of rDNA, and alcohol dehydrogenase 1 (ADH1) gene, respectively, were used to design species-specific LAMP primer sets for F. oxysporum, F. solani, S. rolfsii, and M. circinelloides. The results showed that the LAMP-based toolbox was effective at detecting pathogens in soil and plant materials. We also used this toolbox to investigate pathogen infection in the main planting regions of A. carmichaelii. Before harvesting, F. oxysporum, M. circinelloides, and S. rolfsii were commonly found in the planting fields and in infected A. carmichaelii plants. Therefore, the toolbox we developed will be useful for tracking these infections, as well as for disease control in A. carmichaelii.

Neuroinflammation and Modulation Role of Natural Products After Spinal Cord Injury.

Spinal cord injury (SCI) is a severe traumatic injury of the central nervous system, characterized by neurological dysfunction and locomotor disability. Although the underlying pathological mechanism of SCI is complex and remains unclear, the important role of neuroinflammation has been gradually unveiled in recent years. The inflammation process after SCI involves disruption of the blood-spinal cord barrier (BSCB), activation of gliocytes, infiltration of peripheral macrophages, and feedback loops between different cells. Thus, our first aim is to illustrate pathogenesis, related cells and factors of neuroinflammation after SCI in this review. Due to the good bioactivity of natural products derived from plants and medicinal herbs, these widely exist as food, health-care products and drugs in our lives. In the inflammation after SCI, multiple natural products exert satisfactory effects. Therefore, the second aim of this review is to sum up the effects and mechanisms of 25 natural compounds and 7 extracts derived from plants or medicinal herbs on neuroinflammation after SCI. Clarification of the SCI inflammation mechanism and a summary of the related natural products is helpful for in-depth research and drug development.

Sesamol supplementation alleviates nonalcoholic steatohepatitis and atherosclerosis in high-fat, high carbohydrate and high-cholesterol diet-fed rats.

Sesamol, a major ingredient in sesame seeds (Sesamum indicum L.) and its oil, is considered a powerful functional food ingredient. However, few studies have investigated its effects on high-fat, high carbohydrate and high-cholesterol (HF-HCC) diet-induced nonalcoholic steatohepatitis (NASH) complicated with atherosclerosis. The present study elucidates the protective effects of sesamol against NASH and atherosclerosis in HF-HCC diet-fed rats. Sprague-Dawley rats were supplemented with or without sesamol in drinking water (0.05 mg mL-1, 0.1 mg mL-1 and 0.2 mg mL-1) from the beginning to end. At the end of the experiment, sesamol supplementation suppressed HF-HCC diet-induced body weight gain and increased absolute liver and adipose tissue weights in rats. Serum biochemical analyses showed that sesamol supplementation improved HF-HCC diet-induced metabolism disorders and damaged vascular endothelial function. Histological examinations displayed that dietary sesamol not only alleviated hepatic balloon degeneration, steatosis, inflammation and fibrosis, but also mitigated lipid accumulation and fibrous elements in the aorta arch in HF-HCC diet-fed rats. In addition, sesamol supplementation inhibited hepatic NOD-like receptor protein 3 (NLRP3) expression and ERS-IRE1 signaling pathway activation. Moreover, sesamol treatment decreased uric acid levels both in serum and the liver by its effect on the inhibition of xanthine oxidase (XO) activity and/or its expression, which might be closely associated with the inhibitions of NLRP3 expression and ERS-IRE1 signaling pathway activation in HF-HCC diet-fed rats. These findings demonstrated that sesamol alleviated NASH and atherosclerosis in HF-HCC diet-fed rats, and may be a potent dietary supplement for protection against these diseases.

Progressive microstructural alterations in subcortical nuclei in Parkinson's disease: A diffusion magnetic resonance imaging study.

OBJECTIVES: To explore the microstructural alterations in subcortical nuclei in Parkinson's disease (PD) at different stages with diffusion kurtosis imaging (DKI) and tensor imaging and to test the performance of diffusion metrics in identifying PD. METHODS: 108 PD patients (64 patients in early-stage PD group (EPD) and 44 patients in moderate-late-stage PD group (MLPD)) and 64 healthy controls (HC) were included. Tensor and kurtosis metrics in the subcortical nuclei were compared. Partial correlation was used to correlate the diffusion metrics and Unified Parkinson's Disease Rating Scale part-III (UPDRS-III) score. Logistic regression and receiver operating characteristic analysis were applied to test the diagnostic performance of the diffusion metrics. RESULTS: Compared with HC, both EPD and MLPD patients showed higher fractional anisotropy and axial diffusivity, lower mean kurtosis (MK) and axial kurtosis in substantia nigra, lower MK and radial kurtosis (RK) in globus pallidus (GP) and thalamus (all p < 0.05). Compared with EPD, MLPD patients showed lower MK and RK in GP and thalamus (all p < 0.05). MK and RK in GP and thalamus were negatively correlated with UPDRS-III score (all p < 0.01). The logistic regression model combining kurtosis and tensor metrics showed the best performance in diagnosing PD, EPD, and MLPD (areas under curve were 0.817, 0.769, and 0.914, respectively). CONCLUSIONS: PD has progressive microstructural alterations in the subcortical nuclei. DKI is sensitive to detect microstructural alterations in GP and thalamus during PD progression. Combining kurtosis and tensor metrics can achieve a good performance in diagnosing PD.

First Report of Damping-Off Caused by Mucor circinelloides on Aconitum carmichaelii in China.

Aconitum carmichaelii is a typical traditional Chinese medicinal herb that has been grown for more than one thousand years in China (Singhuber et al. 2009). Surveys for damping-off of A. carmichaelii were conducted from 2016 to 2018 in three of China's major planting areas (Shaanxi, Sichuan, and Yunnan Province). Damping-off was observed from April to June with disease incidences ranging from 5% to 11% in ten investigated fields. In the early stage of disease development, the roots were fully covered by white mycelia. When the disease was severe, seedlings were stunted, turned yellow, had withered roots, and some eventually died. One fungus was consistently isolated from the diseased roots in the planting areas of Shaanxi Province (33°7'42″N and 107°20'27″E) on PDA medium. It was identified as Mucor circinelloides, based on morphological characteristics (Schipper 1976). Three isolates from different regions were characterized by yellowish colonies composed of tall and short sporangiophores 6-11 µm in width, terminal and globose sporangia, ellipsoidal sporangiospores 5-8 µm in length and 4-5 µm in width, and obovoid columellae. The internal transcribed spacer regions (ITS) and the large subunit (28S) of ribosomal RNA gene from the representative isolate, MC180610 (GenBank accession no. MK087755, MT043749), were also amplified and sequenced using the universal primer sets, ITS1/ITS4 and NL1/NL4, respectively. BLAST analyses of the ITS sequence showed 99.38% identity with the type strain (CBS 195.68) of M. circinelloides (GenBank accession no. NR_126116), and the 28S sequence showed 99.44% identity with the strain (CBS 274.49) of M. circinelloides f. circinelloides (GenBank accession no. MH868051). The pathogenicity of M. circinelloides isolate (MC180610) to A. carmichaelii was examined by inoculating 150 ml of the hypha suspension of M. circinelloides prepared from a 10-day-old potato dextrose broth culture into the soils of healthy potted A. carmichaelii plants. Uninoculated potted A. carmichaelii plants served as controls. There were three replicates for the inoculated and control plants. All the potted A. carmichaelii plants were incubated at 25°C under 12 h light 12 h dark conditions. The symptoms that developed on M. circinelloides inoculated A. carmichaelii plants were similar to those observed in the field; control plants did not show symptoms. The pathogen was reisolated from symptomatic roots onto the PDA medium and morphologically identified as M. circinelloides. M. circinelloides has been reported as a pathogen of papaya (Carica papaya), Mandarin fruits (Citrus reticulata), and sweet potatoes (Ipomea batatas), respectively (Cruz-Lachica et al. 2018; Saito et al. 2016; Oladoye et al. 2016), but it has never been reported on A. carmichaelii before. This is the first report of damping-off caused by M. circinelloides on A. carmichaelii. This pathogen may present a threat to the production of A. carmichaelii in China.

Pathway engineering for phenolic acid accumulations in Salvia miltiorrhiza by combinational genetic manipulation.

To produce beneficial phenolic acids for medical and commercial purposes, researchers are interested in improving the normally low levels of salvianolic acid B (Sal B) produced by Salvia miltiorrhiza. Here, we present a strategy of combinational genetic manipulation to enrich the precursors available for Sal B biosynthesis. This approach, involving the lignin pathway, requires simultaneous, ectopic expression of an Arabidopsis Production of Anthocyanin Pigment 1 transcription factor (AtPAP1) plus co-suppression of two endogenous, key enzyme genes: cinnamoyl-CoA reductase (SmCCR) and caffeic acid O-methyltransferase (SmCOMT). Compared with the untransformed control, we achieved a greater accumulation of Sal B (up to 3-fold higher) along with a reduced lignin concentration. This high-Sal B phenotype was stable in roots during vegetative growth and was closely correlated with increased antioxidant capacity for the corresponding plant extracts. Although no outward change in phenotype was apparent, we characterized the molecular phenotype through integrated analysis of transcriptome and metabolome profiling. Our results demonstrated the far-reaching consequences of phenolic pathway perturbations on carbohydrate metabolism, respiration, photo-respiration, and stress responses. This report is the first to describe the production of valuable end products through combinational genetic manipulation in S. miltiorrhiza plants. Our strategy will be effective in efforts to metabolically engineer multi-branch pathway(s), such as the phenylpropanoid pathway, in economically significant medicinal plants.

The Arabidopsis PAP1 transcription factor plays an important role in the enrichment of phenolic acids in Salvia miltiorrhiza.

Phenolic acids are health-promoting but low content secondary metabolites in Salvia miltiorrhiza. Here, the Arabidopsis transcription factor Production of Anthocyanin Pigment 1 (AtPAP1) was expressed in S. miltiorrhiza and improved the antioxidant capacity in transgenic plants up to 3-fold. Salvianolic acid B (Sal B) biosynthesis was strongly induced (10-fold higher) in 1 month old transgenic plantlets, a growth stage not normally characterized by significant levels of phenolic acids. This high-Sal B phenotype was stable in roots during vegetative growth, with tissues accumulating approximately 73.27 mg/g of dry weight. Total phenolics, total flavonoids, anthocyanin, and lignin were also significantly enhanced. Consistent with these biological and phytochemical changes, expression of phenolic acid biosynthetic genes was stimulated. Our results demonstrate that AtPAP1 has an additional, previously unknown, role as a transcriptional activator of phenolic acid biosynthesis in S. miltiorrhiza. The results provide a promising strategy for engineering phenolics production in economically significant medicinal plants.

Generation and analysis of expressed sequence tags from the medicinal plant Salvia miltiorrhiza.

Salvia miltiorrhiza Bge. is a well-known traditional Chinese herb. Its roots have been formulated and used clinically for the treatment of various diseases. However, little genetic information has so far been available and this fact has become a major obstacle for molecular studies. To address this lack of genetic information, an Expressed Sequence Tag (EST) library from whole plantlets of S. miltiorrhiza was generated. From the 12959 cDNA clones that were randomly selected and subjected to single-pass sequencing from their 5' ends, 10288 ESTs (with sizes > or = 100 bp) were selected and assembled into 1288 contigs, leaving 2937 singletons, for a total of 4225 unigenes. These were analyzed using BLASTX (against protein databases), RPS-BLAST (against a conserved domain database) as well as the web-based KEGG Automatic Annotation Server for metabolic enzyme assignment. Based on the metabolic enzyme assignment, expression patterns of 14 secondary metabolic enzyme genes in different organs and under different treatments were verified using real-time PCR analysis. Additionally, a total of 122 microsatellites were identified from the ESTs, with 89 having sufficient flanking sequences for primer design. This set of ESTs represents a significant proportion of the S. miltiorrhiza transcriptome, and gives preliminary insights into the gene complement of S. miltiorrhiza. They will prove useful for uncovering secondary metabolic pathways, analyzing cDNA-array based gene expression, genetic manipulation to improve yield of desirable secondary products, and molecular marker identification.