An Exosome-Based Therapeutic Strategy Targeting Neuroinflammation in Alzheimer's Disease with Berberine and Palmatine.

Introduction: Neuroinflammation is one of the major pathogeneses in Alzheimer's disease (AD) and mainly involves abnormal inflammatory activation of microglia by multiple pathological stimuli. The treatment of AD remains a major challenge due to the multifactorial characterization of AD and the inefficient ability of therapeutic drugs to permeate through the blood‒brain barrier (BBB). Accordingly, drug combination treatment and drug carrier delivery have become important therapeutic tools for the treatment of multifactorial diseases, especially AD. Methods: Inflammatory cytokine levels in microglia, including NO, TNF-α, IL-1ß, IL-4, and IL-10, were detected. The Morris water maze and object location task were used to investigate the learning and memory functions of APP/PS1 mice in different treatment groups. The number of neurons and plasticity of synapses were evaluated by immunofluorescence double labelling. Additionally, the ratio of ß-amyloid plaques and the number of activated microglia were evaluated by immunofluorescence staining. The concentrations of ß-amyloid plaques and inflammatory factors in the hippocampus were determined by ELISA. Microglia-derived exosomes (Exos) were extracted and purified by size exclusion chromatography. The distribution of exosomes and drugs was investigated in vitro and in vivo. Results: Compared to single drug interventions, the combination of Ber and Pal (Ber/Pal) modulated microglial inflammatory cytokine levels. Ber/Pal promoted the recovery of learning and memory impairment in APP/PS1 mice. Immunofluorescence staining indicated that Ber/Pal restored neurons, inhibited Aß plaque formation and microglial activation, and regulated the secretion of inflammatory factors. Exos promoted the accumulation of drugs in cells and tissues and improved the targeting of drugs across the BBB. Conclusion: Ber/Pal could offer a synergistic and more comprehensive therapeutic effect in AD. Additionally, the microglia-derived Exos-Ber/Pal delivery system promoted the targeting and permeation of drugs into the brain, suggesting a creative strategy for targeting AD therapy by regulating neuroinflammation in microglial cells.

Identification of potent target and its mechanism of action of Tripterygium wilfordii Hook F in the treatment of lupus nephritis.

AIM: The Chinese anti-rheumatic herbal remedy Tripterygium wilfordii Hook F (TWHF) has been widely shown to be effective in treating lupus nephritis (LN), but the therapeutic targets and mechanisms of action are still unclear. In this study, we aimed to combine mRNA expression profile analysis and network pharmacology analysis to screen the pathogenic genes and pathways involved in LN and to explore the potential targets of TWHF in the treatment of LN. METHODS: The mRNA expression profiles of LN patients were used to screen differentially expressed genes (DEGs) and to predict associated pathogenic pathways and networks via the Ingenuity Pathway Analysis database. Through molecular docking, we predicted the mechanism by which TWHF interacts with candidate targets. RESULTS: A total of 351 DEGs were screened from the glomeruli of LN patients and were mainly concentrated in the role of pattern recognition receptors in the recognition of bacteria and viruses and interferon signaling pathways. A total of 130 DEGs were screened from the tubulointerstitium of LN patients, which were concentrated in the interferon signaling pathway. TWHF might be effective in treating LN by hydrogen bonding to regulate the functions of 24 DEGs (including HMOX1, ALB, and CASP1), which are mainly concentrated in the B-cell signaling pathway. CONCLUSION: The mRNA expression profile of renal tissue from LN patients revealed a large number of DEGs. TWHF has been shown to interact with the DEGs (including HMOX1, ALB and CASP1) through hydrogen bonding to treat LN.

Neuroimaging Studies of Acupuncture on Low Back Pain: A Systematic Review.

Objectives: This study was conducted in order to investigate the study design and main outcomes of acupuncture neuroimaging studies on low back pain (LBP). Methods: Neuroimaging studies of acupuncture on LBP were collected from three English databases such as PubMed and four Chinese databases such as China National Knowledge Infrastructure (CNKI) from inception to December 31, 2020. Study selection, data extraction, and assessment of risk of bias were performed independently by two investigators. The quality of studies was appraised with the Cochrane's risk of bias tools. Information on basic information, methodology, and brain imaging data were extracted. Results: The literature search returned 310 potentially eligible studies and 19 articles met inclusion criteria; 78.9% of studies chose manual acupuncture as the intervention, 89.5% of studies evaluated functional changes elicited by acupuncture, and 68.4% of studies used resting-state fMRI as imaging condition. The most frequently reported acupuncture-induced brain alterations of LBP patients were in the prefrontal cortex, insula, cerebellum, primary somatosensory cortex, and anterior cingulate cortex. There was a significant correlation between improved clinical outcomes and changes in the brain. Conclusions: The results suggested that improving abnormal structure and functional activities in the brain of the LBP patient is an important mechanism of acupuncture treatment for LBP. The brain regions involved in acupuncture analgesia for LBP were mainly located in the pain matrix, default mode network (DMN), salience network (SN), and descending pain modulatory system (DPMS). However, it was difficult to draw a generalized conclusion due to the heterogeneity of study designs. Further well-designed multimodal neuroimaging studies investigating the mechanism of acupuncture on LBP are warranted.

Acupuncture Modulation Effect on Pain Processing Patterns in Patients With Migraine Without Aura.

INTRODUCTION: In this retrospective study, resting-state functional connectivity (FC) in patients with migraine was analyzed to identify potential pathological pain processing patterns and compared them to those in healthy controls (HCs). The FC patterns in patients between pre- and post-acupuncture sessions were also analyzed to determine how acupuncture affects neurological activity and pain perception during the migraine interictal period. METHODS: In total, 52 patients with migraine without aura (MwoA) and 60 HCs were recruited. Patients with migraine were given acupuncture treatment sessions for 4 weeks. As a primary observation, functional magnetic resonance images were obtained at the beginning and end of the sessions. HCs received no treatment and underwent one functional magnetic resonance imaging (fMRI) scan after enrollment. After the fMRI data were preprocessed, a region of interest (ROI)-to-ROI analysis was performed with predefined ROIs related to pain processing regions. RESULTS: The first analysis showed significantly different FCs between patients with MwoA and HCs [false discovery rate corrected p-value (p-FDR) < 0.05]. The FCs were found to be mainly between the cingulate gyrus (CG) and the insular gyrus, the CG and the inferior parietal lobule (IPL), the CG and the superior frontal gyrus, and the middle frontal gyrus and the IPL. The second analysis indicated that acupuncture treatment partly restored the different FCs found in the first analysis (p-FDR < 0.05). Furthermore, subgroup analysis found different brain activity patterns in headache-intensity restored condition and headache-frequency restored condition. Lastly, the correlation analysis suggested a potential correlation between FCs and clinical symptoms (p < 0.05). CONCLUSION: This study suggests that pain processing is abnormal in migraine, with significantly abnormal FCs in the frontal, parietal, and limbic regions. This finding could be a typical pathological feature of migraine. Acupuncture has been identified to relieve headache symptoms in two ways: it restores the pain processing function and regulates pain perception.

Liquiritigenin suppresses the activation of hepatic stellate cells via targeting miR-181b/PTEN axis.

BACKGROUND: Liquiritigenin (LQ), an aglycone of liquiritin in licorice, has demonstrated antioxidant, anti-inflammatory and anti-tumor activities. Previously, LQ was found to inhibit liver fibrosis progression. PURPOSE: Phosphatase and tensin homolog (PTEN) has been reported to act as a negative regulator of hepatic stellate cell (HSC) activation. However, the roles of PTEN in the effects of LQ on liver fibrosis have not been identified to date. METHODS: The effects of LQ on liver fibrosis in carbon tetrachloride (CCl4) mice as well as primary HSCs were examined. Moreover, the roles of PTEN and microRNA-181b (miR-181b) in the effects of LQ on liver fibrosis were examined. RESULTS: LQ markedly ameliorated CCl4-induced liver fibrosis, with a reduction in collagen deposition as well as α-SMA level. Moreover, LQ induced an increase in PTEN and effectively inhibited HSC activation including cell proliferation, α-SMA and collagen expression, which was similar with curcumin (a positive control). Notably, loss of PTEN blocked down the effects of LQ on HSC activation. PTEN was confirmed as a target of miR-181b and miR-181b-mediated PTEN was involved in the effects of LQ on liver fibrosis. LQ led to a significant reduction in miR-181b expression. LQ-inhibited HSC activation could be restored by over-expression of miR-181b. Further studies demonstrated that LQ down-regulated miR-181b level via Sp1. Collectively, we demonstrate that LQ inhibits liver fibrosis, at least in part, via regulation of miR-181b and PTEN. CONCLUSION: LQ down-regulates miR-181b level, leading to the restoration of PTEN expression, which contributes to the suppression of HSC activation. LQ may be a potential candidate drug against liver fibrosis.

Variations in pH significantly affect cadmium uptake in grafted muskmelon (Cucumis melo L.) plants and drive the diversity of bacterial communities in a seedling substrate.

Substrates are fundamental prerequisites for growing grafted seedlings. In this study, substrates with different pH levels (5.0, 5.5, 6.0, 6.5, 7.0, and 8.0) were set up to elucidate the effect of pH on cadmium (Cd) uptake in grafted muskmelon (Cucumis melo L.) plants. Bacterial diversity was also investigated. Results showed that pH and high Cd concentration greatly affected the growth of grafted plants. The chlorophyll content of the muskmelon leaves decreased at 100 µM Cd. The majority of the Cd ions accumulated in the rootstock rather than in the shoot tissue in all of the treatments. The shoots and roots showed the highest Cd content at pH 5.5 and the lowest Cd content at pH 8.0 regardless of the Cd concentration. The operational taxonomic units belonging to Proteobacteria and Bacteroidetes were significantly (p < 0.05) enriched at different substrate pH levels compared with those at pH 5.0. The operational taxonomic units belonging to the phyla Firmicutes, Acidobacteria, and Chloroflexi were significantly decreased. The available nitrogen, phosphorus, Cd, and pH were strongly linked to bacterial community compositions. On the contrary, the available potassium was weakly correlated with the bacterial structure. This study demonstrates that pH greatly affects Cd uptake in grafted muskmelon plants and predicts microbial community structures in breeding substrates with different pH levels. Our results suggest that Cd accumulation in grafted plants can be reduced by setting the appropriate substrate pH. This work can serve as a reference for growing high-quality grafted plants and ensuring food safety in the presence of Cd contamination.

Immune Signatures in Patients with Psoriasis Vulgaris of Blood-Heat Syndrome: A Systematic Review and Meta-Analysis.

Objective. To determine whether immunological serum markers IFN-γ, IL-4, IL-17, IL-23, IL-6, TNF-α, and IL-10 are elevated or decreased in patients compared with healthy controls. Methods. A complete search of the literature on this topic within the past 30 years was conducted across seven databases. Seventeen studies including 768 individuals were identified. Differences in serum marker levels between subjects and controls were pooled as MDs using the random-effects model. Results. The pooled MDs were higher in patients than in healthy controls for IFN-γ (MD 24.9, 95% CI 12.36-37.43), IL-17 (MD 28.92, 95% CI 17.44-40.40), IL-23 (MD 310.60, 95% CI 4.96-616.24), and TNF-α (MD 19.84, 95% CI 13.80-25.87). Pooled IL-4 (MD -13.5, 95% CI -17.74--9.26) and IL-10 (MD -10.33, 95% CI -12.03--8.63) levels were lower in patients. Conclusion. The pooled analyses suggest that levels of IFN-γ, IL-17, IL-23, and TNF-α are significantly elevated and that levels of IL-4 and IL-10 are significantly decreased in sera of patients with psoriasis vulgaris of blood-heat syndrome. Measuring progression of blood-heat syndrome of psoriasis vulgaris will require additional high-quality data, with a low risk of bias and adequate sample sizes, before and after antipsoriatic therapy.

External Application of Traditional Chinese Medicine for Venous Ulcers: A Systematic Review and Meta-Analysis.

Objective. To evaluate the effectiveness of external application of traditional Chinese medicine (EA-TCM) on venous ulcers. Methods. Seven databases were searched until April 2015 for randomized controlled trials (RCTs) of EA-TCM for venous ulcers. Risk of bias was assessed using Cochrane Handbook guidelines. Study outcomes were presented as risk ratios (RRs) for dichotomous data or mean differences (MDs) for continuous data. Results. Sixteen of 193 potentially relevant trials met the inclusion criteria; however, their methodological qualities were low. Comparison of the same intervention strategies revealed significant differences in total effectiveness rates between EA-TCM and conventional therapy groups (RR = 1.22, 95% confidence interval [CI] = 1.16-1.29, and P < 0.00001). Compared to conventional therapy, EA-TCM combined with conventional therapy had a superior total effectiveness rate (RR = 1.11, 95% CI = 1.04-1.19, and P = 0.003). There were no significant differences in recurrence rates during followup and final pain measurements between the experimental and those in the control groups (RR = 0.86, 95% CI = 0.31-2.39, and P = 0.85; MD -0.75, 95% CI = -2.15-0.65, and P = 0.29). Conclusion. The evidence that EA-TCM is an effective treatment for venous ulcers is encouraging, but not conclusive due to the low methodological quality of the RCTs. Therefore, more high-quality RCTs with larger sample sizes are required.

Effects of chinese formula jueyin granules on psoriasis in an animal model.

Although Traditional Chinese medicine (TCM) is known to be effective for psoriasis patients, the responsible mechanisms still remain poorly understood. In this study, we aimed to evaluate the effect of one formula, named Jueyin granules (JYG) in the mouse model of the vaginal epithelium and tail epidermis. Additionally, we also determined the anti-inflammatory effects of JYG in an imiquimod- (IMQ-) induced psoriasis-like skin mouse model. Our results show that JYG can attenuate the IMQ-induced psoriasis-like inflammation, accompanied with increased epidermal hyperplasia. We also measured estrogenic stage mitosis of vaginal epithelial cells and the formation of granular cell layers in male mouse tails per 100 scales, as well as the tissue nitric oxide (NO) and malondialdehyde (MDA) levels using the ELISA method. The results suggest that JYG significantly inhibited mitosis in mouse vaginal epithelial cells, promoted the formation of the squamous epidermal granular layer in mice tails, and reduced the levels of NO and MDA in an imiquimod-induced psoriasis-like skin mouse model after 14 d (P < 0.05). These results demonstrate that JYG might be an effective clinical treatment for psoriasis and the effects may be related to inhibited keratinocytes proliferation, improved parakeratotic epidermal cells, and reduced expression of NO and MDA.

Determination of BmKCT-13, a chlorotoxin-like peptide, in rat plasma by LC-MS/MS: application to a preclinical pharmacokinetic study.

A novel chlorotoxin-like toxin derived from Buthus martensii Karsch, namely BmKCT-13, is a potential candidate for glioma therapy and highly homologous to the chlorotoxin (CTX) derived from the venom of the scorpion Leiurus quinquestriatus. In this study, a simple, sensitive, and robust analytical method based on liquid chromatography-tandem mass spectrometry has been developed for the determination of BmKCT-13 in rat plasma using CTX as internal standard (IS). After sample preparation by protein precipitation with 0.1% formic acid in methanol, chromatography was performed on a Hanbon Dubhe C18 column (150 mm × 2.1 mm, 5 µm, and 100 Å) using a gradient elution with 0.1% formic acid in water and methanol. Mass spectrometry involved positive electrospray ionization and multiple reaction monitoring of the transitions at m/z 780.2→69.9 for BmKCT-13 and m/z 800.2→69.7 for CTX. The method was linear over the concentration range 10-1000 ng/mL with a lower limit of quantification of 10 ng/mL. Intra- and inter-day precision (expressed as relative standard deviation, RSD) were ≤8.1 and ≤7.9%, respectively, with intra-and inter-day accuracy of 94.5-99.0%. Recoveries of BmKCT-13 and IS were more than 65% and matrix effects were not significant. Stability studies showed that BmKCT-13 was stable under a variety of storage conditions. The method was successfully applied to a pharmacokinetic study involving intravenous administration of BmKCT-13 to rats.