Polyporus umbellatus polysaccharide iron-based nanocomposite for synergistic M1 polarization of TAMs and combinational anti-breast cancer therapy.

M1 polarization of tumor-associated macrophages (TAMs) is a promising approach to breaking through therapeutic barriers imposed by the immunosuppressive tumor microenvironment (TME). As a clinically-used immunopotentiator for cancer patients after chemotherapies; however, the immunomodulatory mechanism and potential of polyporus polysaccharide (PPS) remains unclear. Here, we present mannose-decorated PPS-loaded superparamagnetic iron-based nanocomposites (Man/PPS-SPIONs) for synergistic M1 polarization of TAMs and consequent combinational anti-breast cancer therapy. Once internalized by M2-like TAMs, PPS released from Man/PPS-SPIONs induces the M1 polarization via IFN-γ secretion and downstream NF-κB pathway activating. The SPIONs within the nanocomposites mediate a Fenton reaction, producing OH· and activating the subsequent NF-κB/MAPK pathway, further facilitating the M1 polarization. The Man/PPS-SPIONs thereby establish a positive feedback loop of M1 polarization driven by the "IFN-γ-Fenton-NF-κB/MAPK" multi-pathway, leading to a series of anti-tumoral immunologic responses in the TME and holding promising potential in combinational anticancer therapies. Our study offers a new strategy to amplify TME engineering by combinational natural carbohydrate polymers and iron-based materials.

The modulatory effect of 100 Hz electroacupuncture on striatal synaptic plasticity in unilateral lesioned 6-OHDA rats.

Recent studied have reported that impaired striatal synaptic plasticity played a crucial role in Parkinson's disease (PD). Previous studies have suggested that electroacupuncture (EA) alleviated the motor deficits in PD patients and animal models. However, the mechanisms underlying this protection need to be further elucidated. In this study, we found that EA-induced improvement of motor deficits in the 6-hydroxydopamine (6-OHDA) rat model doesn't act through dopaminergic system. EA rescued the decreased striatal long-term potentiation (LTP) in 6-OHDA rats. In addition, the declined expression of N-methyl-D-aspartic acid receptor subunit 2B (NR2B) in the striatum was remarkably up-regulated by EA. The EA-induced improvement of LTP can be eliminated by NR2B-selective inhibitor. It is indicated that EA-induced recovery of striatal LTP was correlated with the up-regulation of NR2B subunit. EA was also found to rescue the decreased dendritic arborization and the spine density in the striatum of 6-OHDA rats. Meanwhile, EA suppressed striatal glutamate content and vesicular glutamate transporter 1 which is expressed in cortico-striatal glutamatergic projections. The decrease of striatal glutamate content induced by decortication, EA treatment or a combination of both reversed the loss of striatal spine density in 6-OHDA rats. It is indicated that EA-induced reduction of cortico-striatal glutamate transmission contributes to the recovery of striatal spine density. In conclusion, the therapeutic effect of EA on the motor deficits of 6-OHDA rats was mediated by rescuing cortico-striatal glutamate transmission and striatal synaptic plasticity.

Mendelian Randomization Study on the Putative Causal Effects of Omega-3 Fatty Acids on Low Back Pain.

Previous observational studies have suggested an important role of omega-3 in low back pain. In the present study, we used a two-sample Mendelian randomization (MR) study to identify the putative causal link between omega-3 and low back pain. A broadly used genome-wide association study (GWAS) (n = 8,866 individuals from European ancestry) was used to select plasma omega-3 genetic instrumental variables (IVs). A previously reported GWAS (4,863 cases and 74,589 controls from European ancestry) for low back pain were used to assess the effect of plasma omega-3 levels on low back pain. MR-egger_intercept, MR-PRESSO, MR_egger, and inverse variance weighted (IVW) in Cochran's Q-test were used to determine the pleiotropy and heterogeneity, respectively. MR-egger, weighted median, IVW, and weighted mode were used to perform MR analysis. Finally, the effect of a single nucleotide polymorphism (SNP) was used to test the SNP bias. We did not find a significant pleiotropy or heterogeneity of all six selected plasma omega-3 genetic IVs in low back pain GWAS. Expectedly, we found that as plasma omega-3 levels genetically increased, the risk of low back pain had a decreased trend using MR-egger (Beta = -0.593, p = 0.228; OR = 0.553) and weighted mode (Beta = -0.251, p = 0.281; OR = 0.778). This reduced trend was further proven by weighted median (Beta = -0.436, p = 0.025; OR = 0.646) and IVW (Beta = -0.366, p = 0.049; OR = 0.694). Our analysis suggested a putative causal link between genetically increased plasma omega-3 levels and the reduced risk of low back pain in European ancestries. Thus, the supplementation of omega-3 may be important for the prevention and treatment of low back pain.

Mendelian randomization study on the causal effects of omega-3 fatty acids on rheumatoid arthritis.

OBJECTIVES: To resolve the ongoing debate on the role of plasma omega-3 fatty acids in rheumatoid arthritis (RA), we attempted to identify the association between omega-3 intake and the risk of RA. METHODS: We analyzed data from the largest genome-wide association study (GWAS) for omega-3 fatty acids (N = 114,999 of European ancestry) and RA (14,361 cases and 43,923 controls of European ancestry). Mendelian randomization-egger_intercept, MR-PRESSO, and Cochran's Q test were used to determine pleiotropy and heterogeneity. Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode were used to evaluate the causal association of plasma omega-3 levels on RA. RESULTS: We found no significant pleiotropy, heterogeneity, and bias among the omega-3 genetic instrumental variables (IVs) in RA GWAS datasets. MR analysis demonstrated that as omega-3 levels genetically increased, the risk of MS increased using MR-egger (Beta = 0.137, p = 0.037; OR = 1.146, 95% CI: [1.014, 1.296]), weighted median (Beta = 0.162, p = 0.001; OR = 1.176, 95% CI: [1.070, 1.292]), IVW (Beta = 0.102, p = 0.025; OR = 1.108, 95% CI: [1.013, 1.211]), simple mode (Beta = 0.219, p = 0.149; OR = 1.245, 95% CI: [0.931, 1.665]), and weighted mode (Beta = 0.146, p = 0.006; OR = 1.157, 95% CI: [1.051, 1.274]). CONCLUSIONS: Our analysis suggested a causal association between genetically increased plasma omega-3 levels and the increased risk of RA in populations with European ancestry. Thus, to reduce the risk of RA, those of European descent should reduce omega-3 intake. Key Points • No significant pleiotropy or heterogeneity among the omega-3 genetic IVs in RA GWAS datasets. • Genetically increased plasma omega-3 levels enhanced the risk of RA in European lineages.

Organ Specific Differences in Alteration of Aquaporin Expression in Rats Treated with Sennoside A, Senna Anthraquinones and Rhubarb Anthraquinones.

Senna and rhubarb are often used as routine laxatives, but there are differences in mechanism of action and potential side effects. Here, we studied metabolites of senna anthraquinones (SAQ), rhubarb anthraquinones (RAQ) and their chemical marker, sennoside A (SA), in a rat diarrhea model. In in vitro biotransformation experiments, SAQ, RAQ and SA were incubated with rat fecal flora solution and the metabolites produced were analyzed using HPLC. In in vivo studies, the same compounds were investigated for purgation induction, with measurement of histopathology and Aqps gene expression in six organs. The results indicated that SAQ and RAQ had similar principal constituents but could be degraded into different metabolites. A similar profile of Aqps down-regulation for all compounds was seen in the colon, suggesting a similar mechanism of action for purgation. However, in the kidneys and livers of the diarrhea-rats, down-regulation of Aqps was found in the RAQ-rats whereas up-regulation of Aqps was seen in the SAQ-rats. Furthermore, the RAQ-rats showed lower Aqp2 protein expression in the kidneys, whilst the SA-rats and SAQ-rats had higher Aqp2 protein expression in the kidneys. This may have implications for side effects of SAQ or RAQ in patients with chronic kidney or liver diseases.

Effects of Electroacupuncture on Metabolic Changes in Motor Cortex and Striatum of 6-Hydroxydopamine-Induced Parkinsonian Rats.

OBJECTIVE: To explore the possible underlying mechanism by investigating the effect of electroacupuncture (EA) treatment on the primary motor cortex and striatum in a unilateral 6-hydroxydopamine (6-OHDA) induced rat Parkinson's disease (PD) model. METHODS: Male Sprague-Dawley rats were randomly divided into sham group (n=16), model group (n=14), and EA group (n=14). EA stimulation at Dazhui (GV 14) and Baihui (GV20) was applied to PD rats in the EA group for 4 weeks. Behavioral tests were conducted to evaluate the effectiveness of EA treatment. Metabolites were detected by 7.0 T proton nuclear magnetic resonance. RESULTS: Following 4 weeks of EA treatment in PD model rats, the abnormal behavioral impairment induced by 6-OHDA was alleviated. In monitoring changes in metabolic activity, ratios of myoinositol/creatine (Cr) and N-acetyl aspartate (NAA)/Cr in the primary motor cortex were significantly lower at the injected side than the non-injected side in PD rats (P=0.024 and 0.020). The ratios of glutamate + glutamine (Glx)/Cr and NAA/Cr in the striatum were higher and lower, respectively, at the injected side than the non-injected side (P=0.046 and 0.008). EA treatment restored the balance of metabolic activity in the primary motor cortex and striatum. In addition, the taurine/Cr ratio and Glx/Cr ratio were elevated in the striatum of PD model rats compared to sham-lesioned rats (P=0.026 and 0.000). EA treatment alleviated the excessive glutamatergic transmission by down-regulating the striatal Glx/Cr ratio (P=0.001). The Glx/Cr ratio was negatively correlated with floor plane spontaneous locomotion in PD rats (P=0.027 and P=0.0007). CONCLUSIONS: EA treatment is able to normalize the metabolic balance in the primary motor cortex and striatum of PD rats, which may contribute to its therapeutic effect on motor deficits. The striatal Glx/Cr ratio may serve as a potential indicator of PD and a therapeutic target of EA treatment.

The effect of electroacupuncture on proteomic changes in the motor cortex of 6-OHDA Parkinsonian rats.

Electroacupuncture (EA) has been reported to alleviate motor deficits in Parkinson's disease (PD) patients, and PD animal models. However, the mechanisms by which EA improves motor function have not been investigated. We have employed a 6-hydroxydopamine (6-OHDA) unilateral injection induced PD model to investigate whether EA alters protein expression in the motor cortex. We found that 4weeks of EA treatment significantly improved spontaneous floor plane locomotion and rotarod performance. High-throughput proteomic analysis in the motor cortex was employed. The expression of 54 proteins were altered in the unlesioned motor cortex, and 102 protein expressions were altered in the lesioned motor cortex of 6-OHDA rats compared to sham rats. Compared to non-treatment PD control, EA treatment reversed 6 proteins in unlesioned and 19 proteins in lesioned motor cortex. The present study demonstrated that PD induces proteomic changes in the motor cortex, some of which are rescued by EA treatment. These targeted proteins were mainly involved in increasing autophagy, mRNA processing and ATP binding and maintaining the balance of neurotransmitters.

Electroacupuncture Alleviates Depressive-Like Symptoms and Modulates BDNF Signaling in 6-Hydroxydopamine Rats.

Previous studies have identified the beneficial effects of electroacupuncture (EA) on motor behaviors in Parkinson's disease (PD). However, the role and potential mechanisms of EA in PD-associated depression remain unclear. In the present study, a rat model of PD with unilateral 6-hydroxydopamine (6-OHDA) lesions in the medial forebrain bundle was treated using EA for 4 weeks. We found that 100 Hz EA improved several motor phenotypes. In addition, tyrosine hydroxylase (TH) immunohistochemical analysis showed that EA had a minimal impact on the TH-positive profiles of the ipsilateral ventral tegmental area. Compared with the 6-OHDA group, long-term EA stimulation significantly increased sucrose solution consumption and decreased immobility time in the forced swim test. EA treatment did not alter dopamine, norepinephrine, and serotonin levels in the striatum and hippocampus. Noticeably, EA treatment reversed the 6-OHDA-induced abnormal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) in the midbrain and hippocampus. These results demonstrate that EA at 100-Hz possesses the ability to improve depressive-like symptoms in PD rats, which is, at least in part, due to the distinct effect of EA on the mesostriatal and mesocorticolimbic dopaminergic pathways. Moreover, BDNF seems to participate in the effect of EA in PD.