Kai-Xin-San Attenuates Doxorubicin-Induced Cognitive Impairment by Reducing Inflammation, Oxidative Stress, and Neural Degeneration in 4T1 Breast Cancer Mice.

OBJECTIVE: This study explored the potential therapeutic effect and possible mechanism of Kai-Xin-San (KXS) on doxorubicin-induced cognitive impairment in 4T1 breast cancer mice. METHODS: A model of chemotherapy-induced cognitive impairment (CICI) was established with the injection of doxorubicin (DOX, 5 mg/kg) at a 7-day interval in a 4T1 breast cancer mouse. KXS was given (1 g/kg) daily by gavage over three weeks starting at the first week while giving DOX. The Morris water maze task was performed to measure the CICI-like behaviors. Oxidative stress markers in the hippocampus, inflammatory cytokines in the serum and hippocampus, Nissl staining, immunofluorescence staining, and analysis for Glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 of the hippocampus were examined to explore the effect and mechanism of KXS on DOX-induced CICI. Meanwhile, tumor growth and survival time were tested in this study. RESULTS: CICI-like behaviors induced by DOX occurred earlier and were severer than the cognitive impairment induced by the tumor, and the effect of KXS on improving the cognitive impairment was obvious. KXS protected against DOX-induced neuroinflammation by decreasing levels of proinflammatory cytokines interleukin-6, interleukin-12p70, and tumor necrosis factor-alpha in both serum and brain and interleukin-1ß in the brain, increasing the anti-inflammatory cytokines interleukin-4 in the serum and interleukin-10 in the hippocampus, and inhibiting the astrocytic hyperplasia and microglial polarization in the hippocampus. KXS reduced neural degeneration and protected against DOX-induced oxidative stress according to decreased malondialdehyde level, increased glutathione level, and enhanced activities of superoxide dismutase, catalase, and glutathione peroxidase. Moreover, KXS recovered the lost body weights after DOX administration and prolonged the survival times of mice. CONCLUSIONS: KXS may attenuate DOX-induced cognitive impairment by regulating inflammatory responses and reducing oxidative stress and neural degeneration. These findings also presented the role of KXS in improving the quality of life and prolonging survival time in breast cancer mice that received chemotherapy.

Gut microbiota from patients with arteriosclerotic CSVD induces higher IL-17A production in neutrophils via activating RORγt.

The intestinal microbiota shape the host immune system and influence the outcomes of various neurological disorders. Arteriosclerotic cerebral small vessel disease (aCSVD) is highly prevalent among the elderly with its pathological mechanisms yet is incompletely understood. The current study investigated the ecology of gut microbiota in patients with aCSVD, particularly its impact on the host immune system. We reported that the altered composition of gut microbiota was associated with undesirable disease outcomes and exacerbated inflammaging status. When exposed to the fecal bacterial extracts from a patient with aCSVD, human and mouse neutrophils were activated, and capacity of interleukin-17A (IL-17A) production was increased. Mechanistically, RORγt signaling in neutrophils was activated by aCSVD-associated gut bacterial extracts to up-regulate IL-17A production. Our findings revealed a previously unrecognized implication of the gut-immune-brain axis in aCSVD pathophysiology, with therapeutic implications.

Assessing the Population-Level Correlation of Medication Regimen Complexity and Adherence Indices Using Electronic Health Records and Insurance Claims.

BACKGROUND: Nonadherence to medication regimens can lead to adverse health care outcomes and increasing costs. OBJECTIVES: To (a) assess the level of medication complexity at an outpatient setting using population-level electronic health record (EHR) data and (b) evaluate its association with medication adherence measures derived from medication-dispensing claims. METHODS: We linked EHR data with insurance claims of 70,054 patients who had an encounter with a U.S. midwestern health system between 2012 and 2013. We constructed 3 medication-derived indices: medication regimen complexity index (MRCI) using EHR data; medication possession ratio (MPR) using insurance pharmacy claims; and prescription fill rates (PFR; 7 and 30 days) using both data sources. We estimated the partial correlation between indices using Spearman's coefficient (SC) after adjusting for age and sex. RESULTS: The mean age (SD) of 70,054 patients was 37.9 (18.0) years, with an average Charlson Comorbidity Index of 0.308 (0.778). The 2012 data showed mean (SD) MRCI, MPR, and 30-day PFR of 14.6 (17.8), 0.624 (0.310), and 81.0 (27.0), respectively. Patients with previous inpatient stays were likely to have high MRCI scores (36.3 [37.9], P < 0.001) and were less adherent to outpatient prescriptions (MPR = 50.3 [27.6%], P < 0.001; 30-day PFR = 75.7 [23.6%], P < 0.001). However, MRCI did not show a negative correlation with MPR (SC = -0.31, P < 0.001) or with 30-day PFR (SC = -0.17, P < 0.001) at significant levels. CONCLUSIONS: Medication complexity and adherence indices can be calculated on a population level using linked EHR and claims data. Regimen complexity affects patient adherence to outpatient medication, and strength of correlations vary modestly across populations. Future studies should assess the added values of MRCI, MPR, and PFR to population health management efforts. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. The abstract of this work was presented at INFORMS Healthcare Conference, held on July 27-29, 2019, in Cambridge, MA.

Amelioration of experimental autoimmune encephalomyelitis by Rhodiola rosea, a natural adaptogen.

Adaptogens are stress-response modifiers which have been considered to exert important influences on cytokines activities and immune response. Here, we investigated the effects of Rhodiola rosea (R. rosea), a natural adaptogen on the experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We found that R. rosea alleviated the severity of EAE as evaluated by clinical and histopathology scores. R. rosea decreased IL-6, sIL-6R, IFN-γ and IL-17A in both serum and splenocytes supernatants while increased IL-4 in splenocytes supernatants of EAE mice. R. rosea also modulated the T cell response by inhibiting Th1 and Th17 cells, restoring Treg cells, combining with regulated Th17/Th1, Th17/Th2 and Th17/Treg ratios in the spleen, inguinal lymph nodes, brain and spinal cord of EAE mice. Furthermore, R. rosea regulated the expression of JAK1, JAK2, STAT3 and RORγt in the spinal cord of EAE mice. Together, our findings suggested the adaptogenic effects of R. rosea on EAE, which may help to deepen the understanding of potential therapeutic values of traditional Chinese medicines for autoimmune diseases of CNS.

Total glucosides of peony attenuates experimental autoimmune encephalomyelitis in C57BL/6 mice.

Total glucosides of peony (TGP), an active compound extracted from the roots of Paeonia lactiflora Pall, has wide pharmacological effects on nervous system. Here we examined the effects of TGP on experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). The results showed that TGP can reduce the severity and progression of EAE in C57 BL/6 mice. In addition, TGP also down-regulated the Th1/Th17 inflammatory response and prevented the reduced expression of brain-derived neurotrophic factor and 2',3'-cyclic nucleotide 3'-phosphodiesterase of EAE. These findings suggest that TGP could be a potential therapeutic agent for MS.

Berberine attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice.

BACKGROUND: Berberine, an isoquinoline derivative alkaloid, has a wide range of pharmacological properties and is considered to have anti-inflammatory and neuroprotective effects. However, there are no reports about the effects and mechanisms of berberine in experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). METHODOLOGY/PRINCIPAL FINDINGS: Female C57 BL/6 mice immunized with myelin oligodendrocyte glycoprotein 35-55 amino acid peptide were treated with berberine at the day of disease onset and medication was administered daily until mice were sacrificed. Blood-brain barrier (BBB) permeability and the alteration of matrix metalloproteinase-2 (MMP-2, 72 kDa) and matrix metalloproteinase-9 (MMP-9, 92 kDa) in the brain and cerebrospinal fluid (CSF) of EAE mice were detected by quantitative measurement for Evan's blue (EB) content, Western blot and gelatin zymography respectively. The results showed that berberine attenuated clinical and pathological parameters of EAE, reduced the permeability of BBB, inhibited the activity and expression of MMP-9 but not MMP-2 in the CSF and brain of EAE mice. CONCLUSIONS/SIGNIFICANCE: These findings suggest that berberine is effective to attenuate the clinical severity of EAE in C57 BL/6 mice by reducing the permeability of BBB, decreasing the expression and activity of MMP-9, and decreasing the inflammatory infiltration. We think that berberine might be a potential therapeutic agent for MS.