Pterostilbene could alleviate diabetic cognitive impairment by suppressing TLR4/NF-кB pathway through microbiota-gut-brain axis.

Diabetic cognitive impairment (DCI) is a serious neurodegenerative disorder caused by diabetes, with chronic inflammation being a crucial factor in its pathogenesis. Pterostilbene is a well-known natural stilbene derivative that has excellent anti-inflammatory activity, suggesting its potential medicinal advantages for treating DCI. Therefore, this study is to explore the beneficial effects of pterostilbene for improving cognitive dysfunction in DCI mice. A diabetic model was induced by a high-fat diet plus streptozotocin (40 mg·kg-1 ) for consecutive 5 days. After the animals were confirmed to be in a diabetic state, they were treated with pterostilbene (20 or 60 mg·kg-1 , i.g.) for 10 weeks. Pharmacological evaluation showed pterostilbene could ameliorate cognitive dysfunction, regulate glycolipid metabolism disorders, improve neuronal damage, and reduce the accumulation of ß-amyloid in DCI mice. Pterostilbene alleviated neuroinflammation by suppressing oxidative stress and carbonyl stress damage, astrocyte and microglia activation, and dopaminergic neuronal loss. Further investigations showed that pterostilbene reduced the level of lipopolysaccharide, modulated colon and brain TLR4/NF-κB signaling pathways, and decreased the release of inflammatory factors, which in turn inhibited intestinal inflammation and neuroinflammation. Furthermore, pterostilbene could also improve the homeostasis of intestinal microbiota, increase the levels of short-chain fatty acids and their receptors, and suppress the loss of intestinal tight junction proteins. In addition, the results of plasma non-targeted metabolomics revealed that pterostilbene could modulate differential metabolites and metabolic pathways associated with inflammation, thereby suppressing systemic inflammation in DCI mice. Collectively, our study found for the first time that pterostilbene could alleviate diabetic cognitive dysfunction by inhibiting the TLR4/NF-κB pathway through the microbiota-gut-brain axis, which may be one of the potential mechanisms for its neuroprotective effects.

Influence of Melatonin on Behavioral and Neurological Function of Rats with Focal Cerebral Ischemia-Reperfusion Injury via the JNK/FoxO3a/Bim Pathway.

OBJECTIVE: To investigate the influence of melatonin on behavioral and neurological function of rats with focal cerebral ischemia-reperfusion injury via the JNK/FoxO3a/Bim pathway. METHODS: One hundred and twenty healthy male SD rats were randomized into the model group (Model: the middle cerebral artery occlusion (MCAO) model was constructed and received an equal volume of normal saline containing 5% DMSO), sham operation group (Sham: received no treatment except normal feeding), and low, medium, and high dose of melatonin group (L-MT, M-MT, and H-MT intraperitoneally injected 10, 20, and 40 mg/kg melatonin 30 min after IR, respectively), with 24 rats in each group. Following 24 h of reperfusion, the rats in each of the above groups were tested for neurological deficit symptoms and behavioral changes to screen the rats included in the study. HE and TUNEL stainings were performed to observe pathological changes. Levels of oxidative stress-related indexes, inflammatory factor-related indexes, nuclear factor-κB p65 (NF-κB p65), and interferon-γ (IFN-γ) in the rat brain were measured by ELISA. The JNK/FoxO3a/Bim pathway-related proteins as well as Bcl-2, Caspase-3, and Bax were examined using Western blot. RESULTS: Detection of behavioral indicators showed that the MACO model was successfully constructed in rats. L-MT, M-MT, and L-MT groups presented reduced malondialdehyde (MDA), reactive oxygen species (ROS), tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-1ß, IFN-γ, NF-κB p65, and apoptosis compared with the Model group (P < 0.05), and the improvement degree was better in the M-MT group versus the L-HT group. Bcl-2 protein expression in the brain tissue of L-MT, M-MT, and H-MT groups increased significantly, while Bax, Caspase-3, p-JNK, p-FoxO3a, and Bim protein expression declined markedly, versus the Model group (P < 0.05). The changes of indexes were greater in the M-MT group compared with that in the L-MT group. No significant difference was observed in all the above indexes between the M-MT group and the H-MT group (P > 0.05). CONCLUSIONS: In the MACO rat model, melatonin can effectively reduce Bax and Caspase-3 levels by modulating the JNK/FoxO3a/Bim pathway, inhibit neuronal apoptosis, and alleviate neurological deficits by reducing the release of proinflammatory mediators, with anti-inflammatory and antioxidant effects. In addition, 20 mg/kg is the optimal melatonin concentration.

The Effects of Nonnutritive Sweeteners on the Cariogenic Potential of Oral Microbiome.

Nonnutritive sweeteners (NNSs) are sugar substitutes widely used to reduce the negative health effects of excessive sugar consumption. Dental caries, one of the most prevalent chronic diseases globally, results from a pathogenic biofilm with microecological imbalance and frequent exposure to sugars. Some research has shown that certain NNSs possess less cariogenic potential than sucrose, indicating their putative effect on oral microbiome. To uncover the alterations of acidogenic pathogens and alkali-generating commensals, as well as the biofilm cariogenic potential under the influence of NNSs, we selected four common NNSs (acesulfame-K, aspartame, saccharin, and sucralose) and established single-, dual-, and multispecies in vitro culture model to assess their effects on Streptococcus mutans (S. mutans) and/or Streptococcus sanguinis (S. sanguinis) compared to sucrose with the same sweetness. The results showed that NNSs significantly suppressed the planktonic growth, acid production, and biofilm formation of S. mutans or S. sanguinis compared with sucrose in single-species cultures. Additionally, decreased S. mutans/S. sanguinis ratio, less EPS generation, and higher pH value were observed in dual-species and saliva-derived multispecies biofilms with supplementary NNSs. Collectively, this study demonstrates that NNSs inhibit the cariogenic potential of biofilms by maintaining microbial equilibrium, thus having a promising prospect as anticaries agents.

Omega-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: A meta-analysis of randomized controlled trials.

BACKGROUND: Clinical trials examining the therapeutic benefit of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on nonalcoholic fatty liver disease (NAFLD) have reported inconsistent results. We performed a meta-analysis of randomized controlled trials (RCTs) examining the effect of ω-3 PUFA supplementation on NAFLD, and provide substantial evidence on whether ω-3 PUFA supplementation has a favorable effect for treating NAFLD. METHODS: We searched the PubMed, Cochrane Library, Springer Link, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Scientific and Technological Journal (VIP) databases for RCTs on oral ω-3 PUFA supplementation in patients with NAFLD. The data were pooled; meta-analyses were conducted using random-effect or fixed-effect models. RESULTS: Eighteen studies involving 1424 patients were included. We found a significant benefit for ω-3 PUFAs vs control for liver fat, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, triglycerides, insulin resistance, and glucose. However, there was significant interstudy heterogeneity. Subgroup and regression analyses showed no significantly clear methodologic discrepancy. Publication bias and serious adverse events were not detected. CONCLUSIONS: Our meta-analysis suggests that ω-3 PUFA supplementation may decrease liver fat and hepatic enzyme parameters. However, more large-scale, well-designed RCTs are needed to confirm the effect of ω-3 PUFA supplementation on these parameters.

New metric for optimizing Continuous Loop Averaging Deconvolution (CLAD) sequences under the 1/f noise model.

Continuous loop averaging deconvolution (CLAD) is one of the proven methods for recovering transient auditory evoked potentials (AEPs) in rapid stimulation paradigms, which requires an elaborated stimulus sequence design to attenuate impacts from noise in data. The present study aimed to develop a new metric in gauging a CLAD sequence in terms of noise gain factor (NGF), which has been proposed previously but with less effectiveness in the presence of pink (1/f) noise. We derived the new metric by explicitly introducing the 1/f model into the proposed time-continuous sequence. We selected several representative CLAD sequences to test their noise property on typical EEG recordings, as well as on five real CLAD electroencephalogram (EEG) recordings to retrieve the middle latency responses. We also demonstrated the merit of the new metric in generating and quantifying optimized sequences using a classic genetic algorithm. The new metric shows evident improvements in measuring actual noise gains at different frequencies, and better performance than the original NGF in various aspects. The new metric is a generalized NGF measurement that can better quantify the performance of a CLAD sequence, and provide a more efficient mean of generating CLAD sequences via the incorporation with optimization algorithms. The present study can facilitate the specific application of CLAD paradigm with desired sequences in the clinic.

Noise Attenuation Estimation for Maximum Length Sequences in Deconvolution Process of Auditory Evoked Potentials.

The use of maximum length sequence (m-sequence) has been found beneficial for recovering both linear and nonlinear components at rapid stimulation. Since m-sequence is fully characterized by a primitive polynomial of different orders, the selection of polynomial order can be problematic in practice. Usually, the m-sequence is repetitively delivered in a looped fashion. Ensemble averaging is carried out as the first step and followed by the cross-correlation analysis to deconvolve linear/nonlinear responses. According to the classical noise reduction property based on additive noise model, theoretical equations have been derived in measuring noise attenuation ratios (NARs) after the averaging and correlation processes in the present study. A computer simulation experiment was conducted to test the derived equations, and a nonlinear deconvolution experiment was also conducted using order 7 and 9 m-sequences to address this issue with real data. Both theoretical and experimental results show that the NAR is essentially independent of the m-sequence order and is decided by the total length of valid data, as well as stimulation rate. The present study offers a guideline for m-sequence selections, which can be used to estimate required recording time and signal-to-noise ratio in designing m-sequence experiments.

Lack of association between SREBF-1c gene polymorphisms and risk of non-alcoholic fatty liver disease in a Chinese Han population.

The transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) is a key regulator of lipogenesis and insulin sensitivity, and is associated with non-alcoholic fatty liver disease (NAFLD). Here, we assessed the impact of common single nucleotide polymorphisms (SNPs) in SREBF-1c on NAFLD susceptibility and associated metabolic phenotypes in a Han Chinese population. Four common SNPs (rs62064119, rs2297508, rs11868035 and rs13306741) in the SREBP-1c gene were selected and genotyped in 593 patients with NAFLD and 593 healthy controls. Unconditional logistic regression was performed to assess the risk of NAFLD by determining odds ratios and 95% confidence intervals (CIs). No significant differences in genotype and allele frequencies of these four SNPs were found between the NAFLD population and the controls (all P > 0.05). In addition, we did not find any association between the SREBF-1c SNPs and the clinical and biochemical parameters, such as body mass index, total cholesterol, high density lipoprotein-and low density lipoprotein-cholesterol or systolic and diastolic blood pressure, except that the rs2297508 C-allele or rs11868035 G-allele showed significant associations with lower triglyceride levels in control subjects (P < 0.01). Our findings suggested that the four polymorphisms in SREBF-1c gene are not associated with risk of NAFLD in the Chinese Han population.

Comparison of Auditory Middle-Latency Responses From Two Deconvolution Methods at 40 Hz.

GOAL: Auditory middle-latency responses (MLRs) are reported to be particularly susceptible to stimulation rate. Deconvolution methods are necessary to unwrap the overlapping responses at a high rate under the linear superposition assumption. This study aims to investigate and compare the MLR characteristics at high and conventional stimulation rates. METHODS: The characteristics were examined in healthy adults by using two closely related deconvolution paradigms, namely continuous-loop averaging deconvolution and multirate steady-state averaging deconvolution at a mean rate of 40 Hz, and a conventional low rate of 5 Hz. RESULTS: The morphology and stability of the MLRs can benefit from a high-rate stimulation. It appears that stimulation sequencing strategies of deconvolution methods exerted divergent rate effects on MLR characteristics, which might be associated with different adaptation mechanisms. CONCLUSION: MLRs obtained by two deconvolution methods and the conventional reference feature differently from one another. SIGNIFICANCE: These findings have critical implications in our current understanding of the rate effects on MLR characteristics which may inspire further studies to explore the characteristics of evoked responses at high rates and deconvolution paradigms.

A phase II study of preoperative chemotherapy with modified FOLFOX6 followed by surgery and postoperative chemoradiation in patients with localized gastric adenocarcinoma.

The optimal neoadjuvant and adjuvant treatment for gastric cancer remains controversial. We conducted a phase II study using preoperative chemotherapy with modified FOLFOX6 followed by surgical resection and postoperative chemoradiation in patients with gastric carcinoma. Preoperative chemotherapy (two or three cycles) consisted of a 2-h infusion of oxaliplatin (100 mg/m2) and folinic acid (100 mg/m2) followed by a 46-h continuous infusion of 5-fluorouracil (5-FU; 2,400 mg/m2). Surgical resection was planned 4 weeks after the last chemotherapy cycle. Patients underwent postsurgical chemoradiation, receiving a total dose of 45 Gy and 5-FU continuous infusion (350 mg/m2/day). The primary end points were feasibility, overall response rate, and R0 resectability rate after preoperative chemotherapy. The secondary end points were tolerability, treatment-associated complications, disease-free survival, and overall survival. Nineteen patients were enrolled in this study. After neoadjuvant treatment, four patients (21.1%) experienced progressive disease, six patients (31.6%) showed partial remission, and nine patients (47.3%) showed stable disease. In 15 patients (78.9%) R0 resectability could be achieved. Eleven of these patients (73.3%) were able to undergo postoperative chemoradiation. Notably, eight (72.7%) of these patients were disease free and alive at median follow-up of 60 months. Chemotherapy associated neutropenia, neutropenic fever, and anastomotic dehiscence were observed. The combination of preoperative chemotherapy and postoperative chemoradiation is feasible in a significant subset of gastric cancer patients.

Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population.

We investigated the possible association between genetic variants in the Patatin like phospholipase-3 (PNPLA3) gene and nonalcoholic fatty liver disease (NAFLD) in a Han Chinese population. We evaluated twelve tagging single-nucleotide polymorphisms (tSNPs) of the PNPLA3 gene in a frequency matched case-control study from Fuzhou city of China (553 cases, 553 controls). In the multivariate logistic regression analysis, the rs738409 GG or GC, and rs139051 TT genotypes were found to be associated with increased risk of NAFLD, and a significant trend of increased risk with increasing numbers of risk genotype was observed in the cumulative effect analysis of these single nucleotide polymorphisms. Furthermore, haplotype association analysis showed that, compared with the most common haplotype, the CAAGAATGCGTG and CGAAGGTGTCCG haplotypes conferred a statistically significant increased risk for NAFLD, while the CGGGAACCCGCG haplotype decreased the risk of NAFLD. Moreover, rs738409 C>G appeared to have a multiplicative joint effect with tea drinking (P<0.005) and an additive joint effect with obesity (Interaction contrast ratio (ICR) = 2.31, 95% CI: 0.7-8.86), hypertriglyceridemia (ICR = 3.07, 95% CI: 0.98-5.09) or hypertension (ICR = 1.74, 95% CI: 0.52-3.12). Our data suggests that PNPLA3 genetic polymorphisms might influence the susceptibility to NAFLD development independently or jointly in Han Chinese.

[Clinical observation on acupuncture combined with Yizhi Jiannao granules for treatment of Alzheimer's disease].

OBJECTIVE: To observe clinical therapeutic effect of acupuncture combined with Yizhi Jiannao Granules for treatment of Alzheimer's disease and its effects on intelligence, daily life and social activity ability. METHODS: Eighty-four cases were randomly divided into 3 groups, 28 cases in each group. The combined acupuncture and medication group was treated with acupuncture at Baihui (GV 20), Sishencong (EX-HN 1), Dazhui (GV 14), Guanyuan (CV 4), etc. and oral administration of Yizhi Jiannao Granules; the Chinese herb group was treated with Yizhi Jiannao Granules, and the western medicine group with oral administration of Aricept. The scores for the Mini-Mental State Examination (MMSE), Ability of Daily Life (ADL) and the therapeutic effects were assessed and compared before treatment and after treatment for 12 weeks among the groups. RESULTS: After treatment, the scores for MMSE and ADL were improved in the combined acupuncture and medication group, the Chinese herb group and the western medicine group, which were better in the combined acupuncture and medication group (P < 0.05). The total effective rate of 85.7% in the combined acupuncture and medication group was better than 71.4% in the Chinese herb group and 67.9% in the western medicine group. CONCLUSION: Acupuncture combined with Yizhi Jiannao Granules has a significant therapeutic effect on Alzheimer's disease, which is better than that of Yizhi Jiannao Granules or Aricept.