Methenamine for urinary tract infection prophylaxis: A systematic review.

Urinary tract infections (UTIs) commonly affect many patient populations. Recurrent UTIs (rUTIs) can be particularly problematic and lead to potential hospitalizations, multiple antibiotic courses, and have a potential negative impact on quality of life. To prevent UTIs, antibiotics are frequently used for prophylaxis; however, antibiotic prophylaxis has notable untoward consequences including but not limited to potential adverse effects and development of antibiotic resistance. Methenamine, an antiseptic agent initially available in 1967, has re-emerged as a potential option for UTI prophylaxis in various populations, including older adults and renal transplant recipients. The objective of this systematic review was to evaluate the clinical effectiveness and safety of methenamine for UTI prophylaxis. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance was performed. A PubMed, Embase, and Cochrane library search was conducted to identify relevant English-language studies evaluating methenamine for UTI prophylaxis including randomized controlled trials, case-control studies, and meta-analyses through June 2023. Articles were excluded if the studies did not primarily describe or evaluate methenamine for UTI prophylaxis, were commentaries/viewpoints articles, point prevalence studies, review articles, studies that evaluated methenamine used with another agent, and any duplicate publications from searched databases. A total of 11 articles were identified for inclusion. This systematic review suggests methenamine generally appears to be an effective and well-tolerated antibiotic-sparing option for UTI prophylaxis. Furthermore, the pharmacology, dosage and formulation, warnings, precautions, and safety considerations of methenamine that provide potential clinical considerations regarding its use for UTI prophylaxis are described. Further studies are needed to evaluate the clinical utility of methenamine for UTI prophylaxis.

Bioactive diterpenoids isolated from the twigs and leaves of Casearia velutina.

Nine previously undescribed clerodane-type diterpenoids (1-9), named caseabalanspenes A-I, along with six know compounds (10-15), were isolated from the twigs and leaves of Casearia velutina. Spectroscopic data (1D and 2D NMR) analysis permitted the definition of their structures and then determination of the molecular formula of the compound by high resolution mass spectrometry (HR-ESI-MS). It is worth noting that compound 7 contains N- heterocycle. Compounds 1-8 were tested the anti-inflammasome activity, and compound 3 exhibited potent activity and decreased LDH level in a dose-dependent manner, with IC50 values of 2.90 µM.

A pair of new oxindole alkaloids isolated from Uncaria macrophylla.

A pair of new oxindole alkaloids, named macrophyllines C (1) and D (2), together with two known oxindole alkaloids isorhynchophylline (3) and corynoxine (4) were isolated from Uncaria macrophylla. Their structures were elucidated based on detailed spectroscopic analysis and by comparison with literature data. In addition, all the isolates were tested for their anti-HIV activities and cytotoxicities in C8166 cells and compounds 2-4 showed weak anti-HIV activities with EC50 values of 11.31 ± 3.29 µM, 18.77 ± 6.14 µM and 30.02 ± 3.73 µM, respectively.

Cystathionine ß-Synthase Regulates the Proliferation, Migration, and Invasion of Thyroid Carcinoma Cells.

Thyroid cancer is considered to be one of the most common endocrine tumors worldwide. Cystathionine ß-synthase (CBS) plays a crucial role in the occurrence of several types of malignancies. And yet, the mechanism of action of CBS in the growth of thyroid carcinoma cells is still unrevealed. We found that CBS level in thyroid carcinoma tissue was higher than that in adjacent normal tissue. The overexpression of CBS enhanced the proliferation, migration, and invasion of thyroid cancer cells, while the downregulation of CBS exerted reverse effects. CBS overexpression reduced the levels of cleaved caspase-3 and cleaved poly ADP-ribose polymerase in thyroid cancer cells, whereas CBS knockdown showed reverse trends. CBS overexpression decreased reactive oxygen species (ROS) levels but increased the levels of Wnt3a and phosphorylations of phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB/AKT), mammalian target of rapamycin (mTOR), ß-catenin, and glycogen synthase kinase-3 beta, while CBS knockdown exerted opposite effects. In addition, CBS overexpression promoted the growth of xenografted thyroid carcinoma, whereas CBS knockdown decreased the tumor growth by modulating angiogenesis, cell cycle, and apoptosis. Furthermore, aminooxyacetic acid (an inhibitor of CBS) dose-dependently inhibited thyroid carcinoma cell growth. CBS can regulate the proliferation, migration, and invasion of human thyroid cancer cells via ROS-mediated PI3K/AKT/mTOR and Wnt/ß-catenin pathways. CBS can be a potential biomarker for diagnosing or prognosing thyroid carcinoma. Novel donors that inhibit the expression of CBS can be developed in the treatment of thyroid carcinoma.

Short-Chain Fatty Acids Ameliorate Depressive-like Behaviors of High Fructose-Fed Mice by Rescuing Hippocampal Neurogenesis Decline and Blood-Brain Barrier Damage.

Excessive fructose intake is associated with the increased risk of mental illness, such as depression, but the underlying mechanisms are poorly understood. Our previous study found that high fructose diet (FruD)-fed mice exhibited neuroinflammation, hippocampal neurogenesis decline and blood-brain barrier (BBB) damage, accompanied by the reduction of gut microbiome-derived short-chain fatty acids (SCFAs). Here, we found that chronic stress aggravated these pathological changes and promoted the development of depressive-like behaviors in FruD mice. In detail, the decreased number of newborn neurons, mature neurons and neural stem cells (NSCs) in the hippocampus of FruD mice was worsened by chronic stress. Furthermore, chronic stress exacerbated the damage of BBB integrity with the decreased expression of zonula occludens-1 (ZO-1), claudin-5 and occludin in brain vasculature, overactivated microglia and increased neuroinflammation in FruD mice. These results suggest that high fructose intake combined with chronic stress leads to cumulative negative effects that promote the development of depressive-like behaviors in mice. Of note, SCFAs could rescue hippocampal neurogenesis decline, improve BBB damage and suppress microglia activation and neuroinflammation, thereby ameliorate depressive-like behaviors of FruD mice exposed to chronic stress. These results could be used to develop dietary interventions to prevent depression.

Inhibition of endothelial Nox2 activation by LMH001 protects mice from angiotensin II-induced vascular oxidative stress, hypertension and aortic aneurysm.

Endothelial oxidative stress and inflammation attributable to the activation of a Nox2-NADPH oxidase are key features of many cardiovascular diseases. Here, we report a novel small chemical compound (LMH001, MW = 290.079), by blocking phosphorylated p47phox interaction with p22phox, inhibited effectively angiotensin II (AngII)-induced endothelial Nox2 activation and superoxide production at a small dose (IC50 = 0.25 µM) without effect on peripheral leucocyte oxidative response to pathogens. The therapeutic potential of LMH001 was tested using a mouse model (C57BL/6J, 7-month-old) of AngII infusion (0.8 mg/kg/d, 14 days)-induced vascular oxidative stress, hypertension and aortic aneurysm. Age-matched littermates of p47phox knockout mice were used as controls of Nox2 inhibition. LMH001 (2.5 mg/kg/d, ip. once) showed no effect on control mice, but inhibited completely AngII infusion-induced excess ROS production in vital organs, hypertension, aortic walls inflammation and reduced incidences of aortic aneurysm. LMH001 effects on reducing vascular oxidative stress was due to its inhibition of Nox2 activation and was abrogated by knockout of p47phox. LMH001 has the potential to be developed as a novel drug candidate to treat oxidative stress-related cardiovascular diseases.

p47phox-Dependent Oxidant Signalling through ASK1, MKK3/6 and MAPKs in Angiotensin II-Induced Cardiac Hypertrophy and Apoptosis.

The p47phox is a key regulatory subunit of Nox2-containing NADPH oxidase (Nox2) that by generating reactive oxygen species (ROS) plays an important role in Angiotensin II (AngII)-induced cardiac hypertrophy and heart failure. However, the signalling pathways of p47phox in the heart remains unclear. In this study, we used wild-type (WT) and p47phox knockout (KO) mice (C57BL/6, male, 7-month-old, n = 9) to investigate p47phox-dependent oxidant-signalling in AngII infusion (0.8 mg/kg/day, 14 days)-induced cardiac hypertrophy and cardiomyocyte apoptosis. AngII infusion resulted in remarkable high blood pressure and cardiac hypertrophy in WT mice. However, these AngII-induced pathological changes were significantly reduced in p47phox KO mice. In WT hearts, AngII infusion increased significantly the levels of superoxide production, the expressions of Nox subunits, the expression of PKCα and C-Src and the activation of ASK1 (apoptosis signal-regulating kinase 1), MKK3/6, ERK1/2, p38 MAPK and JNK signalling pathways together with an elevated expression of apoptotic markers, i.e., γH2AX and p53 in the cardiomyocytes. However, in the absence of p47phox, although PKCα expression was increased in the hearts after AngII infusion, there was no significant activation of ASK1, MKK3/6 and MAPKs signalling pathways and no increase in apoptosis biomarker expression in cardiomyocytes. In conclusion, p47phox-dependent redox-signalling through ASK1, MKK3/6 and MAPKs plays a crucial role in AngII-induced cardiac hypertrophy and cardiomyocyte apoptosis.

Multidimensional fatigue in patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy: incidence, severity, and risk factors.

PURPOSE: To explore the incidence, severity, and risk factors of multidimensional fatigue in patients with nasopharyngeal carcinoma (NPC) receiving concurrent chemoradiotherapy (CCRT). METHODS: This prospective study included 79 patients with NPC in Guangzhou (China) from June 2015 to July 2018. Data were collected before and after CCRT, including demographic and clinical characteristics, nutritional parameters, and fatigue scores, based on completion of the Multiple Dimensional Inventory-20 Questionnaire, with five subscales: General Fatigue, Mental Fatigue, Physical Fatigue, Reduced Activity, and Reduced Motivation. RESULTS: Increased general fatigue was found to be associated with lower lymphocyte count and body mass index <23 kg/m2. Increased physical fatigue was related to age > 42 years. Higher scores for reduced activity were associated with age > 42 years, female sex, and lower serum sodium. Increased mental fatigue was related with lower lymphocyte count and unemployment; and increased total fatigue was associated with lower lymphocyte count, age > 42 years, and 3-6 courses of treatment. Furthermore, 3-6 courses of treatment was an independent predictor of severe general fatigue, while age >42 years was an independent predictor of severe physical fatigue. Importantly, cancer stage IVB and 3-6 courses of treatment could predict severe total fatigue. CONCLUSIONS: Our data demonstrate that fatigue is increased in all dimensions in NPC patients following CCRT, and that the predictors differ for each fatigue dimension. These results could guide the development of targeted interventions that may reduce the impact of cancer-related fatigue in patients with NPC.

Exploration of Alcohol Consumption Behaviours and Health-Related Influencing Factors of Young Adults in the UK.

Hazardous alcohol consumption is ranked above illicit drug use with regards to health deterioration and social and economic burden. This study sought to clarify the factors influencing alcohol consumption and its prevalence in young adults. Demographics, alcohol consumption and lifestyle information were gathered via anonymous questionnaires during 2011-2019, crossing Reading, Surrey and Farnborough universities, UK. Controlling for confounders, a multinomial logistic regression was performed using SAS® 9.4 software. A total of 1440 students (43.5% males, 56.5% females; 54.4% Caucasians) with a mean (SD) age of 19.9 (2.73) were included. Among them, 68.9% consumed alcohol frequently and 31.7% had ≥12 units/week. Statistical analysis revealed that males consumed twice more alcohol than females, odds ratio (OR) 1.67 (95% confidence interval (CI) = 1.34-2.09), p-value < 0.01. Caucasians consumed up to five times more alcohol than other ethnicities, OR 4.55 (3.57-5.56), p-value < 0.01. Smokers consumed three times more alcohol than non-smokers, OR 2.69 (1.82, 3.99), p-value < 0.01. In general, the levels of alcohol consumption were positively associated with the levels of physical activity, OR 2.00 (1.17-3.42), p-value < 0.05 and negatively associated with recreational sedentary screen-time activities in males, OR 0.31 (0.12-0.86), p-value = 0.03. Focusing alcohol interventions toward Caucasians, smokers and physically active students, particularly males, may guide university strategies to reduce alcohol-related societal harm and risks of morbidity and mortality.

In vivo and in silico characterization of apocynin in reducing organ oxidative stress: A pharmacokinetic and pharmacodynamic study.

Apocynin has been widely used in vivo as a Nox2-contaninig nicotinamide adenine dinucleotide phosphate oxidase inhibitor. However, its time-dependent tissue distribution and inhibition on organ reactive oxygen species (ROS) production remained unclear. In this study, we examined apocynin pharmacokinetics and pharmacodynamics (PKPD) after intravenous (iv) injection (bolus, 5 mg/kg) of mice (CD1, 12-week). Apocynin was detected using a HPLC coupled to a linear ion-trap tandem mass spectrometer. Apocynin peak concentrations were detected in plasma at 1 minute (5494 ± 400 ng/mL) (t1/2  = 0.05 hours, clearance = 7.76 L/h/kg), in urine at 15 minutes (14 942 ± 5977 ng/mL), in liver at 5 minutes (2853 ± 35 ng/g), in heart at 5 minutes (3161 ± 309 ng/g) and in brain at 1 minute (4603 ± 208 ng/g) after iv injection. These were accompanied with reduction of ROS production in the liver, heart and brain homogenates. Diapocynin was not detected in these samples. Therapeutic effect of apocynin was examined using a mouse model (C57BL/6J) of high-fat diet (HFD, 16 weeks)-induced obesity and accelerated aging. Apocynin (5 mmol/L) was supplied in drinking water during the HFD period and was detected at the end of treatment in the brain (5369 ± 1612 ng/g), liver (4818 ± 1340 ng/g) and heart (1795 ± 1487 ng/g) along with significant reductions of ROS production in these organs. In conclusion, apocynin PKPD is characterized by a short half-life, rapid clearance, good distribution and inhibition of ROS production in major organs. Diapocynin is not a metabolite of apocynin in vivo. Apocynin crosses easily the blood-brain barrier and reduces brain oxidative stress associated with metabolic disorders and aging.

Recognition of 16-18-Year-Old Adolescents for Guiding Physical Activity Interventions: A Cross-Sectional Study.

Adolescence is a rapid life stage requiring special attention wherein personal autonomy is developed to govern independent lifestyles. Unhealthy lifestyles are integral to prevailing adolescent physical inactivity patterns. Understudied 16-18-year-olds were investigated to establish physical activity prevalences and influencing health-related lifestyle factors. Adolescents were recruited randomly across 2017-2019 from Farnborough College of Technology and North Kent College, UK. Demographic and health-related lifestyle information were gathered anonymously and analysed using SAS® 9.4 software. Among the 414 adolescents included (48.3% male and 51.7% female), the mean (standard deviation (SD)) age was 16.9 (0.77). Approximately 15.2% smoked and 20.8% were overweight/obese. There were 54.8% perceiving themselves unfit and 33.3% spent >4 h/day on leisure-time screen-based activity. Around 80.4% failed to meet the recommended fruit/vegetable daily intake and 90.1% failed to satisfy UK National Physical Activity Guidelines, particularly females (p = 0.0202). Physical activity levels were significantly associated with gender, body mass index, smoking status, leisure sedentary screen-time, fruit/vegetable consumption and fitness perceptions. Those who were female, overweight/obese, non-smoking, having poor fitness perceptions, consuming low fruit/vegetables and engaging in excess screen-based sedentariness were the groups with lowest physical activity levels. Steering physical activity-oriented health interventions toward these at-risk groups in colleges may reduce the UK's burden of adolescent obesity.

Impact of unhealthy lifestyle on cardiorespiratory fitness and heart rate recovery of medical science students.

BACKGROUND: Medical science students represent valuable labour resources for better future medicine and medical technology. However, little attention was given to the health and well-being of these early career medical science professionals. The aim of this study is to investigate the impact of lifestyle components on cardiorespiratory fitness and heart rate recovery measured after moderate exercise in this population. METHODS: Volunteers without documented medical condition were recruited randomly and continuously from the first-year medical science students during 2011-2014 at the University of Surrey, UK. Demographics and lifestyle components (the levels of smoking, alcohol intake, exercise, weekend outdoor activity and screen-time, daily sleep period, and self-assessment of fitness) were gathered through pre-exercise questionnaire. Cardiorespiratory fitness (VO2max) and heart rate recovery were determined using Åstrand-Rhyming submaximal cycle ergometry test. Data were analysed using SPSS version 25. RESULTS: Among 614 volunteers, 124 had completed both lifestyle questionnaire and the fitness test and were included for this study. Within 124 participants (20.6 ± 4 years), 46.8% were male and 53.2% were female, 11.3% were overweight and 8.9% were underweight, 8.9% were current smokers and 33.1% consumed alcohol beyond the UK recommendation. There were 34.7% of participants admitted to have < 3 h/week of moderate physical activity assessed according to UK Government National Physical Activity Guidelines and physically not fit (feeling tiredness). Fitness test showed that VO2max distribution was inversely associated with heart rate recovery at 3 min and both values were significantly correlated with the levels of exercise, self-assessed fitness and BMI. Participants who had < 3 h/week exercise, or felt not fit or were overweight had significantly lower VO2max and heart rate recovery than their peers. CONCLUSION: One in three new medical science students were physically inactive along with compromised cardiorespiratory fitness and heart rate recovery, which put them at risk of cardiometabolic diseases. Promoting healthy lifestyle at the beginning of career is crucial in keeping medical science professionals healthy.

Nox2 dependent redox-regulation of Akt and ERK1/2 to promote left ventricular hypertrophy in dietary obesity of mice.

BACKGROUND: A Nox2 containing NADPH oxidase (Nox2) is involved in the global oxidative stress found in dietary obesity and metabolic disorders. However, the effects of high fat diet (HFD) on cardiac Nox2 activation and signaling in left ventricular hypertrophy (LVH) remain unknown. METHODS: Left ventricular (LV) tissues isolated from C57BL/6J wild-type (WT) and Nox2 knockout (Nox2KO) mice (11 months old, n = 6 per group) after 4 months of HFD treatment were used. Cardiomyocyte sizes were measured digitally on LV cross-sections. The levels of cardiac reactive oxygen species (ROS) production was determined using lucigenin-chemiluminescence and in situ dihydroethidium (DHE) fluorescence. The levels of Nox subunit expression and redox signaling were examined by immunoblotting and immunofluorescence. RESULTS: In comparison to WT normal chow diet control hearts, WT HFD hearts had 1.8-fold increases in cardiomyocyte size, a sign of cardiac hypertrophy, and this was accompanied with ≥2-fold increase in the levels of ROS production, Nox2 expression and the phosphorylation of Akt and ERK1/2. Increased ROS production measured in HFD heart homogenates was inhibited to control levels by Tiron (a cell membrane permeable O2•-scavenger), diphenyleneiodonium (DPI, a flavohaemoprotein inhibitor) and Nox2 ds-tat (a Nox2 assembly inhibitor). However, all of these abnormalities were significantly reduced or absent in Nox2KO hearts under the same HFD. CONCLUSIONS: Nox2 activation in response to dietary obesity and metabolic disorders plays a key role in cardiac oxidative stress, aberrant redox signaling and cardiomyocyte hypertrophy. Knockout of Nox2 protects hearts from oxidative damage associated with obesity and metabolic disorders.

Potential effect of herbal antidepressants on cognitive deficit: Pharmacological activity and possible molecular mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Cognitive symptom is a "core" symptom of major depressive disorder (MDD) patients with clear deficit in memory, social and occupational function, and may persist during the remitting phase. Therefore, the remission of cognitive symptom has been considered as one of the main objectives in the treatment of MDD. Herbal antidepressants have been used to treat MDD, and there has been great advances in the understanding of the ability of these herbs to improve cognitive deficit linked to brain injury and various diseases including depression, Alzheimer disease, diabetes and age-related disorders. This systematic review summarizes the evidence from preclinical studies and clinical trials of herbal antidepressants with positive effects on cognitive deficit. The potential mechanisms by which herbal antidepressants prevent cognitive deficit are also reviewed. This review will facilitate further research and applications. MATERIALS AND METHODS: We conducted an open-ended, English restricted search of MEDLINE (PubMed), Web of Science and Scopus for all available articles published or online before 31 December 2019, using terms pertaining to medical herb/phytomedicine/phytochemical/Chinese medicine and depression/major depressive disorder/antidepressant and/or cognitive impairment/cognitive deficit/cognitive dysfunction. RESULTS: 7 prescriptions, more than 30 individual herbs and 50 phytochemicals from China, Japan, Korea and India with positive effects on the depressive state and cognitive deficit are reviewed herein. The evidence from preclinical studies and clinical trials proves that these herbal antidepressants exhibit positive effects on one or more aspects of cognitive defect including spatial, episodic, aversive, and short- and long-term memory. The action mode of the improvement of cognitive deficit by these herbal antidepressants is mediated mainly through two pathways. One pathway is to promote hippocampal neurogenesis through activating brain derived neurotrophic factor-tropomyosin-related kinase B signaling. The other pathway is to prevent neuronal apoptosis through the inhibition of neuro-inflammation and neuro-oxidation. CONCLUSION: These herbal antidepressants, having potential therapy for cognitive deficit, may prevent pathological processes of neurodegenerative diseases. Furthermore, these herbal medicines should provide a treasure trove, which will accelerate the development of new antidepressants that can effectively improve cognitive symptom in MDD. Studies on their molecular mechanisms may provide more potential targets and therapeutic approaches for new drug discovery.

Nox2 dependent redox-regulation of microglial response to amyloid-ß stimulation and microgliosis in aging.

Microglia express constitutively a Nox2 enzyme that is involved in neuroinflammation by the generation of reactive oxygen species (ROS). Amyloid ß (Aß) plays a crucial role in Alzheimer's disease. However, the mechanism of Aß-induced microglial dysfunction and redox-regulation of microgliosis in aging remains unclear. In this study, we examined Nox2-derived ROS in mediating microglial response to Aß peptide 1-42 (Aß42) stimulation in vitro, in aging-associated microgliosis in vivo and in post-mortem human samples. Compared to controls, Aß42 markedly induced BV2 cell ROS production, Nox2 expression, p47phox and ERK1/2 phosphorylation, cell proliferation and IL-1ß secretion. All these changes could be inhibited to the control levels in the presence of Nox2 inhibitor or superoxide scavenger. Compared to young (3-4 months) controls, midbrain tissues from wild-type aging mice (20-22 months) had significantly higher levels of Nox2-derived ROS production, Aß deposition, microgliosis and IL-1ß production. However, these aging-related changes were reduced or absent in Nox2 knockout aging mice. Clinical significance of aging-associated Nox2 activation, microgliosis and IL-1ß production was investigated using post-mortem midbrain tissues of humans at young (25-38 years) and old age (61-85 years). In conclusion, Nox2-dependent redox-signalling is crucial in microglial response to Aß42 stimulation and in aging-associated microgliosis and brain inflammation.

Construction of a comprehensive nutritional index and its correlation with quality of life and survival in patients with nasopharyngeal carcinoma undergoing IMRT: A prospective study.

OBJECTIVES: The aim of this study was to investigate the relationship between a comprehensive nutritional index (CNI) and QoL in patients with NPC who undergo IMRT and to explore the relationship between CNI and survival. METHODS: 359 patients with newly diagnosed NPC were enrolled. QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 and Quality of Life Questionnaire Head and Neck Cancer Module at three time points: before, immediately after, and 3 months after IMRT. The CNI comprised five values including body mass index, usual body weight percentage, hemoglobin, albumin, and total lymphocyte count, and was evaluated before and immediately after IMRT. The correlation between the CNI and QoL and the effect of CNI on prognosis were analysed. RESULTS: QoL and CNI scores decreased remarkably after IMRT (P < 0.05). The CNI was quite low in patients with III-IV clinical tumor stage and those undergoing induction chemotherapy plus concurrent chemotherapy. After IMRT, lower CNI score correlated worse QoL (P < 0.05). The Kaplan-Meier curve indicated that patients with lower CNI had significantly poorer survival outcomes (P = 0.02). In multivariate analysis, CNI remained an independent prognostic factor of overall survival (P = 0.046). CONCLUSIONS: CNI can be recommended as an appropriate indicator reflecting the integrated nutrition status of NPC patients. Low CNI was associated with poor QoL and predicted a poor survival outcome. More interventions should be taken to improve the nutrition status of NPC patients to improve QoL and enhance survival outcomes.

Dietary fructose-induced gut dysbiosis promotes mouse hippocampal neuroinflammation: a benefit of short-chain fatty acids.

BACKGROUND: Western-style diets arouse neuroinflammation and impair emotional and cognitive behavior in humans and animals. Our previous study showed that a high-fructose diet caused the hippocampal neuroinflammatory response and neuronal loss in animals, but the underlying mechanisms remained elusive. Here, alterations in the gut microbiota and intestinal epithelial barrier were investigated as the causes of hippocampal neuroinflammation induced by high-fructose diet. RESULTS: A high-fructose diet caused the hippocampal neuroinflammatory response, reactive gliosis, and neuronal loss in C57BL/6N mice. Depletion of the gut microbiota using broad-spectrum antibiotics suppressed the hippocampal neuroinflammatory response in fructose-fed mice, but these animals still exhibited neuronal loss. Gut microbiota compositional alteration, short-chain fatty acids (SCFAs) reduction, intestinal epithelial barrier impairment, NOD-like receptor family pyrin domain-containing 6 (NLRP6) inflammasome dysfunction, high levels of serum endotoxin, and FITC-dextran were observed in fructose-fed mice. Of note, SCFAs, as well as pioglitazone (a selective peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist), shaped the gut microbiota and ameliorated intestinal epithelial barrier impairment and NLRP6 inflammasome dysfunction in fructose-fed mice. Moreover, SCFAs-mediated NLRP6 inflammasome activation was inhibited by histamine (a bacterial metabolite) in ex vivo colonic explants and suppressed in murine CT26 colon carcinoma cells transfected with NLRP6 siRNA. However, pioglitazone and GW9662 (a PPAR-γ antagonist) exerted no impact on SCFAs-mediated NLRP6 inflammasome activation in ex vivo colonic explants, suggesting that SCFAs may stimulate NLRP6 inflammasome independently of PPAR-γ activation. SCFAs and pioglitazone prevented fructose-induced hippocampal neuroinflammatory response and neuronal loss in mice. Additionally, SCFAs activated colonic NLRP6 inflammasome and increased DCX+ newborn neurons in the hippocampal DG of control mice. CONCLUSIONS: Our findings reveal that gut dysbiosis is a critical factor for a high-fructose diet-induced hippocampal neuroinflammation in C57BL/6N mice possibly mediated by impairing intestinal epithelial barrier. Mechanistically, the defective colonic NLRP6 inflammasome is responsible for intestinal epithelial barrier impairment. SCFAs can stimulate NLRP6 inflammasome and ameliorate the impairment of intestinal epithelial barrier, resulting in the protection against a high-fructose diet-induced hippocampal neuroinflammation and neuronal loss. This study addresses a gap in the understanding of neuronal injury associated with Western-style diets. A new intervention strategy for reducing the risk of neurodegenerative diseases through SCFAs supplementation or dietary fiber consumption is emphasized.