Overexpression of forebrain PTP1B leads to synaptic and cognitive impairments in obesity.

Obesity has reached pandemic proportions and is a risk factor for neurodegenerative diseases, including Alzheimer's disease. Chronic inflammation is common in obese patients, but the mechanism between inflammation and cognitive impairment in obesity remains unclear. Accumulative evidence shows that protein-tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. We investigated the causal role of PTP1B in obesity-induced cognitive impairment and the beneficial effect of PTP1B inhibitors in counteracting impairments of cognition, neural morphology, and signaling. We showed that obese individuals had negative relationship between serum PTP1B levels and cognitive function. Furthermore, the PTP1B level in the forebrain increased in patients with neurodegenerative diseases and obese cognitive impairment mice with the expansion of white matter, neuroinflammation and brain atrophy. PTP1B globally or forebrain-specific knockout mice on an obesogenic high-fat diet showed enhanced cognition and improved synaptic ultrastructure and proteins in the forebrain. Specifically, deleting PTP1B in leptin receptor-expressing cells improved leptin synaptic signaling and increased BDNF expression in the forebrain of obese mice. Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-1436, well-tolerated in Phase 1 and 1b clinical trials for obesity and type II diabetes) prevented these alterations, including improving cognition, neurite outgrowth, leptin synaptic signaling and BDNF in both obese cognitive impairment mice and a neural cell model of PTP1B overexpression. These findings suggest that increased forebrain PTP1B is associated with cognitive decline in obesity, whereas inhibition of PTP1B could be a promising strategy for preventing neurodegeneration induced by obesity.

Olanzapine attenuates 5-HT2cR and GHSR1a interaction to increase orexigenic hypothalamic NPY: Implications for neuronal molecular mechanism of metabolic side effects of antipsychotics.

The main cause of second-generation antipsychotic (SGA)-induced obesity is considered due to the antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling. It is reported that 5-HT2cR interacted with GHSR1a, however it is unknown whether one of the SGA olanzapine alters the 5-HT2cR/GHSR1a interaction, affecting orexigenic neuropeptide signalling in the hypothalamus. We found that olanzapine treatment increased average energy intake and body weight gain in mice; olanzapine treatment also increased orexigenic neuropeptide (NPY) and GHSR1a signaling molecules, pAMPK, UCP2, FOXO1 and pCREB levels in the hypothalamus. By using confocal fluorescence resonance energy transfer (FRET) technology, we found that 5-HT2cR interacted/dimerised with the GHSR1a in the hypothalamic neurons. As 5-HT2cR antagonist, both olanzapine and S242084 decreased the interaction between 5-HT2cR and GHSR1a and activated GHSR1a signaling. The 5-HT2cR agonist lorcaserin counteracted olanzapine-induced attenuation of interaction between 5-HT2cR and GHSR1a and inhibited activation of GHSR1a signalling and NPY production. These findings suggest that 5-HT2cR antagonistic effect of olanzapine in inhibition of the interaction of 5-HT2cR and GHSR1a, activation GHSR1a downstream signaling and increasing hypothalamic NPY, which may be the important neuronal molecular mechanism underlying olanzapine-induced obesity and target for prevention metabolic side effects of antipsychotic management in psychiatric disorders.

Meta-analysis of the hazards of microplastics in freshwaters using species sensitivity distributions.

The environmental hazards of microplastics have raised concerns about their potential ecological risks. However, our understanding of the true risks may be limited because most laboratory studies used pristine microplastics. Here, we analyzed the available literature about ecotoxicological effects of microplastics, including weathered microplastics in particular, on freshwater biota and performed probabilistic species sensitivity distributions. The predicted no-effect concentrations for pristine microplastics were lower than those for weathered microplastics, both in mass concentration (6.1 and 4.8 × 102 µg/L) and number concentration (2.6 × 104 and 2.0 × 106 part/m3). In addition, the toxicological studies on microplastics contains often inconsistent and inconclusive information due to the complexity of the microplastics and the employed exposure conditions. The available data for Daphnia magna and Danio rerio was analyzed in detail to understand the effects of microplastic size, shape and polymer type on their ecotoxicity. Microplastic size was the biggest driving factor, followed by shape and polymer type. There was a tendency for increasing toxicity with smaller size, however, a high variability of effect data was observed for small microplastics. This study provided further insights into the effect thresholds for ecological risk assessment of microplastics and the effects of microplastic characteristics on toxicity.

Propofol EC50 for inducing loss of consciousness in patients under combined epidural-general anesthesia or general anesthesia alone: a randomized double-blind study.

Background: Combined epidural-general anesthesia (GA + EA) has been recommended as a preferred technique for both thoracic and abdominal surgery. The epidural anesthesia on the general anesthetic (GA) requirements has not been well investigated. Therefore, we conducted the present study to explore the predicted effect-site concentration of propofol (Ceprop) required for achieving the loss of consciousness (LOC) in 50% of patients (EC50) with or without epidural anesthesia. Methods: Sixty patients scheduled for gastrectomy were randomized into the GA + EA group or GA alone group to receive general anesthesia alone. Ropivacaine 0.375% was used for epidural anesthesia to achieve a sensory level of T4 or above prior to the induction of general anesthesia. The EC50 of predicted Ceprop for LOC was determined by the up-down sequential method. The consumption of anesthetics, emergence time from anesthesia, and postoperative outcomes were also recorded and compared. Results: The EC50 of predicted Ceprop for LOC was lower in the GA + EA group than in the GA alone group [2.97 (95% CI: 2.63-3.31) vs. 3.36 (95% CI: 3.19-3.53) µg mL-1, (p = 0.036)]. The consumption of anesthetics was lower in the GA + EA group than in the GA alone group (propofol: 0.11 ± 0.02 vs. 0.13 ± 0.02 mg kg-1 min-1, p = 0.014; remifentanil: 0.08 ± 0.03 vs. 0.14 ± 0.04 µg kg-1 min-1, p < 0.001). The emergence time was shorter in the GA + EA group than in the GA alone group (16.0 vs. 20.5 min, p = 0.013). Conclusion: Concomitant epidural anesthesia reduced by 15% the EC50 of predicted Ceprop for LOC, decreased the consumptions of propofol and remifentanil during maintenance of anesthesia, and fastened recovery from anesthesia. Clinical trial registration: ClinicalTrials.gov, identifier: NCT05124704.

Increasing dopamine synthesis in nigrostriatal circuits increases phasic dopamine release and alters dorsal striatal connectivity: implications for schizophrenia.

One of the most robust neurochemical abnormalities reported in patients with schizophrenia is an increase in dopamine (DA) synthesis and release, restricted to the dorsal striatum (DS). This hyper functionality is strongly associated with psychotic symptoms and progresses in those who later transition to schizophrenia. To understand the implications of this progressive neurobiology on brain function, we have developed a model in rats which we refer to as EDiPs (Enhanced Dopamine in Prodromal schizophrenia). The EDiPs model features a virally mediated increase in dorsal striatal (DS) DA synthesis capacity across puberty and into adulthood. This protocol leads to progressive changes in behaviour and neurochemistry. Our aim in this study was to explore if increased DA synthesis capacity alters the physiology of DA release and DS connectivity. Using fast scan cyclic voltammetry to assess DA release we show that evoked/phasic DA release is increased in the DS of EDiPs rats, whereas tonic/background levels of DA remain unaffected. Using quantitative immunohistochemistry methods to quantify DS synaptic architecture we show a presynaptic marker for DA release sites (Bassoon) was elevated within TH axons specifically within the DS, consistent with the increased phasic DA release in this region. Alongside changes in DA systems, we also show increased density of vesicular glutamate transporter 1 (VGluT1) synapses in the EDiPs DS suggesting changes in cortical connectivity. Our data may prove relevant in understanding the long-term implications for DS function in response to the robust and prolonged increases in DA synthesis uptake and release reported in schizophrenia.

Changes in sulfur in soybean rhizosphere soil and the response of microbial flora in a continuous cropping system mediated by Funneliformis mosseae.

Soybean is an S-loving crop, and continuous cropping might cause soil sulfur shortage. The primary objectives of this study are to determine whether Funneliformis mosseae (F. mosseae) can enhance the content of available S in S-deficient soil and thereby improve the sulfur utilization rate in soybean. The experiment used Heinong 48 (HN48), a soybean variety with a vast planting area in Heilongjiang Province, and F. mosseae was inoculated in the soil of soybean that had been continuously cropped for 0 and 3 years. The results of the barium sulfur turbidimetric assay show that the sulfur content in the soil and soybean was reduced by continuous cropping and increased by inoculation with F. mosseae; the results of the macro-genome sequencing technology, show that the diversity and abundance of bacteria in the soil was decreased by continuous cropping and increased by inoculation with F. mosseae. The sulfur-oxidizing bacteria (SOB) activity and sulfur-related gene expression levels were lower in the continuous crop group compared to the control group and higher in the F.mosseae-inoculated group compared to the control group. Continuous cropping reduced the sulfur content and ratio of soybean rhizosphere soil, affecting soil flora activity and thus soybean growth; F. mosseae inoculation increased the sulfur content of soybean root-perimeter soil and plants, increased the diversity and abundance of rhizosphere soil microorganisms, increased the expression of genes for sulfur transport systems, sulfur metabolism, and other metabolic functions related to elemental sulfur, and increased the species abundance and metabolic vigor of most SOB. In summary, continuous cropping inhibits soil sulfur uptake and utilization in soybean while the inoculation with F. mosseae can significantly improve this situation. This study offers a theoretical research foundation for using AMF as a bio-fungal agent to enhance soil sulfur use. It also supports the decrease of chemical fertilizers, their substitution, and the protection of native soil.

Developmental vitamin D-deficiency produces autism-relevant behaviours and gut-health associated alterations in a rat model.

Developmental vitamin D (DVD)-deficiency is an epidemiologically established risk factor for autism. Emerging studies also highlight the involvement of gut microbiome/gut physiology in autism. The current study aims to examine the effect of DVD-deficiency on a broad range of autism-relevant behavioural phenotypes and gut health. Vitamin D deficient rat dams exhibited altered maternal care, DVD-deficient pups showed increased ultrasonic vocalizations and as adolescents, social behaviour impairments and increased repetitive self-grooming behaviour. There were significant impacts of DVD-deficiency on gut health demonstrated by alterations to the microbiome, decreased villi length and increased ileal propionate levels. Overall, our animal model of this epidemiologically validated risk exposure for autism shows an expanded range of autism-related behavioural phenotypes and now alterations in gut microbiome that correlate with social behavioural deficits raising the possibility that DVD-deficiency induced ASD-like behaviours are due to alterations in gut health.

Theoretical Study on the Formation and Decomposition Mechanisms of Coelenterazine Dioxetanone.

Bioluminescence has been drawing broad attention due to its high signal-to-noise ratio and high bioluminescence quantum yields, which has been widely applied in the fields of biomedicine, bioanalysis, and so on. Among numerous bioluminescent substrates, coelenterazine is famous for its wide distribution. However, the oxygenation reaction mechanism of coelenterazine is far from being completely understood. In this paper, the formation and decomposition mechanisms of coelenterazine dioxetanone were investigated via density functional theory (DFT) and time-dependent (TD) DFT approaches. The results showed that the oxygenation reaction first occurred along the triplet-state potential energy surface (PES), after the intersystem crossing (ISC), second jumped to the diradical-state PES, and ultimately formed coelenterazine dioxetanone. For the decomposition mechanism of dioxetanone, the computational results showed that the chemiexcitation of neutral dioxetanone was more efficient than that of other dioxetanone species. Moreover, the diradical properties and the degree of ionic character are modified by the counter ions.

Vitamin D: A potent regulator of dopaminergic neuron differentiation and function.

Vitamin D has been identified as a key factor in dopaminergic neurogenesis and differentiation. Consequently, developmental vitamin D (DVD) deficiency has been linked to disorders of abnormal dopamine signalling with a neurodevelopmental basis such as schizophrenia. Here we provide further evidence of vitamin D's role as a mediator of dopaminergic development by showing that it increases neurite outgrowth, neurite branching, presynaptic protein re-distribution, dopamine production and functional release in various in vitro models of developing dopaminergic cells including SH-SY5Y cells, primary mesencephalic cultures and mesencephalic/striatal explant co-cultures. This study continues to establish vitamin D as an important differentiation agent for developing dopamine neurons, and now for the first time shows chronic exposure to the active vitamin D hormone increases the capacity of developing neurons to release dopamine. This study also has implications for understanding mechanisms behind the link between DVD deficiency and schizophrenia.

Vitamin D and the Central Nervous System: Causative and Preventative Mechanisms in Brain Disorders.

Twenty of the last one hundred years of vitamin D research have involved investigations of the brain as a target organ for this hormone. Our group was one of the first to investigate brain outcomes resulting from primarily restricting dietary vitamin D during brain development. With the advent of new molecular and neurochemical techniques in neuroscience, there has been increasing interest in the potential neuroprotective actions of vitamin D in response to a variety of adverse exposures and how this hormone could affect brain development and function. Rather than provide an exhaustive summary of this data and a listing of neurological or psychiatric conditions that vitamin D deficiency has been associated with, here, we provide an update on the actions of this vitamin in the brain and cellular processes vitamin D may be targeting in psychiatry and neurology.

Hydrogen Sulfide Attenuates High-Fat Diet-Induced Obesity: Involvement of mTOR/IKK/NF-κB Signaling Pathway.

Obesity has become a public health epidemic worldwide and is associated with many diseases with high mortality including hypertension, diabetes, and heart disease. High-fat diet (HFD)-induced energy imbalance is one of the primary causes of obesity, but the underlying mechanisms are not fully elucidated. Our study showed that HFD reduced the level of hydrogen sulfide (H2S) and its catalytic enzyme cystathionine ß-synthase (CBS) in mouse hypothalamus and plasma. We found that HFD activated mTOR, IKK/NF-κB, the main pathway regulating inflammation. Activation of inflammatory pathway promoted the production of pro-inflammatory cytokines including IL-6, IL-1ß, and TNF-α, which caused cell damage and loss in the hypothalamus. The disturbance of the hypothalamic neuron circuits resulted in body weight gain in HFD-induced mice. Importantly, we also showed that restoration of H2S level with NaHS or activation of CBS with SAMe attenuated HFD-induced activation of mTOR, IKK/NF-κB signaling, which reduced the inflammation and the neuronal cell loss in the hypothalamus, and also inhibited body weight gain in mice. The same effects were obtained by inhibiting mTOR or NF-κB, which suggested that mTOR and NF-κB were the critical molecular factors involved in hypothalamic inflammation. Taken together, this study identified that HFD-induced hypothalamus inflammation plays a critical role in the development of obesity. Moreover, the inhibition of hypothalamic inflammation by regaining H2S level could be a potential therapeutic to prevent the development of obesity.

Prenatal hypoxia alters the early ontogeny of dopamine neurons.

Dopaminergic (DA) dysfunction is a significant feature in the pathophysiology of schizophrenia. Established developmental risk factors for schizophrenia such as maternal immune activation (MIA) or developmental vitamin D (DVD) deficiency, when modelled in animals, reveal the differentiation of early DA neurons in foetal brains is delayed suggesting this may be a convergent aetiological pathway. Here we have assessed the effects of prenatal hypoxia, another well-known developmental risk factor for schizophrenia, on developing DA systems. Pregnant mice were exposed to a hypoxic environment of 10% oxygen for 48 h from embryonic day 10 (E10) to E12. Embryonic brains were collected and the positioning of mesencephalic cells, expression of DA specification and maturation factors were examined along with the expression of factors that may govern the migration of these neurons. We show that prenatal hypoxia results in a decrease in dopaminergic progenitors retards early DA neuron lateral migration and reduces expression of the receptors known to govern this process. A second time-point, postnatal day 10 (P10) was also examined in order to assess whether prenatal hypoxia alters early presynaptic architecture in the developing striatum. We show reduced expression of tyrosine hydroxylase (TH) in the postnatal striatum along with increases in the density of high-probability DA release sites within TH varicosities. These findings add to the emerging literature showing that multiple epidemiologically validated environmental risk factors for schizophrenia may induce early alterations to develop DA systems. This may represent a possible convergent mechanism in the onset of presynaptic DA dysfunction in patients.

Developmental vitamin D-deficiency increases the expression of microRNAs involved in dopamine neuron development.

Schizophrenia is a neurodevelopmental disorder associated with abnormal dopamine (DA) signalling and disruptions in early brain development. We have shown that developmental vitamin D-deficiency (DVD-deficiency) increases the risk of schizophrenia in offspring and impairs various aspects of brain development in rodents, particularly that of DA neurons, however the molecular basis of these impairments remains unclear. Here, we explore whether small non-coding microRNAs (miRNAs) are involved. miRNAs regulate gene expression post-transcriptionally via translational repression and destabilisation of mRNA. While dysregulation of multiple miRNAs has been reported in post-mortem brain of patients with schizophrenia, the biological pathways affected by these small RNAs are not clear. Here we identified differential expression of 18 miRNAs in DA neurons isolated from DVD-deficient embryos. Three miRNAs were selected for further functional studies of dopaminergic neuron differentiation based on their interactions with transcripts involved in neuronal maturation. In particular, we show upregulation of miR-181c-5p suppresses neurite outgrowth of dopaminergic neurons. These findings provide further evidence that an environmental risk factor for schizophrenia - DVD-deficiency - disrupts the development of DA neurons and suggests increased miRNA expression may be one possible mechanism. This disruption potentially underlies the long-term alterations in DA mediated brain function in DVD-deficient offspring, and by inference in schizophrenia.

Three Different Types of ß-Glucans Enhance Cognition: The Role of the Gut-Brain Axis.

Background: Dietary fiber is fermented in the lower gastrointestinal tract, potentially impacting the microbial ecosystem and thus may improve elements of cognition and brain function via the gut-brain axis. ß-glucans, soluble dietary fiber, have different macrostructures and may exhibit different effects on the gut-brain axis. This study aimed to compare the effects of ß-glucans from mushroom, curdlan and oats bran, representing ß-(1,3)/(1,6)-glucan, ß-(1,3)-glucan or ß-(1,3)/(1,4)-glucan, on cognition and the gut-brain axis. Methods: C57BL/6J mice were fed with either control diet or diets supplemented with ß-glucans from mushroom, curdlan and oats bran for 15 weeks. The cognitive functions were evaluated by using the temporal order memory and Y-maze tests. The parameters of the gut-brain axis were examined, including the synaptic proteins and ultrastructure and microglia status in the hippocampus and prefrontal cortex (PFC), as well as colonic immune response and mucus thickness and gut microbiota profiles. Results: All three supplementations with ß-glucans enhanced the temporal order recognition memory. Brain-derived neurotrophic factor (BDNF) and the post-synaptic protein 95 (PSD95) increased in the PFC. Furthermore, mushroom ß-glucan significantly increased the post-synaptic thickness of synaptic ultrastructure in the PFC whilst the other two ß-glucans had no significant effect. Three ß-glucan supplementations decreased the microglia number in the PFC and hippocampus, and affected complement C3 and cytokines expression differentially. In the colon, every ß-glucan supplementation increased the number of CD206 positive cells and promoted the expression of IL-10 and reduced IL-6 and TNF-α expression. The correlation analysis highlights that degree of cognitive behavior improved by ß-glucan supplementations was significantly associated with microglia status in the hippocampus and PFC and the number of colonic M2 macrophages. In addition, only ß-glucan from oat bran altered gut microbiota and enhanced intestinal mucus. Conclusions: We firstly demonstrated long-term supplementation of ß-glucans enhanced recognition memory. Comparing the effects of ß-glucans on the gut-brain axis, we found that ß-glucans with different molecular structures exhibit differentia actions on synapses, inflammation in the brain and gut, and gut microbiota. This study may shed light on how to select appropriate ß-glucans as supplementation for the prevention of cognitive deficit or improving immune function clinically.

The cadmium decontamination and disposal of the harvested cadmium accumulator Amaranthus hypochondriacus L.

The heavy metal accumulated biomass after phytoremediation needs to be decontaminated before disposal. Liquid extraction is commonly used to remove and recycle toxic heavy metals from contaminated biomass. In this study, we examined the cadmium (Cd) removal efficiency using different chemical reagents (hydrochloric acid, nitric acid, sulfuric acid, and ethylenediaminetetraacetic acid disodium) of the post-harvest Amaranthus hypochondriacus L. biomass. The purifications for the extracted liquids and ecological risk assessments for the extracted residues were also investigated. We have found that 77.8% of Cd in stems and 62.1% of Cd in leaves were removed by 0.25 M HCl after 24 h. In addition, K2CO3, KOH, and 4 Å molecular sieve could remove ≥89.0% of Cd in the extracted liquids. Finally, after we returned the extracted residues to the earthworm-incubated soil, the extracted biomass negatively affected the growth (weight loss ≥ 11.0%) and survival (mortality ≥ 33.3%) of Eisenia fetida. It should be noted that earthworms decreased soil available Cd concentrations from 0.14-0.05 mg kg-1 to 0.11-0.04 mg kg-1 and offset the negative effects of the Cd-contaminated biomass on soil microbes. Overall, given the cost of reagents, the Cd removal efficiency, and the ecological risks of the extracted biomass, using 0.25 M HCl for liquid extraction and K2CO3 for purification should be recommended. This work highlights the potential of liquid extraction for immediately and directly removing the Cd from fresh contaminated accumulator biomass and the resource cycling potential of the extracted liquids and biomass after purification.

Curcumin Protects against Renal Ischemia/Reperfusion Injury by Regulating Oxidative Stress and Inflammatory Response.

OBJECTIVE: The aim of this study was to explore the pharmacological effects of curcumin on oxidative stress and inflammatory response of renal dysfunction induced by renal ischemia/reperfusion (RIRI). METHODS: Fifty male SD rats (Sprague Dawley) were randomly divided into the sham group, RIRI group, and curcumin group (low, medium, and high). The RIRI model was established by clipping the left renal artery for 45 min and then reperfusion for 24 h and resection of the contralateral kidney. In the curcumin group, curcumin was intraperitoneally injected once a day for 3 consecutive days using different dosage regimens. The RIRI group was intraperitoneally administered with normal saline. Renal injury was evaluated by measuring the concentration of creatinine (Cr) and urea nitrogen (BUN) in serum. Oxidative stress was assessed by assessing the level of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), and iron reduction/antioxidant capacity (FRAP) in tissues. In addition, the protective effect of RIRI was investigated by measuring Paller scores, the level of serum inflammatory factors and caspase-3, and the number of apoptotic cells. RESULTS: Ischemia/reperfusion resulted in increased levels of Cr and BUN in serum and MDA in tissues and decreased levels of SOD, CAT, GPx, GSH, and FRAP. Curcumin pretreatment strikingly increased the level of SOD, CAT, GPx, GSH, IL-10, IFN-γ, and FRAP and significantly decreased MDA, Cr, BUN, IL-8, TNF-α, IL-6, and myeloperoxidase (MPO) expressions in tissues. CONCLUSION: Curcumin can relieve the degree of renal injury and improve renal function in ischemia-reperfusion, which may be related to the fact that curcumin can increase SOD content in serum and reduce MDA and FRAP levels in the rat model.

A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites.

BACKGROUND: Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis. RESULTS: In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment. CONCLUSIONS: This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases. Video Abstract.

Smoking is a risk factor for postoperative ileus after radical resection in male patients.

ABSTRACT: Most smokers are males, and smoking has been indicated as a risk factor for many cancers as well as postoperative complications after cancer surgery. However, little is known about whether smoking is a risk factor for postoperative ileus (POI) after radical rectal cancer resection in males. The aim of this study was to assess whether smoking is a risk factor for POI after radical resection in male rectal cancer patients.Data of 1486 patients who underwent radical resection for rectal cancer were extracted from the clinical medical system in our hospital and were statistically analyzed. POI was defined as nausea, vomiting or pain, failure to have bowel function for more than 4 days postoperatively, and absence of a mechanical bowel obstruction.The rate of POI was 12.79%. Univariate analysis showed that patients in the POI group were more likely to have a history of smoking and drinking and receive intraperitoneal chemotherapy and had a larger intraperitoneal chemotherapy dosage. In the multivariable analysis, smoking remained significantly associated with a higher incidence of POI (OR 2.238, 95% CI [1.545-3.240], P = .000). The results also showed that patients who received postoperative patient-controlled intravenous analgesia had a lower incidence of POI.Male patients with a history of smoking who undergo elective radical resection for rectal cancer have an increased risk for POI complications.

Three LHPP gene-targeting co-expressed microRNAs (microRNA-765, microRNA-21, and microRNA-144) promote proliferation, epithelial-mesenchymal transition, invasion, and are independent prognostic biomarkers in renal cell carcinomas patients.

BACKGROUND: Renal cell carcinoma (RCC) is one of the highly malignant tumors in the world. Global Cancer Statistics 2020 estimated that there were 179,368 deaths from kidney tumors. Therefore, exploring the prognostic biomarkers of RCC is of great significance for RCC patients. This study aims to explore the potential mechanism and prognostic value of phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) gene-targeting co-expression microRNAs in RCC patients. METHODS: A total of 60 RCC patients were included. Quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry were used for LHPP, microRNA-765, microRNA-21, and microRNA-144 levels evaluation. Cell Counting Kit-8 assay, dual-luciferase reporter gene assay, invasion assay, and RNA fluorescence in situ hybridization were used for functional analyses. RESULTS: Compared with adjacent tissues, LHPP levels in cancer tissues were significantly increased (p < .001). Herein, we confirmed that microRNA-765, microRNA-21, and microRNA-144 were direct biological targets of LHPP. MicroRNA-765 (r = -0.570, p < 0.001), microRNA-21 (r = -0.495, p < .001), and microRNA-144 (r = -0.463, p < .001) expression levels were negatively correlated with LHPP expression levels. The high expression levels of microRNA-765, microRNA-21, and microRNA-144 in RCC tissues were associated with poor differentiation, recurrence, and poor prognosis (p < .05). In vitro, microRNA-765, microRNA-21, and microRNA-144 act as oncogenes to promote proliferation, invasion, and epithelial-mesenchymal transition (EMT) through targeting LHPP. CONCLUSIONS: MicroRNA-765, microRNA-21, and microRNA-144 are independent risk biomarkers for RCC patients. Inhibiting the expression levels of microRNA-765, microRNA-21, and microRNA-144 can reduce the proliferation, EMT, and invasion of RCC cells. Therefore, the above three microRNAs are expected to become molecular biomarkers for RCC therapy.

Developmental Inhibition of Long Intergenic Non-Coding RNA, HOTAIRM1, Impairs Dopamine Neuron Differentiation and Maturation.

The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is controlled by a complex web of transcriptional factors that dictate DA neuron specification, differentiation, and maturation. A growing body of evidence suggests that these transcriptional factors are under the regulation of newly discovered non-coding RNAs. However, with regard to DA neuron development, little is known of the roles of non-coding RNAs. The long non-coding RNA (lncRNA) HOX-antisense intergenic RNA myeloid 1 (HOTAIRM1) is present in adult DA neurons, suggesting it may have a modulatory role in DA systems. Moreover, HOTAIRM1 is involved in the neuronal differentiation in human stem cells suggesting it may also play a role in early DA neuron development. To determine its role in early DA neuron development, we knocked down HOTAIRM1 using RNAi in vitro in a human neuroblastoma cell line, and in vivo in mouse DA progenitors using a novel in utero electroporation technique. HOTAIRM1 inhibition decreased the expression of a range of key DA neuron specification factors and impaired DA neuron differentiation and maturation. These results provide evidence of a functional role for HOTAIRM1 in DA neuron development and differentiation. Understanding of the role of lncRNAs in the development of DA systems may have broader implications for brain development and neurodevelopmental disorders such as schizophrenia.