Gut microbiota regulates chronic ethanol exposure-induced depressive-like behavior through hippocampal NLRP3-mediated neuroinflammation.

Chronic ethanol exposure (CEE), which can lead to neuroinflammation, is an increasing risk factor for depression disorder, but the underlying mechanism is not clear. Recent observations have revealed the associations among psychiatric disorders, ethanol exposure and alterations of the gut microbiota. Here, we found that CEE induced depressive-like behavior, which could be alleviated by probiotics and transferred from donor to recipient mice by fecal microbiota transplantation (FMT). Neuroinflammation and the activation of the NLRP3 inflammasome were also observed in recipient mice. The downregulation of NLRP3 in the hippocampus mitigated CEE-induced depressive-like behavior and neuroinflammation but had no significant effect on FMT recipient mice. Moreover, elevated serum inflammatory factors in recipient mice showed a significant mediation effect between the gut microbiota and depressive-like behavior. Together, our study findings indicate that the gut microbiota contributes to both hippocampal NLRP3-mediated neuroinflammation and depressive-like behavior induced by CEE, which may open avenues for potential interventions against CEE-associated psychiatric disorders.

Retinoic Acid-Induced Regulation of Inflammatory Pathways Is a Potential Sepsis Treatment.

Sepsis is among the most dangerous known diseases, resulting from the dysregulation of the innate immune system in a process that is characterized largely by proinflammatory cytokines. It manifests as an excessive immune response to a pathogen and often leads to life-threatening complications such as shock and multiple-organ failure. Within the past several decades, much progress has been made to better understand the pathophysiology of sepsis and improve treatment. However, the average case-fatality rate for sepsis remains high. Current anti-inflammatory therapeutics for sepsis are not effective for use as first-line treatments. Focusing on all-trans-retinoic acid (RA), or activated vitamin A, as a novel anti-inflammatory agent, we have shown both in vitro and in vivo that RA decreases the production of proinflammatory cytokines. In vitro studies using mouse RAW 264.7 macrophages show that RA decreases tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) and increases mitogen-activated protein kinase phosphatase 1 (MKP-1). RA treatment was also associated with the reduced phosphorylation of key inflammatory signaling proteins. Using a lipopolysaccharide and cecal slurry sepsis model, we found that RA significantly reduced mortality rates in mice, downregulated proinflammatory cytokine production, decreased neutrophil infiltration into lung tissue, and reduced the destructive lung histopathology typically seen in sepsis. We propose that RA may increase the function of native regulatory pathways and serve as a novel treatment for sepsis.

Pinaverium Bromide Attenuates Lipopolysaccharide-Induced Excessive Systemic Inflammation via Inhibiting Neutrophil Priming.

Dominant infiltration of neutrophils is a hallmark of many inflammatory diseases, especially in septic shock. IL-1ß as one of the most early released proinflammatory cytokine in neutrophil, plays a pivotal role in the progress of sepsis. In this study, we built a high-throughput-compatible drug screen assay platform based on our newly constructed reporter C57BL/6 mice, pIL1-DsRed, expressing the DsRed gene under the control of the IL-1ß promoter. After screening 1200 U.S. Food and Drug Administration-approved compounds, we found that pinaverium bromide (PVB) significantly suppressed the DsRed expression of primed neutrophil and improved the survival rate of mice given LPS in an endotoxin challenge analogous to sepsis, regardless of whether PVB was administered before or after LPS. PVB also protected the liver and lung from LPS-induced damage and reduced organ-specific inflammatory responses. PVB decreased the production of IL-1ß, IL-6, and CXCL1 mRNA in the lungs of LPS-treated mice and decreased the serum levels of liver transaminases (alanine aminotransferase and aspartate aminotransferase) at multiple time points and doses tested. PVB can significantly suppress primed neutrophil-specific respiratory bursts and migration as well. Lastly, PVB affected neutrophils' gene expression and phenotypic changes during neutrophil priming. PVB downregulated GM-CSF-induced expression of CD54 and dectin-2 (markers of fully primed neutrophils) at both mRNA and protein levels during late-phase neutrophil priming. In summary, we demonstrated that PVB can be used as a potential therapeutic agent for sepsis by inhibiting neutrophil priming.

AMPAkine CX516 alleviated chronic ethanol exposure-induced neurodegeneration and depressive-like behavior in mice.

Chronic ethanol exposure (CEE) is associated with greater neurodegenerative effects and an increased risk of depression disorder. The AMPAR is thought to be involved in depression and a reduction in its GluA1 subunit was observed in the mouse hippocampus after CEE. AMPAkines are positive allosteric modulators of the AMPA receptor and have improved depressive-like behavior. However, the role of AMPARs in CEE-induced depressive-like behavior is not clear. It is unclear whether AMPAkines, positive allosteric agonists of AMPARs, protect against ethanol-induced depression. We investigated the effects of CX516 on ethanol-induced depressive-like behavior in a mouse model. CX516 (5 mg/kg) administration alleviated 20% (m/V) ethanol-induced depressive-like behavior in mice. Furthermore, CX516 significantly diminished the inhibition of the ERK1/2-BDNF-TrkB pathway in the hippocampus of ethanol-exposed mice. In addition, CX516 attenuated the levels of pro-inflammatory (IL-6, IL-1ß), apoptosis (BAX, BCL-2), and neurodegeneration (FJC) in the mouse hippocampus induced by CEE.

Chronic ethanol exposure induced anxiety-like behaviour by altering gut microbiota and GABA system.

Ethanol, also known as alcohol, is one of the most common drinks in the world. Chronic ethanol exposure has been reported to induce mental disorders. Ethanol also has a strong effect on the gut microbiota. The gut microbiota has been reported to affect the brain via multiple pathways, including changes in γ-aminobutyric acid (GABA) system, and cause a variety of mental disorders. The GABA system in the cortex is associated with anxiety. However, the role of gut microbiota played in ethanol exposure-induced changes in the GABA system and anxiety is still not clear. We established a 30-day ethanol exposure mouse model and investigated the effects of microbiota using the antibiotic minocycline. Minocycline alleviated ethanol-induced anxiety-like behaviour, dysbiosis of microbiota, intestinal barrier disruption, increased serum endotoxin and interleukin (IL)-6. Minocycline also attenuated ethanol-induced apoptosis and decreased expression of glutamate decarboxylases (GADs) and GABRA1 in the prefrontal cortex. Our results indicated that gut microbiota plays an important role in ethanol-induced anxiety-like behaviour by altering the function of GABA system. In addition, causal mediation analysis showed that endotoxin and IL-6 may mediate the connection between the gut microbiota and the expression of GABAA receptor in the prefrontal cortex.

Amp 1q21 is more predictable with dismal survival than gain 1q21 of newly diagnosed multiple myeloma in real-world analysis.

INTRODUCTION: The gain/amplification (amp) of 1q21 is one of the most common high-risk chromosome abnormality (HRCA) in multiple myeloma (MM). The prognostic value of 1q21+ remains to be controversial on the status of gain or amp and the combination of other HRCAs. METHODS: In this retrospective study, we included 318 newly diagnosed MM (NDMM) patients who had fluorescence in situ hybridization (FISH) data and treated with novel agents in our department. RESULTS: Our study noted MM patients with amp 1q21 were more likely accompanied with t(4;14), t(14;16), and t(14;20). Patients with amp 1q21 presented with elder age, advanced Revised International Staging System (R-ISS) stages, anemia, and more plasma cells in bone marrow compared to patients with gain 1q21 alone and no 1q21+. Moreover, amp 1q21 alone correlated with shorter progression-free survival (PFS) (22.8m vs. 40.5m vs. 39.6m) and overall survival (OS) (45.2m vs. NA vs. 83.5m) compared with gain 1q21 alone and no FISH abnormalities. Although the high ratio of proteasome inhibitor and immunomodulatory drugs used in patients with amp 1q21, the overall response (ORR) was the lowest compared with no 1q21+ and gain 1q21. Multivariate analysis defined amp 1q21 as an independent prognostic marker for NDMM patients, rather than gain 1q21. CONCLUSION: The amp 1q21 predict inferior treatment response and survival, especially coexisted with high-risk IgH translocation.

Enhanced protection against lipopolysaccharide-induced acute lung injury by autologous transplantation of adipose-derived stromal cells combined with low tidal volume ventilation in rats.

Adipose-derived stromal cells (ADSCs) showed excellent capacity in regeneration and tissue protection. Low tidal volume ventilation (LVT) strategy demonstrates a therapeutic benefit on the treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). This study, therefore, aimed to undertaken determine whether the combined LVT and ADSCs treatment exerts additional protection against lipopolysaccharide (LPS)-induced ALI in rats. The animals were randomized into seven groups: Group I (control), Group II (instillation of LPS at 10 mg/kg intratracheally), Group III (LPS+LVT 6 ml/kg), Group IV (LPS+intravenous autologous 5 × 106 ADSCs which were pretreated with a scrambled small interfering RNA [siRNA] of keratinocyte growth factor [KGF] negative control), Group V (LPS+ADSCs which were pretreated with a scrambled siRNA of KGF, Group VI (LPS+LVT and ADSCs as in the Group IV), and Group VII (LPS+LVT and ADSCs as in the Group V). We found that levels of tumor necrosis factor-α, transforming growth factor-ß1, and interleukin (IL)-1ß and IL-6, the proinflammatory cytokines, were remarkably increased in LPS rats. Moreover, the expressions of ENaC, activity of Na, K-ATPase, and alveolar fluid clearance (AFC) were obviously reduced by LPS-induced ALI. The rats treated by ADSCs showed improved effects in all these changes of ALI and further enhanced by ADSCs combined with LVT treatment. Importantly, the treatment of ADSCs with siRNA-mediated knockdown of KGF partially eliminated the therapeutic effects. In conclusion, combined treatment with ADSCs and LVT not only is superior to either ADSCs or LVT therapy alone in the prevention of ALI. Evidence of the beneficial effect may be partly due to improving AFC by paracrine or systemic production of KGF and anti-inflammatory properties.

Caregiver burden among informal caregivers of hospitalized patients with frailty: A cross-sectional survey.

This study aimed to investigate the status of caregiver burden among informal caregivers of hospitalized frail older patients and explore the associated factors. A total of 191 frail older patients and their informal caregivers were recruited from the inpatient units of the three teaching hospitals. We collected data using the FRAIL scale, the Zarit Burden Interview, and the Simplified Coping Style Questionnaire. We used descriptive statistics, Pearson correlation coefficients, one-way analysis of variance, and multiple linear regression for the data analysis. The caregivers of hospitalized frail older patients experienced a moderate caregiver burden (26.476±11.289). The regression model for caregiver burden was significant. Male caregivers, taking care of patients before hospitalization, experiencing negative emotions, and negative coping styles were significantly associated with caregiver burden, F (7, 183) = 15.13, p <. 001. The findings suggest that early identification of caregiver burden and focused interventions for alleviating caregiver burden are needed.

Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease.

AIM: Muscle weakness is commonly among chronic kidney disease (CKD) patients. Muscle mitochondrial dysfunction and decreased pyruvate dehydrogenase (PDH) activity occur in CKD animals but have not been confirmed in humans, and changes in pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) expression have not been evaluated in CKD muscle. We presume that the reduction of muscle mitochondria and post-translational modification of PDH may cause muscle weakness in CKD patients. Herein, we explored changes in mitochondrial morphology, PDH expression and activity, and PDK/PDP expression in CKD patient muscle. METHODS: Twenty patients with stage 4-5 CKD (CKD group) and 24 volunteers (control group) were included. Clinical characteristics, biochemical information and handgrip strength (HGS) were determined. Skeletal muscle samples were collected from eight stage 5 CKD patients from CKD group. Other eight non-CKD surgical subjects' muscle samples were collected as control. PDH activity was determined using a PDH enzyme activity assay kit, and real-time PCR and western blotting analyses were performed to measure gene expression and protein levels, respectively. Transmission electron microscopy was used to study mitochondria morphology. RESULTS: CKD patients had lower HGS than non-CKD subjects, and HGS was correlated with gender, age, haemoglobin and albumin. Mitochondria were decreased in end-stage renal disease (ESRD) patients muscle. Mfn-1 expression and phospho-Drp1(S637)/Drp1 ratio were inhibited in the ESRD group, implicating dysfunctional mitochondrial dynamics. Muscle PDH activity and phospho-PDH(S293) were decreased in ESRD patient muscle, while PDK4 protein level was up regulated. CONCLUSION: Decreased mitochondria and PDH deficiency caused by up regulation of PDK 4 contribute to muscle dysfunction, and could be responsible for muscle weakness in CKD patients.

Effectiveness of auricular point therapy for cancer-related fatigue: A systematic review and meta-analysis.

AIMS: To systemically review the efficacy and safety of auricular point therapy in patients with cancer-related fatigue. DESIGN: A systematic review and meta-analysis of randomized controlled trials. DATA SOURCES: Eight electronic databases (PubMed, CENTRAL, Embase, CINAHL, Web of Science, China Biology Medicine, China National Knowledge Infrastructure and WanFang Data Knowledge Service Platform) were explored for randomized controlled trials from their inception to 1 December 2018. REVIEW METHODS: The risk of bias assessment tool was adopted in accordance with Cochrane Handbook 5.3.0. All included studies reported the effects on cancer-related fatigue as the primary outcome. Effect size was estimated using relative risk, standardized mean difference or mean difference with a corresponding 95% confidence interval. Review Manager 5.3 was used for meta-analysis. RESULTS: Six studies comprising 394 patients were included. The results of meta-analysis showed that auricular point therapy plus standard care produced more positive effects on cancer-related fatigue and quality of life than standard care alone. It could significantly improve the role, emotional, cognitive, and social functions of patients with cancer-related fatigue. CONCLUSIONS: Auricular point therapy may be a safe therapy to relieve cancer-related fatigue and enhance the quality of life of patients with cancer. However, the evidence was inconclusive due to limitations on the quantity and quality of included studies. Rigorously designed randomized controlled trials should be conducted to verify the results. IMPACT: Auricular point therapy is a simple and safe therapeutic approach that may alleviate cancer-related fatigue of common complications in patients with cancer and it is worth promoting in the community, family, and hospital. Moreover, the research findings can provide suggestions and inspiration for nurses and researchers to implement the proposal, which is conducive to design more rigorous and high-quality randomized controlled trials.

The color/shape/flavor of yam gel with double emulsified microcapsules changed synchronously in 4D printing induced by microwave.

The feasibility of 3D printing the color, aroma and shape changes of yam gel with microwave heating as stimulus and soybean protein isolate-chitosan-maltodextrin complex coacervated microcapsules rich in water-soluble betacyanin and rose essence as stimulus-response materials was discussed. The morphology of microcapsules presented irregular spherical structure, and the surface was relatively smooth and slightly concave. Microwave heating led to the gradual destruction of microcapsules in yam gel, releasing internal pigments and essence, and enhancing the redness and flavor of printed samples. The release of the water phase and oil phase of the microcapsules and the hot-spot expansion effect of the models made the 3D printed bird models bend and deform, realizing the deformation effect of "spreading of wings", which realized a three-response synchronous change in color, shape, and flavor of the printed samples within 45 s. In this study, a variety of 4D printed foods with synchronous changes in sensory characteristics were created, which increased sensory enjoyment on the basis of ensuring the nutritional needs of food.

A PACAP-activated network for secretion requires coordination of Ca 2+ influx and Ca 2+ mobilization.

Chromaffin cells of the adrenal medulla transduce sympathetic nerve activity into stress hormone secretion. The two neurotransmitters principally responsible for coupling cell stimulation to secretion are acetylcholine and pituitary adenylate activating polypeptide (PACAP). In contrast to acetylcholine, PACAP evokes a persistent secretory response from chromaffin cells. However, the mechanisms by which PACAP acts are poorly understood. Here, it is shown that PACAP induces sustained increases in cytosolic Ca 2+ which are disrupted when Ca 2+ influx through L-type channels is blocked or internal Ca 2+ stores are depleted. PACAP liberates stored Ca 2+ via inositol trisphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER), thereby functionally coupling Ca 2+ mobilization to Ca 2+ influx and supporting Ca 2+ -induced Ca 2+ -release. These Ca 2+ influx and mobilization pathways are unified by an absolute dependence on phospholipase C epsilon (PLCε) activity. Thus, the persistent secretory response that is a defining feature of PACAP activity, in situ , is regulated by a signaling network that promotes sustained elevations in intracellular Ca 2+ through multiple pathways.

A PACAP-activated network for secretion requires coordination of Ca2+ influx and Ca2+ mobilization.

Chromaffin cells of the adrenal medulla transduce sympathetic nerve activity into stress hormone secretion. The two neurotransmitters principally responsible for coupling cell stimulation to secretion are acetylcholine and pituitary adenylate activating polypeptide (PACAP). In contrast to acetylcholine, PACAP evokes a persistent secretory response from chromaffin cells. However, the mechanisms by which PACAP acts are poorly understood. Here, it is shown that PACAP induces sustained increases in cytosolic Ca2+ which are disrupted when Ca2+ influx through L-type channels is blocked or internal Ca2+ stores are depleted. PACAP liberates stored Ca2+ via inositol trisphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER), thereby functionally coupling Ca2+ mobilization to Ca2+ influx and supporting Ca2+-induced Ca2+-release. These Ca2+ influx and mobilization pathways are unified by an absolute dependence on phospholipase C epsilon (PLCε) activity. Thus, the persistent secretory response that is a defining feature of PACAP activity, in situ, is regulated by a signaling network that promotes sustained elevations in intracellular Ca2+ through multiple pathways.

Microwave-Induced Rapid Shape Change of 4D Printed Vegetable-Based Food.

Microwave heating acts as an environmental stimulus factor to induce rapid shape changes in 4D-printed stereoscopic models over time. The influence of microwave power and model structure on the shape change behavior was explored, and the applicability of the deformed method to other vegetable-based gels was verified. The results described that the G', G″, η, and proportion of bound water of yam gels increased with the increase in yam powder content, and the yam gel with 40% content had the best printing effect. The IR thermal maps showed the microwaves first gathered in the designed gully region caused the swelling phenomenon, which induced the printed sample to undergo a bird-inspired "spreading of wings" process within 30 s. Increasing the microwave power and microwave heating time were able to increase the bending angles and dehydration rates of the printed samples, thus improving the deformed degree and deformed speed. Different model base thicknesses (4, 6, 8, and 10 mm) also had significant effects on the shape change of the printed structures. The efficiency of the shape changes of 4D-printed structures under microwave induction can be judged by studying the dielectric properties of the materials. In addition, the deformed behaviors of other vegetable gels (pumpkin and spinach) verified the applicability of the 4D deformed method. This study aimed to create 4D-printed food with personalized and rapid shape change behavior, providing a basis for the application scenarios of 4D-printed food.