The oncogenic kinase TOPK upregulates in psoriatic keratinocytes and contributes to psoriasis progression by regulating neutrophils infiltration.

BACKGROUND: T-LAK cell-oriented protein kinase (TOPK) strongly promotes the malignant proliferation of cancer cells and is recognized as a promising biomarker of tumor progression. Psoriasis is a common inflammatory skin disease featured by excessive proliferation of keratinocytes. Although we have previously reported that topically inhibiting TOPK suppressed psoriatic manifestations in psoriasis-like model mice, the exact role of TOPK in psoriatic inflammation and the underlying mechanism remains elusive. METHODS: GEO datasets were analyzed to investigate the association of TOPK with psoriasis. Skin immunohistochemical (IHC) staining was performed to clarify the major cells expressing TOPK. TOPK conditional knockout (cko) mice were used to investigate the role of TOPK-specific deletion in IMQ-induced psoriasis-like dermatitis in mice. Flow cytometry was used to analyze the alteration of psoriasis-related immune cells in the lesional skin. Next, the M5-induced psoriasis cell model was used to identify the potential mechanism by RNA-seq, RT-RCR, and western blotting. Finally, the neutrophil-neutralizing antibody was used to confirm the relationship between TOPK and neutrophils in psoriasis-like dermatitis in mice. RESULTS: We found that TOPK levels were strongly associated with the progression of psoriasis. TOPK was predominantly increased in the epidermal keratinocytes of psoriatic lesions, and conditional knockout of TOPK in keratinocytes suppressed neutrophils infiltration and attenuated psoriatic inflammation. Neutrophils deletion by neutralizing antibody greatly diminished the suppressive effect of TOPK cko in psoriasis-like dermatitis in mice. In addition, topical application of TOPK inhibitor OTS514 effectively attenuated already-established psoriasis-like dermatitis in mice. Mechanismly, RNA-seq revealed that TOPK regulated the expression of some genes in the IL-17 signaling pathway, such as neutrophils chemokines CXCL1, CXCL2, and CXCL8. TOPK modulated the expression of neutrophils chemokines via activating transcription factors STAT3 and NF-κB p65 in keratinocytes, thereby promoting neutrophils infiltration and psoriasis progression. CONCLUSIONS: This study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.

Transplant of fecal microbiota from healthy young mice relieves cognitive defects in late-stage diabetic mice by reducing metabolic disorders and neuroinflammation.

Fecal microbiota transplant (FMT) is becoming as a promising area of interest for treating refractory diseases. In this study, we investigated the effects of FMT on diabetes-associated cognitive defects in mice as well as the underlying mechanisms. Fecal microbiota was prepared from 8-week-aged healthy mice. Late-stage type 1 diabetics (T1D) mice with a 30-week history of streptozotocin-induced diabetics were treated with antibiotics for 7 days, and then were transplanted with bacterial suspension (100 µL, i.g.) once a day for 14 days. We found that FMT from healthy young mice significantly alleviated cognitive defects of late-stage T1D mice assessed in Morris water maze test. We revealed that FMT significantly reduced the relative abundance of Gram-negative bacteria in the gut microbiota and enhanced intestinal barrier integrity, mitigating LPS translocation into the bloodstream and NLRP3 inflammasome activation in the hippocampus, thereby reducing T1D-induced neuronal loss and astrocytic proliferation. FMT also reshaped the metabolic phenotypes in the hippocampus of T1D mice especially for alanine, aspartate and glutamate metabolism. Moreover, we showed that application of aspartate (0.1 mM) significantly inhibited NLRP3 inflammasome activation and IL-1ß production in BV2 cells under a HG/LPS condition. We conclude that FMT can effectively relieve T1D-associated cognitive decline via reducing the gut-brain metabolic disorders and neuroinflammation, providing a potential therapeutic approach for diabetes-related brain disorders in clinic.

Reversible Mechanical Switching of Ferroelastic Stripe Domains in Multiferroic Thin Films.

The application potential of ferroelectric thin films largely relies on the controllability of their domain structure. Among the various proposed strategies, mechanical switching is being considered as a potential alternative to replace electrical switching for control of the domain structure of ferroelectric thin films via, e.g., the flexoelectric effect. So far, studies on mechanical switching are confined to out-of-plane polarization switching in ferroelectric thin films, which are in pristine or prepoled single-domain states. In this work, we report reversible in-plane mechanical switching of the monoclinic phase (MC phase) stripe domains in BiFeO3 thin films can be realized by scanning tip force. Via controlling the fast scan direction of the scanning probe microscopy tip and the magnitude of the tip force, the effective trailing field induced by the local tip force can be rotated to consequently switch the net in-plane polarization of the two-variant stripe domain patterns by either 90° or 180°. Moreover, the monoclinic to rhombohedral (MC-R) phase transition occurs during mechanical switching with the distribution of R-phase domains dependent on the switching paths. These results extend our current understanding of the mechanical switching behavior in ferroelectric thin films and should be instructive for their future applications.

On-surface conversion reaction realizes advanced red phosphorus/carbon anode for high-performance lithium-ion batteries.

Red phosphorus (RP), the one of the most prospective anodes in lithium-ion batteries (LIBs), has been severely limited due to the intrinsic defects of massive volume expansion and low electronic conductivity. The vaporization-condensation-conversion (VCC), which confines RP nanoparticles into carbon host, is the most widely used method to address the above drawbacks and prepare RP/C nanostructured composites. However, the volume effect-dominated RP caused by the inevitably deposition of RP vapor on the surface of carbon material suffers from the massive volume change and unstable solid electrolyte interface (SEI) film. Herein, we propose a simple interfacial modification method to eliminate the superficial RP and yield stable surface composed of ion-conducting Li3PS4 solid electrolyte, endowing RP/AC composites excellent cycling performance and ultrafast reaction kinetics. Therefore, the RP/AC@S composites exhibit 926 mAh/g after 320 cycles at 0.2 A/g (running over 181 days), with 81.6 % capacity retention and a corresponding capacity decay rate of as low as 0.059 %. When coupled with LiFePO4 cathode, the full cells present superior cycling performance (62.1 mAh/g after 500 cycles at 1 A/g) and excellent rate capability (81.1 mAh/g at 1.0 A/g).

Effect of Supplementation with Black Soldier Fly Extract on Intestinal Function in Piglets Infected with Porcine Epidemic Diarrhea Virus.

Porcine epidemic diarrhea virus (PEDV) has developed as a global problem for the pig business, resulting in significant financial losses. Black soldier fly extract (BFE) has been proven to improve intestinal growth in pigs after weaning. Consequently, the goal of the present investigation was to explore the effects of BFE supplementation on intestinal function in PEDV-infected piglets. Eighteen piglets were randomly allocated to three groups: control, PEDV, and BFE + PEDV. The piglets in the BFE + PEDV group received 500 mg/kg BW of BFE orally for seven days from day 4 to 10 of the study. On day 9 of the study, six pigs from each group received either clean saline or PEDV solution at a dosage of 106 TCID50 (50% tissue culture infectious dose) per pig. On day 11, samples of blood and intestine were taken for additional investigation. The results indicated a significant decrease in the average daily gain (ADG) of piglets infected with PEDV (p < 0.05). Additionally, PEDV infection led to an alteration of blood indexes and a reduction in plasma D-xylose concentration and villi height in the small intestine, while it increased plasma diamine oxidase activity and small intestinal crypt depth in piglets (p < 0.05). The PEDV infection significantly reduced antioxidant enzyme activity in plasma and the gut, including total superoxide dismutase and catalase, while increasing contents of oxidation-relevant products such as malondialdehyde and hydrogen peroxide in piglets. Moreover, PEDV infection increased the mRNA expression level of antiviral-related genes (p < 0.05). Nutritional supplementation with BFE improved intestinal histomorphological indicators and reduced oxidative stress produced by PEDV infection in piglets. Interestingly, BFE could significantly promote the mRNA expression level of antiviral-related genes in the ileum (p < 0.05). Overall, the preliminary results suggest that dietary BFE could improve intestinal function in piglets after PEDV infection. Currently, the findings put a spotlight on the role of BFE in the prevention and treatment of PED in piglets.

Lactobacillus rhamnosus GG powder supplementation alleviates intestinal injury in piglets challenged by porcine epidemic diarrhea virus.

Porcine epidemic diarrhea virus (PEDV) has become a challenging problem in pig industry worldwide, causing significant profit losses. Lactobacillus rhamnosus GG (LGG) has been regarded as a safe probiotic strain and has been shown to exert protective effects on the intestinal dysfunction caused by PEDV. This study evaluated the effect of LGG on the gut health of lactating piglets challenged with PEDV. Fifteen piglets at 7 days of age were equally assigned into 3 groups (5 piglets per group): 1) control group (basal diet); 2) PEDV group: (basal diet + PEDV challenged); 3) LGG + PEDV group (basal diet + 3×109 CFU/pig/day LGG + PEDV). The trial lasted 11 days including 3 days of adaptation. The treatment with LGG was from D4 to D10. PEDV challenge was carried out on D8. PEDV infection disrupted the cell structure, undermined the integrity of the intestinal tract, and induced oxidative stress, and intestinal damage of piglets. Supplementation of LGG improved intestinal morphology, enhanced intestinal antioxidant capacity, and alleviated jejunal mucosal inflammation and lipid metabolism disorders in PEDV-infected piglets, which may be regulated by LGG by altering the expression of TNF signaling pathway, PPAR signaling pathway, and fat digestion and absorption pathway.

Effect of supplementation with yeast polysaccharides on intestinal function in piglets infected with porcine epidemic diarrhea virus.

Porcine epidemic diarrhea virus (PEDV) has caused huge economic losses to the pig industry. Yeast polysaccharides (YP) has been used as a feed additive in recent years and poses good anti-inflammatory and antiviral effects. The present study aimed to explore the protective effect of YP on intestinal damage in PEDV-infected piglets. Eighteen 7-day-old piglets with similar body weights were randomly divided into three groups: Control group (basal diet), PEDV group (basal diet), and PEDV+YP group (basal diet +20 mg/kg BW YP), six replicates per group and one pig per replicate. Piglets in PEDV group and PEDV+YP group were orally given PEDV (dose: 1 × 106 TCID50) at 19:30 PM on the 8th day of the experiment. The control group received the same volume of PBS solution. Weight was taken on an empty stomach in the morning of the 11th day, blood was collected and then anesthetic was administered with pentobarbital sodium (50 mg/kg·BW) by intramuscular injection, and samples were slaughtered after the anesthetic was complete. The results showed that YP could alleviate the destruction of intestinal villus morphology of piglets caused by PEDV. Meanwhile, PEDV infection can reduce the activity of glutathione peroxidase, superoxide dismutase and catalase, and increase the content of malondialdehyde. YP can improve the antioxidative capacity in the serum and small intestine of PEDV-infected piglets. In addition, YP inhibited the replication of PEDV in the jejunum ileum and colon. Moreover, YP can regulate the mRNA levels of inflammatory genes (IL-1ß and iNOS) and lipid metabolic genes (APOA4 and APOC3) in the small intestine. In summary, YP could inhibit virus replicates, improve intestinal morphology, enhance antioxidant capacity, relieve inflammation and regulate the metabolism of the intestine in PEDV-infected piglets.

Raspberry polysaccharides attenuate hepatic inflammation and oxidative stress in diet-induced obese mice by enhancing butyrate-mediated intestinal barrier function.

Obesity and associated liver diseases are becoming global public health challenges. Raspberry (Rubus chingii Hu.), as a medicine food homology plant, possesses a series of health-promoting properties, but its protective effect on obesity-related liver injury and the potential mechanisms remain obscure. Herein high-fat diet (HFD)-fed mice were orally treated with raspberry polysaccharides (RCP) for 14 weeks. Treatment with RCP alleviated obesity and associated symptoms including hyperglycemia, hyperlipemia, endotoxemia, as well as hepatic inflammation and oxidant stress in HFD-induced obese mice. RCP restructured the gut microbiota and host metabolism especially by increasing the levels of Dubosiella and its metabolite butyrate. Besides, exogenous butyrate supplementation protected against intestinal barrier disruption, and thereby reduced inflow of lipopolysaccharide and mitigated inflammation and oxidative injury in the liver of obese mice. Therefore, we suggest that RCP can be utilized as a novel prebiotics to improve obesity-induced hepatic oxidative injury by enhancing butyrate-mediated intestinal barrier function.

Protein profiles in the transfected oviductal secreting cells of laying hen (Gallus gallus domesticus).

Due to the intensive development of novel biopharming applications, there is a need for the in vitro verification models prior to in vivo testing. Laying hen has been already applied as an animal bioreactor to produce the therapeutical enzyme in a rare disease called lysosomal acid lipase deficiency. In this study, we aimed to verify how the proteome of the transfected oviduct epithelial cells would be affected by genetic nonviral modification with the human exogene. The study was based on a previously developed method to cultivate chicken oviduct epithelial cells (COEC). The typical characteristics of the COEC epithelial cells were retained across the experiments. The mean efficiency of nucleofection ranged from 2.6 to 19.7% depending on the cells' isolation and location in the oviduct (upper, infundibulum site, or magnum). The PCR confirmed the incorporation of human interferon alpha2a (hIFNα2a) exogene into the nucleofected COEC but, the production of hIFNα2a protein did not exceed the detection level in this study. The ovalbumin protein was detected in the nontransfected and transfected COEC, which confirmed the normal secreting functions of the cells subject to modification. Proteomic analysis revealed an increase in abundance of the cell adhesion molecules and collagen molecules after introducing gene under ovalbumin promoter. According to the bioinformatic analyses there was a limited negative impact of transfection on cells, and the normal biochemical pathways were not severely disordered. In conclusion, the observations provide new knowledge about the proteomic profile of the manipulated COEC with regard to the retained normal functionality of the cells, which can be informative for avian biopharma research.

Untargeted metabolomics analysis reveals spatial metabolic heterogeneity in different intestinal segments of type 1 diabetic mice.

Type 1 diabetes (T1D) has been reported to cause systematic metabolic disorders, but metabolic changes in different intestinal segments of T1D remain unclear. In this study, we analyzed metabolic profiles in the jejunum, ileum, cecum and colon of streptozocin-induced T1D and age-matched control (CON) mice by an LC-MS-based metabolomics method. The results show that segment-specific metabolic disorders occurred in the gut of T1D mice. In the jejunum, we found that T1D mainly led to disordered amino acid metabolism and most amino acids were significantly lower relative to CON mice. Moreover, fatty acid metabolism was disrupted mainly in the ileum, cecum and colon of T1D mice, such as arachidonic acid, alpha-linolenic acid and linoleic acid metabolism. Thus, our study reveals spatial metabolic heterogeneity in the gut of T1D mice and provides a metabolic view on diabetes-associated intestinal diseases.

A Review on Development of Industrial Solid Waste in Tunnel Grouting Materials: Feasibility, Performance, and Prospects.

With rapid infrastructure development worldwide, the generation of industrial solid waste (ISW) has substantially increased, causing resource wastage and environmental pollution. Meanwhile, tunnel engineering requires large quantities of grouting material for ground treatment and consolidation. Using ISW as a component in tunnel grouts provides a sustainable solution to both issues. This paper presented a comprehensive review of the recent advancements in tunnel grouting materials using ISW, focusing on their feasibility, mechanical characteristics, and future development directions. Initially, the concept and classification of ISW were introduced, examining its feasibility and advantages as grouting materials in tunnels. Subsequently, various performances of ISW in tunnel grouting materials were summarized to explore the factors influencing mechanical strength, fluidity, durability, and microstructure characteristics. Simultaneously, this review analyzed current research trends and outlines future development directions. Major challenges, including quality assurance, environmental risks, and lack of standardized specifications, are discussed. Future research directions, including multifunctional grouts, integrated waste utilization, and advanced characterization techniques, are suggested to further advance this field. These findings provided useful insights for the continued development of high-performance and environmentally friendly ISW-based grouting materials.

Cellular Mechanisms of Psoriasis Pathogenesis: A Systemic Review.

Psoriasis is a common inflammatory skin disease characterized by abnormal proliferation of epidermal keratinocytes and massive infiltration of inflammatory cells. Many kinds of cells, including keratinocytes, T lymphocytes, dendritic cells, neutrophils, and macrophages, are reported to play critical roles in the pathogenesis and progression of psoriasis. However, to date, the role of each kind of cell in the pathogenesis and development of psoriasis has not been systematically reviewed. In addition, although antibodies developed targeting cytokines (e.g. IL-23, IL-17A, and TNF-α) released by these cells have shown promising results in the treatment of psoriasis patients, these targeted antibodies still do not cure psoriasis and only provide short-term relief of symptoms. Furthermore, long-term use of these antibodies has been reported to have adverse physical and psychological effects on psoriasis patients. Therefore, gaining a deeper understanding of the cellular and molecular pathogenesis of psoriasis and providing new thoughts on the development of psoriasis therapeutic drugs is of great necessity. In this review, we summarize the roles of various cells involved in psoriasis, aiming to provide new insights into the pathogenesis and development of psoriasis at the cellular level and hoping to provide new ideas for exploring new and effective psoriasis treatments.

Topical application of TOPK inhibitor OTS514 suppresses psoriatic progression by inducing keratinocytes cell cycle arrest and apoptosis.

T-LAK cell-oriented protein kinase (TOPK) potently promotes malignant proliferation of tumour cells and is considered as a maker of tumour progression. Psoriasis is a common inflammatory skin disease characterized by abnormal proliferation of keratinocytes. However, the role of TOPK in psoriasis has not been well elucidated. This study aims to investigate the expression and role of TOPK in psoriasis, and the role of TOPK inhibitor in psoriasis attenuation. Gene Expression Omnibus datasets derived from psoriasis patients and psoriatic model mice were screened for analysis. Skin specimens from psoriasis patients were collected for TOPK immunohistochemical staining to investigate the expression and localization of TOPK. Next, psoriatic mice model was established to further confirm TOPK expression pattern. Then, TOPK inhibitor was applied to investigate the role of TOPK in psoriasis progression. Finally, cell proliferation assay, apoptosis assay and cell cycle analysis were performed to investigate the potential mechanism involved. Our study showed that TOPK was upregulated in the lesions of both psoriasis patients and psoriatic model mice, and TOPK levels were positively associated with psoriasis progression. TOPK was upregulated in psoriatic lesions and expressed predominantly by epidermal keratinocytes. In addition, TOPK levels in epidermal keratinocytes were positively correlated with epidermal hyperplasia. Furthermore, topical application of TOPK inhibitor OTS514 obviously alleviated disease severity and epidermal hyperplasia. Mechanismly, inhibiting TOPK induces G2/M phase arrest and apoptosis of keratinocytes, thereby attenuating epidermal hyperplasia and disease progression. Collectively, this study identifies that upregulation of TOPK in keratinocytes promotes psoriatic progression, and inhibiting TOPK attenuates epidermal hyperplasia and psoriatic progression.

Microbiota from healthy mice alleviates cognitive decline via reshaping the gut-brain metabolic axis in diabetic mice.

Diabetic cognitive decline has been associated with the gut microbial disorders, but its potential gut-brain axis mechanisms remain unclear. Herein we transplanted the gut microbiota from healthy mice into type 1 diabetic (T1D) mice and then investigated the effect of fecal microbiota transplantation (FMT) on cognitive function and the gut-brain metabolic axis. The results demonstrate that FMT from healthy mice effectively improved the learning and memory abilities in T1D mice, and significantly reduced neuroinflammation and neuron injury in the cortex and hippocampus. Moreover, FMT partly reversed the gut microbiota and gut-brain metabolic disorders, particularly glutamate metabolism. In vitro study, we found that glutamate notably decreased microglia activation and the expression levels of proinflammatory factor. Hence, our study suggests that glutamate serves as a key signal metabolite connecting the gut to brain and affects cognitive functions.

Influence of a Commercial Synbiotic Administered In Ovo and In-Water on Broiler Chicken Performance and Meat Quality.

The present study aimed to test the synbiotic PoultryStar® solUS delivered in ovo to evaluate its effect on hatchability, productive performance and meat quality, compared to its post-hatch administration in water. On the twelfth day of embryonic incubation, 1200 fertile eggs were divided into synbiotic groups injected with 2 mg/embryo (T1) and 3 mg/embryo (T2), a saline group injected with physiological saline and an uninjected control group (C). After hatching, 120 male chicks/group were reared and chicks from the saline group were supplemented with the synbiotic via drinking water (T3). Hatchability was low in both T1 and T2 groups. Growth performance was not affected by the treatments. However, in the second rearing phase (15-36 days), birds from the C and T3 groups were heavier than T1 birds, due to a higher feed intake and daily weight gain. Neither route of synbiotic administration influenced final body weight (at 56 days), weight and yield of the carcass or commercial cuts. Physico-chemical properties, total lipid, cholesterol and fatty acid composition of breast muscle were not affected by the treatments. Considering its exploratory nature, this study has raised many questions that need further investigation, such as the bioactive combination and the effect on embryonic development.

Protective effects and mechanisms of N-acetylcysteine on indomethacin-induced intestinal injury in a porcine model.

This study aimed to investigate the effect of N-acetylcysteine (NAC) on indomethacin (IDMT)-induced intestinal injury in a piglet model and explore the underlying molecular mechanisms. Piglets were randomly divided into 3 treatment groups: (1) control group; (2) IDMT group; (3) NAC+IDMT group. The results showed that NAC administration significantly increased the average daily gain of piglets, attenuated the intestine hyperemia, and restored normal jejunal morphology. Further studies indicated that NAC administration significantly increased plasma citrulline concentration and jejunal villin expression, but decreased the content of proinflammatory cytokines in plasma and jejunum of IDMT-stimulated piglets. NAC administration selectively decreased the proportion of eosinophils but not neutrophils in plasma. Furthermore, NAC administration significantly increased the activities of superoxide dismutase and catalase in plasma but decreased the concentrations of hydrogen peroxide (plasma) and malondialdehyde (plasma and jejunum), as well as the activity of myeloperoxidase (jejunum) when comparing NAC+IDMT group with IDMT group. Gene Ontology analysis showed that the significantly enriched molecular function term was "ubiquitin-like protein ligase binding" for NAC+IDMT versus IDMT differentially regulated genes. In the biological process category, differentially regulated genes of NAC+IDMT versus IDMT were mainly enriched in immune-related terms. The major enrichments for differentially regulated proteins (DRPs) of NAC+IDMT versus IDMT were terms involved in lipid metabolism and immune response. KEGG pathway enrichment analysis showed that "arginine biosynthesis" was a significant enrichment term for the DRPs of NAC+IDMT versus IDMT. Further studies demonstrated that NAC administration up-regulated argininosuccinate synthase 1 mRNA expression and down-regulated arginase mRNA expression in the jejunum of IDMT-stimulated piglets. Moreover, the content of nitric oxide was restored to a normal level with the reduction of nitric oxide synthase activity. NAC administration ameliorated intestinal injury in IDMT-challenged piglets by enhancing antioxidant and anti-inflammatory functions and modulating arginine metabolism in the small intestine.