Increased FGF-21 Improves Ectopic Lipid Deposition in the Liver and Skeletal Muscle.

Obesity can lead to excessive lipid accumulation in non-adipose tissues, such as the liver and skeletal muscles, leading to ectopic lipid deposition and damaging target organ function through lipotoxicity. FGF-21 is a key factor in regulating lipid metabolism, so we aim to explore whether FGF-21 is involved in improving ectopic lipid deposition. We observed the characteristics of ectopic lipid deposition in the liver and skeletal muscles of obesity-resistant mice, detected the expression of FGF-21 and perilipin, and found that obesity-resistant mice showed a decrease in ectopic lipid deposition in the liver and skeletal muscles and increased expression of FGF-21. After inhibiting the expression of FGF-21, a more severe lipid deposition in liver cells and skeletal muscle cells was found. The results indicate that inhibiting FGF-21 can exacerbate ectopic lipid deposition via regulating lipid droplet synthesis and decomposition, as well as free fatty acid translocation and oxidation. In conclusion, FGF-21 is involved in improving ectopic lipid deposition caused by obesity in the liver and skeletal muscles.

CD3ε of a pan T cell marker involved in mouse Aspergillus fumigatus keratitis.

AIM: To explore whether CD3ε is involved in the adaptive immunity of Aspergillus fumigatus (A. fumigatus) keratitis in mice and the role of innate and adaptive immunity in it. METHODS: Mice models of A. fumigatus keratitis were established by intra-stromal injection and corneal epithelial scratching. Subconjunctival injections of natamycin, wedelolactone, LOX-1 inhibitor (poly I) or Dectin-1 inhibitor (laminarin) were used to treat mice with A. fumigatus keratitis. Mice were pretreated by intraperitoneal injection of anti-mouse CD3ε. We observed the corneal infection of mice under the slit lamp microscope and made a clinical score. The protein expression of CD3ε and interleukin-10 (IL-10) was determined by Western blotting. RESULTS: With the disease progresses, the degree of corneal opacity and edema augmented. In the intra-stromal injection models, CD3ε protein expression began to increase significantly on the 2nd day. However, in the scraping epithelial method models, CD3ε only began to increase on the 3rd day. After natamycin treatment, the degree of corneal inflammation in mice was significantly attenuated on the 3rd day. After wedelolactone treatment, the severity of keratitis worsened. And the amount of CD3ε protein was also reduced, compared with the control group. By inhibiting LOX-1 and Dectin-1, there was no significant difference in CD3ε production compared with the control group. After inhibiting CD3ε, corneal ulcer area and clinical score increased, and IL-10 expression was downregulated. CONCLUSION: As a pan T cell marker, CD3ε participate in the adaptive immunity of A. fumigatus keratitis in mice. In our mice models, the corneas will enter the adaptive immune stage faster. By regulating IL-10, CD3ε exerts anti-inflammatory and repairs effects in the adaptive immune stage.

AdipoRon promotes amyloid-ß clearance through enhancing autophagy via nuclear GAPDH-induced sirtuin 1 activation in Alzheimer's disease.

BACKGROUND AND PURPOSE: Amyloid-ß (Aß) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of Aß. Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of Aß and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects Aß clearance remain unclear. EXPERIMENTAL APPROACH: We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice. We also investigated the signalling pathway involved and used pharmacological inhibitors to examine the role of autophagy in this process. KEY RESULTS: AdipoRon promotes Aß clearance by activating neuronal autophagy in the APP/PS1 transgenic mice. Interestingly, we found that AdipoRon induces the nuclear translocation of GAPDH, where it interacts with the SIRT1/DBC1 complex. This interaction then leads to the release of DBC1 and the activation of SIRT1, which in turn activates autophagy. Importantly, we found that inhibiting either GAPDH or SIRT1 to suppress the activity of SIRT1 counteracts the elevated autophagy and decreased Aß deposition caused by AdipoRon. This suggests that SIRT1 plays a critical role in the effect of AdipoRon on autophagic induction in AD. CONCLUSION AND IMPLICATIONS: AdipoRon promotes the clearance of Aß by enhancing autophagy through the AdipoR1/AMPK-dependent nuclear translocation of GAPDH and subsequent activation of SIRT1. This novel molecular pathway sheds light on the modulation of autophagy in AD and may lead to the development of new therapeutic strategies targeting this pathway.

Histamine and receptors in neuroinflammation: Their roles on neurodegenerative diseases.

Histamine, an auto-reactive substance and mediator of inflammation, is synthesized from histidine through the action of histidine decarboxylase (HDC). It primarily acts on histamine receptors in the central nervous system (CNS). Increasing evidence suggests that histamine and its receptors play a crucial role in neuroinflammation, thereby modulating the pathology of neurodegenerative diseases. Recent studies have demonstrated that histamine regulates the phenotypic switching of microglia and astrocytes, inhibits the production of pro-inflammatory cytokines, and alleviates inflammatory responses. In the CNS, our research group has also found that histamine and its receptors are involved in regulating inflammatory responses and play a central role in ameliorating chronic neuroinflammation in neurodegenerative diseases. In this review, we will discuss the role of histamine and its receptors in neuroinflammation associated with neurodegenerative diseases, potentially providing a novel therapeutic target for the treatment of chronic neuroinflammation-related neurodegenerative diseases in clinical settings.

Subtle 2D/2D MXene-Based Heterostructures for High-Performance Electrocatalytic Water Splitting.

Developing efficient electrocatalysts is significant for the commercial application of electrocatalytic water splitting. 2D materials have presented great prospects in electrocatalysis for their high surface-to-volume ratio and tunable electronic properties. Particularly, MXene emerges as one of the most promising candidates for electrocatalysts, exhibiting unique advantages of hydrophilicity, outstanding conductivity, and exceptional stability. However, it suffers from lacking catalytic active sites, poor oxidation resistance, and easy stacking, leading to a significant suppression of the catalytic performance. Combining MXene with other 2D materials is an effective way to tackle the aforementioned drawbacks. In this review, the focus is on the accurate synthesis of 2D/2D MXene-based catalysts toward electrocatalytic water splitting. First, the mechanisms of electrocatalytic water splitting and the relative properties and preparation methods of MXenes are introduced to offer the basis for accurate synthesis of 2D/2D MXene-based catalysts. Then, the accurate synthesis methods for various categories of 2D/2D MXene-based catalysts, such as wet-chemical, phase-transformation, electrodeposition, etc., are systematically elaborated. Furthermore, in-depth investigations are conducted into the internal interactions and structure-performance relationship of 2D/2D MXene-based catalysts. Finally, the current challenges and future opportunities are proposed for the development of 2D/2D MXene-based catalysts, aiming to enlighten these promising nanomaterials for electrocatalytic water splitting.

Role and mechanism of PVN-sympathetic-adipose circuit in depression and insulin resistance induced by chronic stress.

Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain-sympathetic nerve-adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin-sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. ß-adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive-like behaviours and insulin resistance. We finally show that AP-1 has a role in the regulation of adipokine expression under chronic stress.

Mo-Ni-based Heterojunction with Fine-customized d-Band Centers for Hydrogen Production Coupled with Benzylamine Electrooxidation in Low Alkaline Medium.

Benzylamine electrooxidation reaction (BAOR) is a promising route to produce value-added, easy-separated benzonitrile, and effectively hoist H2 production. However, achieving excellent performance in low alkaline medium is a huge challenge. The performance is intimately correlated with effective coupling of HER and BAOR, which can be achieved by manipulating the d-electron structure of catalyst to regulate the active species from water. Herein, we constructed a biphasic Mo0.8 Ni0.2 N-Ni3 N heterojunction for enhanced bifunctional performance toward HER coupled with BAOR by customizing the d-band centers. Experimental and theoretical calculations indicate that charge transfer in the heterojunction causes the upshift of the d-band centers, which one side facilitates to decrease water activation energy and optimize H* adsorption on Mo0.8 Ni0.2 N for promoting HER activity, the other side favors to more easily produce and adsorb OH* from water for forming NiOOH on Ni3 N and optimizing adsorption energy of benzylamine, thus catalyzing BAOR effectively. Accordingly, it shows an industrial current density of 220 mA cm-2 at 1.59 V and high Faradaic efficiencies (>99 %) for H2 production and converting benzylamine to benzonitrile in 0.1 M KOH/0.5 M Na2 SO4 . This work guides the design of excellent bifunctional electrocatalysts for the scalable production of green hydrogen and value-added products.

Therapeutic effect of Atractylenolide I on Aspergillus fumigatus keratitis by affecting MyD88/ NF-κB pathway and IL-1ß, IL-10 expression.

PURPOSE: Atractylenolide I (AT-I) is a natural sesquiterpene with anti-inflammatory effects. The purpose of this study was to research the anti-inflammatory effect of AT-I on Aspergillus fumigatus(A. fumigatus) keratitis in mice. METHODS: Cytotoxicity test and cell scratch test were used to determine the therapeutic concentrations of corneal infections. In vivo and in vitro studies, mouse cornea and human corneal epithelial cells (HCECs) infected with A. fumigatus were treated with AT-I or dimethyl sulfoxide (DMSO). Then, to analyze the effect of AT-I on inflammatory response, namely neutrophil or macrophage recruitment and the expression of cytokines involving MyD88, NF-κB, interleukin 1ß (IL-1ß) and interleukin 10 (IL-10). To study the effects of the drug, the techniques used include slit-lamp photography, immunofluorescence, myeloperoxidase (MPO) detection, quantitative real-time polymerase chain reaction (QRT-PCR), and western blot. At the same time, in order to explore the combined effect of the drug and natamycin, slit-lamp photographs and clinical scores were used to visually display the disease process. RESULTS: No cytotoxicity was observed under the action of AT-I at a concentration of 800 µM. In mouse models, AT-I significantly suppressed inflammatory responses, reduced neutrophil and macrophage recruitment, and decreased myeloperoxidase levels early in infection. Studies have shown that AT-I may reduce the levels of IL-1ß and IL-10 by inhibiting the MyD88/ NF-κB pathway. The drug combined with natamycin can increase corneal transparency in infected mice. CONCLUSION: AT-I may inhibit MyD88 / NF-κB pathway and the secretion of inflammatory factors IL-1 ß and IL-10 to achieve the therapeutic effect of fungal keratitis.

Thymol Ameliorates Aspergillus fumigatus Keratitis by Downregulating the TLR4/ MyD88/ NF-kB/ IL-1ß Signal Expression and Reducing Necroptosis and Pyroptosis.

Fungal keratitis is a refractory kind of keratopathy. We attempted to investigate the anti-inflammatory role of thymol on Aspergillus fumigatus (A. fumigatus) keratitis. Wound healing and fluorescein staining of the cornea were applied to verify thymol's safety. Mice models of A. fumigatus keratitis underwent subconjunctival injection of thymol. The anti-inflammatory roles of thymol were verified by hematoxylin-eosin (HE) staining, slit lamp observation, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. In contrast with the DMSO group, more transparent corneas and less inflammatory cells infiltration were detected in mice treated with 50 µg/ml thymol. Thymol downregulated the synthesis of TLR4, MyD88, NF-kB, IL-1ß, NLRP3, caspase 1, caspase 8, GSDMD, RIPK3 and MLKL. In summary, we proved that thymol played a protective part in A. fumigatus keratitis by cutting down inflammatory cells aggregation, downregulating the TLR4/ MyD88/ NF-kB/ IL-1ß signal expression and reducing necroptosis and pyroptosis.

5-Aza-2'-Deoxycytidine Regulates White Adipocyte Browning by Modulating miRNA-133a/Prdm16.

The conversion of white adipocytes into brown adipocytes improves their thermogenesis and promotes energy consumption. Epigenetic modifications affect related genes and interfere with energy metabolism, and these are the basis of new ideas for obesity treatment. Neonatal mice show high levels of DNA hypermethylation in white adipose tissue early in life and low levels in brown adipose tissue. Thus, we considered that the regulation of DNA methylation may play a role in the conversion of white adipose to brown. We observed growth indicators, lipid droplets of adipocytes, brown fat specific protein, and miRNA-133a after treatment with 5-Aza-2'-deoxycytidine. The expression of Prdm16 and Ucp-1 in adipocytes was detected after inhibiting miRNA-133a. The results showed a decrease in total lipid droplet formation and an increased expression of the brown fat specific proteins Prdm16 and Ucp-1. This study indicated that 5-Aza-2'-deoxycytidine promotes white adipocyte browning following DNA demethylation, possibly via the modulation of miR-133a and Prdm16.

Caspase-8 is involved in pyroptosis, necroptosis and the maturation and release of IL-1ß in Aspergillus fumigatus keratitis.

PURPOSE: To explore the role of caspase-8 in mediating the transition between different death modes in fungal keratitis. METHODS: The expression of caspase-8 in Aspergillus fumigatus (A. fumigatus) keratitis was detected using western blotting and immunofluorescence. After subconjunctival injection of Z-IETD-FMK (caspase-8 inhibitor) or VX765 (caspase-1 inhibitor), the mice corneas of A. fumigatus keratitis were observed and scored under a slit lamp. Colony plate count, immunofluorescence staining, western blotting and qRT-PCR experiments were used to detect fungal load, inflammatory cells, and the production of related mRNAs and proteins. In vitro experiments, the LDH release test, Cell Count Kit-8(CCK-8) assay, ELISA, qRT-PCR and western blotting were used to detect cell viability, related mRNAs and proteins. RESULTS: The caspase-8 protein was upregulated following fungal infection. Compared with the A. fumigatus keratitis group, the mice treated with Z-IETD-FMK had heavier corneal turbidity, higher clinical scores, more fungal load and fewer inflammatory cells. The expression of NLRP3, cleaved-caspase-1, N-GSDMD, and IL-1ß in the fungal infection group after Z-IETD-FMK pretreatment were downregulated, while RIPK3 and p-MLKL were upregulated. In the fungal infection group after VX765 pretreatment, the expression of cleaved-caspase-8 was up-regulated, while N-GSDMD was downregulated. CONCLUSIONS: Caspase-8 is involved in the early immune defense response of A. fumigatus keratitis. It is essential for the recruitment of inflammatory cells and the clearance of the fungus. In A. fumigatus keratitis, activated caspase-8 promoted the caspase-1/GSDMD signaling pathway to participate in pyroptosis, inhibited RIPK3/MLKL signaling pathway-mediated necroptosis, and promoted IL-1ß maturation and release by activating the NLRP3 inflammasomes.

Histamine H3R antagonist counteracts the impaired hippocampal neurogenesis in Lipopolysaccharide-induced neuroinflammation.

Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with numerous neurodegenerative diseases such as aging and Alzheimer's disease (AD). Overactivation of microglia induced neuroinflammation is well acknowledged to contribute to the impaired neurogenesis in pathologies of these diseases and then leading to cognitive dysfunction. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia to modulate inflammatory response. However, whether inhibition of H3R is responsible for the neurogenesis and cognition in chronic neuroinflammation induced injury and the mechanism remains unclear. In this study, we found that inhibition of H3R by thioperamide reduced the microglia activity and promoted a phenotypical switch from pro-inflammatory M1 to anti-inflammatory M2 in microglia, and ultimately attenuated lipopolysaccharide (LPS) induced neuroinflammation in mice. Additionally, thioperamide rescued the neuroinflammation induced impairments of neurogenesis and cognitive function. Mechanically, the neuroprotection of thioperamide was involved in histamine dependent H2 receptor (H2R) activation, because cimetidine, an H2R antagonist but not pyrilamine, an H1R antagonist reversed the above effects of thioperamide. Moreover, thioperamide activated the H2R downstream phosphorylated protein kinase A (PKA)/cyclic AMP response element-binding protein (CREB) pathway but inhibited nuclear factor kappa-B (NF-κB) signaling. Activation of CREB by thioperamide promoted interaction of CREB-CREB Binding Protein (CBP) to increase anti-inflammatory cytokines (Interleukin-4 and Interleukin-10) and brain-derived neurotrophic factor (BDNF) release but inhibited NF-κB-CBP interaction to decrease pro-inflammatory cytokines (Interleukin-1ß, Interleukin-6 and Tumor necrosis factor α) release. H89, an inhibitor of PKA/CREB signaling, abolished effects of thioperamide on neuroinflammation and neurogenesis. Taken together, these results suggested under LPS induced neuroinflammation, the H3R antagonist thioperamide inhibited microglia activity and inflammatory response, and ameliorated impairment of neurogenesis and cognitive dysfunction via enhancing histamine release. Histamine activated H2R and reinforced CREB-CBP interaction but weakened NF-κB-CBP interaction to exert anti-inflammatory effects. This study uncovered a novel histamine dependent mechanism behind the therapeutic effect of thioperamide on neuroinflammation.

Unraveling the mechanism for paired electrocatalysis of organics with water as a feedstock.

Paired electroreduction and electrooxidation of organics with water as a feedstock to produce value-added chemicals is meaningful. A comprehensive understanding of reaction mechanism is critical for the catalyst design and relative area development. Here, we have systematically studied the mechanism of the paired electroreduction and electrooxidation of organics on Fe-Mo-based phosphide heterojunctions. It is shown that active H* species for organic electroreduction originate from water. As for organic electrooxidation, among various oxygen species (OH*, OOH*, and O*), OH* free radicals derived from the first step of water dissociation are identified as active species. Furthermore, explicit reaction pathways and their paired advantages are proposed based on theoretical calculations. The paired electrolyzer powered by a solar cell shows a low voltage of 1.594 V at 100 mA cm-2, faradaic efficiency of ≥99%, and remarkable cycle stability. This work provides a guide for sustainable synthesis of various value-added chemicals via paired electrocatalysis.

Two-dimensional assembly made up of ZIF-8 particles for the high-efficient capture of the iodine and dyes.

The removal of the pollutants from the environment is the need of the environmental protection. ZIF-8 is promising adsorbents, and the construction of ZIF-8 assembly is essential to boost its performance. Here, we showed the easy synthesis of two-dimensional (2D) assembly built by ZIF-8 particles (2D A-ZIF-8) for the high-efficient capture of the iodine (I2) and dyes. The assembly was synthesized by the controllable reaction of 2-methylimidazole (2-MIM) with 2D Zn-glycerol (Zn-GL) precursor. Time-dependent experiments showed the predominant replacement of GL at outer boundary and then basic plane of the precursor by 2-MIM. The assembly can be synthesized with high output and combined the advantage of large accessible surface of 2D sheets, the plentiful pores of ZIF-8 and enhanced stability of assembly, endowing the large potential as adsorbent. The high adsorption capacity of I2 (200 wt%) was achieved on A-ZIF-8, while it is about 128 wt% on traditional dodecahedronal ZIF-8. The assembly also showed the excellent adsorption capacity for methyl orange (MO) (46.3 mg g-1) and methylene blue (MB) (46.5 mg g-1) at a concentration of 50 mg L-1. It can be easily separated for reuse benefited from the large size and enhanced stability of assembly.

CCPG1 involved in corneal Aspergillus fumigatus infection.

AIM: To investigate whether non-canonical autophagy transport receptor cell cycle progression 1 (CCPG1) is involved in the corneal antifungal immune response. METHODS: Human corneal epithelial cells (HCECs) and human myeloid leukemia mononuclear cells (THP-1) macrophages stimulated by Aspergillus fumigatus (A. fumigatus) were used as cell models. The expression of CCPG1 mRNA was detected by qRT-PCR. Western blot was used to determine the protein expression of CCPG1 and interleukin-1ß (IL-1ß). The dectin-1 neutralizing antibody was used to detect the association between dectin-1 and CCPG1. Immunofluorescence was used to observe the colocalization of CCPG1 and C-type lectin-like receptor-1 (CLEC-1) in THP-1 macrophages. RESULTS: The expression of CCPG1 started to increase at 4h after infection and increased in a time-dependent manner in HCECs and THP-1 macrophages. With dectin-1 neutralizing antibody pretreatment, the expression of IL-1ß was down-regulated. CCPG1 up-regulation in response to A. fumigatus infection was independent of dectin-1. Immunofluorescence showed the colocalization of CCPG1 and CLEC-1 in THP-1 macrophages. CONCLUSION: As a specific autophagy protein of non-canonical autophagy pathway, CCPG1 is involved in corneal infection with A. fumigatus.

Thymol Protects against Aspergillus Fumigatus Keratitis by Inhibiting the LOX-1/IL-1ß Signaling Pathway.

OBJECTIVE: To explore the anti-inflammatory effects and mechanisms of action of thymol in Aspergillus fumigatus (A. fumigatus) keratitis. METHODS: The minimum inhibitory concentration of thymol against A. fumigatus was detected. To characterize the anti-inflammatory effects of thymol, mouse corneas and human corneal epithelial cells were pretreated with thymol or dimethyl sulfoxide (DMSO) before infection with A. fumigatus spores. Slit-lamp microscopy, immunohistochemistry, myeloperoxidase detection, quantitative real-time polymerase chain reaction, and Western blotting were used to assess infection. Neutrophil and macrophage recruitment, in addition to the secretion of LOX-1 and IL-1ß, were quantified to evaluate the relative contribution of thymol to the inflammatory response. RESULTS: We confirmed that the growth of A. fumigatus was directly inhibited by thymol. In contrast with the DMSO group, there was a lower degree of inflammation in the mouse corneas of the thymol-pretreated group. This was characterized by significantly lower clinical scores, less inflammatory cell infiltration, and lower expression of LOX-1 and IL-1ß. Similarly, in vitro experiments indicated that the production of LOX-1 and IL-1ß was significantly inhibited after thymol treatment, in contrast with the DMSO-pretreated group. CONCLUSION: Our findings demonstrate that thymol exerted a direct fungistatic activity on A. fumigatus. Furthermore, thymol played a protective role in fungal keratitis by inhibiting LOX-1/IL-1ß signaling pathway and reducing the recruitment of neutrophils and macrophages.

Vanadium-Incorporated CoP2 with Lattice Expansion for Highly Efficient Acidic Overall Water Splitting.

A proton exchange membrane water electrolyzer (PEMWE) in acidic medium is a hopeful scenario for hydrogen production using renewable energy, but the grand challenge lies in substituting noble-metal catalysts. Herein, a robust electrocatalyst of V-CoP2 porous nanowires arranged on a carbon cloth is successfully fabricated by incorporating vanadium into the CoP2 lattice. Structural characterizations and theoretical analysis indicate that lattice expansion of CoP2 caused by V incorporation results in the upshift of the d-band center, which is conducive to hydrogen adsorption for boosting the hydrogen evolution reaction (HER). Besides, V promotes surface reconstruction to generate a thicker Co3 O4 layer with an oxygen vacancy that enhances acid-corrosion resistance and optimizes the adsorption of water and oxygen-containing species, thus improving activity and stability toward the oxygen evolution reaction (OER). Accordingly, it presents a superior acidic overall water splitting activity (1.47 V@10 mA cm-2 ) to Pt-C/CC||RuO2 /CC (1.59 V@10 mA cm-2 ), and remarkable stability. This work proposes a new route to design efficient non-noble metal electrocatalysts for PEMWE.

Thioperamide attenuates neuroinflammation and cognitive impairments in Alzheimer's disease via inhibiting gliosis.

Alzheimer's disease (AD) is an age-related neurodegenerative disease, which characterized by deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles, neuronal loss, and accompanied by neuroinflammation. Neuroinflammatory processes are well acknowledged to contribute to the progression of AD pathology. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia and astrocytes. H3R antagonist has been reported to have anti-inflammatory efficacy. However, whether inhibition of H3R is responsible for the anti-neuroinflammation in glial cells and neuroprotection on APPswe, PSEN1dE9 (APP/PS1 Tg) mice remain unclear. In this study, we found that inhibition of H3R by thioperamide reduced the gliosis and induced a phenotypical switch from A1 to A2 in astrocytes, and ultimately attenuated neuroinflammation in APP/PS1 Tg mice. Additionally, thioperamide rescued the decrease of cyclic AMP response element-binding protein (CREB) phosphorylation and suppressed the phosphorylated P65 nuclear factor kappa B (p-P65 NF-κB) in APP/PS1 Tg mice. H89, an inhibitor of CREB signaling, abolished these effects of thioperamide to suppress gliosis and proinflammatory cytokine release. Lastly, thioperamide alleviated the deposition of amyloid-ß (Aß) and cognitive dysfunction in APP/PS1 mice, which were both reversed by administration of H89. Taken together, these results suggested the H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated gliosis and inflammation inhibiting, which contributed to Aß clearance. This study uncovered a novel mechanism involving inflammatory regulating behind the therapeutic effect of thioperamide in AD.

Disulfiram inhibits IL-1ß secretion and inflammatory cells recruitment in Aspergillus fumigatus keratitis.

PURPOSE: Disulfiram, an inhibitor of gasdermin D-induced pore formation, is known to suppress interleukin (IL)-1ß secretion and pyroptosis. However, its effects on fungal keratitis remain unknown. Therefore, we investigated the role of disulfiram in Aspergillus fumigatus keratitis. METHODS: In vitro, Cell Count Kit-8 (CCK8) assay and cell scratch test were performed to determine optimal concentration. In vivo and in vitro experiments were conducted in a mouse model, human neutrophils, and mouse peritoneal macrophages. We pre-treated the mice or cells with disulfiram and infected them with A. fumigatus at specific times. We subsequently evaluated the development of fungal keratitis lesions, the recruitment of inflammatory cells, and the production of inflammatory cytokines using slit lamp microscopy, clinical evaluation, quantitative reverse transcription polymerase chain reaction, immunofluorescence staining, enzyme-linked immunosorbent assay, and western blotting. We also used slit lamp microscopy and clinical evaluation to assess the effect of natamycin with or without disulfiram. RESULTS: Disulfiram at 20 µM has no significant cytotoxic effect and does not affect cell migration. In the mouse model, disulfiram significantly suppressed inflammatory responses, reduced neutrophil and macrophage recruitment, and down-regulated myeloperoxidase and nitric oxide synthase levels at earlier stages of infection. Disulfiram had no effect on IL-1ß production and maturation, but it inhibited IL-1ß secretion in macrophages. Disulfiram combined with natamycin significantly increased corneal transparency in the mice model. CONCLUSION: Overall, disulfiram reduced the host immune response in fungal keratitis by attenuating neutrophil and macrophage recruitment and inhibiting IL-1ß secretion in macrophages. Disulfiram in combination with antifungal agents may serve as a novel therapeutic method for reducing corneal opacity in fungal keratitis.

Prdm16-Mediated Browning is Involved in Resistance to Diet-Induced and Monosodium Glutamate-Induced Obesity.

PURPOSE: To investigate resistance to diet-induced obesity (DIO) and monosodium glutamate (MSG)-induced obesity as well as the underlying mechanisms. METHODS: Newborn mice were used to construct DIO and MSG-induced obesity models. Obesity indices, such as body weight, body length, Lee index, body temperature, food intake, fat weight, and leptin level, were examined. Mice that did not exhibit obesity were defined as the obesity-resistant group. The morphological changes of white adipose tissue were observed by hematoxylin and eosin staining, and expression levels of PR domain containing 16 (Prdm16) and uncoupling protein-1 (Ucp-1) in white adipose tissue were measured by Western blot. RESULTS: Obesity-resistant mice fed a high-fat diet showed resistance beginning at week 5 along with lower weights and lengths than those in the obesity group from weeks 5 to 12. MSG-induced obesity-resistant mice showed features consistent with resistance to obesity from week 1 along with higher body lengths relative to the obesity group; however, the weight difference was not significant until week 10, when body weights decreased significantly in obesity-resistant mice. The Lee index was lower in obesity-resistant mice than in the obesity group and the normal group, further suggesting obesity resistance. Additionally, obesity-resistant mice showed higher levels of leptin, whereas obese mice induced by a high-fat diet showed leptin resistance. Furthermore, Prdm16 and Ucp-1 levels were both downregulated in the obesity group and upregulated in obesity-resistant mice, showing that white fat browning was highest in obesity-resistant mice. CONCLUSION: The phenotypes of mice with DIO and MSG-induced obesity differed. Obesity resistance might be related to Prdm16 and Ucp-1-mediated white adipocyte browning.