A stable liver-specific urate oxidase gene knockout hyperuricemia mouse model finds activated hepatic de novo purine biosynthesis and urate nephropathy.

Urate oxidase (Uox)-deficient mice could be an optimal animal model to study hyperuricemia and associated disorders. We develop a liver-specific conditional knockout Uox-deficient (UoxCKO) mouse using the Cre/loxP gene targeting system. These UoxCKO mice spontaneously developed hyperuricemia with accumulated serum urate metabolites. Blocking urate degradation, the UoxCKO mice showed significant de novo purine biosynthesis (DNPB) in the liver along with amidophosphoribosyltransferase (Ppat). Pegloticase and allopurinol reversed the elevated serum urate (SU) levels in UoxCKO mice and suppressed the Ppat up-regulation. Although urate nephropathy occurred in 30-week-old UoxCKO mice, 90 % of Uox-deficient mice had a normal lifespan without pronounced urate transport abnormality. Thus, UoxCKO mice are a stable model of human hyperuricemia. Activated DNPB in the UoxCKO mice provides new insights into hyperuricemia, suggesting increased SU influences purine synthesis.

ALDOB/KAT2A interactions epigenetically modulate TGF-ß expression and T cell functions in hepatocellular carcinogenesis.

BACKGROUND AND AIMS: Cross talk between tumor cells and immune cells enables tumor cells to escape immune surveillance and dictate responses to immunotherapy. Previous studies have identified that downregulation of the glycolytic enzyme fructose-1,6-bisphosphate aldolase B (ALDOB) in tumor cells orchestrated metabolic programming to favor HCC. However, it remains elusive whether and how ALDOB expression in tumor cells affects the tumor microenvironment in HCC. APPROACH AND RESULTS: We found that ALDOB downregulation was negatively correlated with CD8 + T cell infiltration in human HCC tumor tissues but in a state of exhaustion. Similar observations were made in mice with liver-specific ALDOB knockout or in subcutaneous tumor models with ALDOB knockdown. Moreover, ALDOB deficiency in tumor cells upregulates TGF-ß expression, thereby increasing the number of Treg cells and impairing the activity of CD8 + T cells. Consistently, a combination of low ALDOB and high TGF-ß expression exhibited the worst overall survival for patients with HCC. More importantly, the simultaneous blocking of TGF-ß and programmed cell death (PD) 1 with antibodies additively inhibited tumorigenesis induced by ALDOB deficiency in mice. Further mechanistic experiments demonstrated that ALDOB enters the nucleus and interacts with lysine acetyltransferase 2A, leading to inhibition of H3K9 acetylation and thereby suppressing TGFB1 transcription. Consistently, inhibition of lysine acetyltransferase 2A activity by small molecule inhibitors suppressed TGF-ß and HCC. CONCLUSIONS: Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-ß signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy.

Multimaterial 3D and 4D Bioprinting of Heterogenous Constructs for Tissue Engineering.

Additive manufacturing (AM), which is based on the principle of layer-by-layer shaping and stacking of discrete materials, has shown significant benefits in the fabrication of complicated implants for tissue engineering (TE). However, many native tissues exhibit anisotropic heterogenous constructs with diverse components and functions. Consequently, the replication of complicated biomimetic constructs using conventional AM processes based on a single material is challenging. Multimaterial 3D and 4D bioprinting (with time as the fourth dimension) has emerged as a promising solution for constructing multifunctional implants with heterogenous constructs that can mimic the host microenvironment better than single-material alternatives. Notably, 4D-printed multimaterial implants with biomimetic heterogenous architectures can provide a time-dependent programmable dynamic microenvironment that can promote cell activity and tissue regeneration in response to external stimuli. This paper first presents the typical design strategies of biomimetic heterogenous constructs in TE applications. Subsequently, the latest processes in the multimaterial 3D and 4D bioprinting of heterogenous tissue constructs are discussed, along with their advantages and challenges. In particular, the potential of multimaterial 4D bioprinting of smart multifunctional tissue constructs is highlighted. Furthermore, this review provides insights into how multimaterial 3D and 4D bioprinting can facilitate the realization of next-generation TE applications.

Asymmetric variation in DNA methylation during domestication and de-domestication of rice.

Hundreds of plant species have been domesticated to feed human civilization, while some crops have undergone de-domestication into agricultural weeds, threatening global food security. To understand the genetic and epigenetic basis of crop domestication and de-domestication, we generated DNA methylomes from 95 accessions of wild rice (Oryza rufipogon L.), cultivated rice (Oryza sativa L.) and weedy rice (O. sativa f. spontanea). We detected a significant decrease in DNA methylation over the course of rice domestication but observed an unexpected increase in DNA methylation through de-domestication. Notably, DNA methylation changes occurred in distinct genomic regions for these 2 opposite stages. Variation in DNA methylation altered the expression of nearby and distal genes through affecting chromatin accessibility, histone modifications, transcription factor binding, and the formation of chromatin loops, which may contribute to morphological changes during domestication and de-domestication of rice. These insights into population epigenomics underlying rice domestication and de-domestication provide resources and tools for epigenetic breeding and sustainable agriculture.

Metallurgical manipulation of surface Volta potential in bimetals and cell response of human mesenchymal stem cells.

Bioelectricity plays an overriding role in directing cell migration, proliferation, differentiation etc. Tailoring the electro-extracellular environment through metallurgical manipulation could modulate the surrounding cell behaviors. In this study, different electric potential patterns, in terms of Volta potential distribution and gradient, were created on the metallic surface as an electric microenvironment, and their effects on adherent human mesenchymal stem cells were investigated. Periodically and randomly distributed Volta potential pattern, respectively, were generated on the surface through spark plasma sintering of two alternatively stacked dissimilar metals films and of a mixture of metallic powders. Actin cytoskeleton staining demonstrated that the Volta potential pattern strongly affected cell attachment and deformation. The cytoskeletons of cells were observed to elongate along the Volta potential gradient and across the border of adjacent regions with higher and lower potentials. Moreover, the steepest potential gradient resulting from the drastic compositional changes on the periodic borders gave rise to the strongest osteogenic tendency among all the samples. This study suggests that tailoring the Volta potential distribution and gradient of metallic biomaterials via metallurgical manipulation is a promising approach to activate surrounding cells, providing an extra degree of freedom for designing desirable bone-repairing metallic implants.

Koumine alleviates rheumatoid arthritis by regulating macrophage polarization.

ETHNOPHARMACOLOGICAL RELEVANCE: The imbalance between M1-and M2-polarized macrophages is one of the major pathophysiological changes in RA. Therefore, targeted macrophage polarization may be an effective therapy for RA. Koumine, an alkaloid monomer with the highest content and low toxicity in Gelsemium elegans Benth., has the effect of treating RA by playing an immunomodulatory role by influencing various immune cells. However, whether koumine affects macrophage polarization in RA and the associated molecular mechanisms remain unknown. AIM OF THE STUDY: To investigate the mechanism of the anti-RA effect of koumine on macrophage polarization. MATERIALS AND METHODS: The effect of koumine on macrophage polarization was investigated in vivo and in vitro. We first explored the effects of koumine on AIA rats and detected the levels of M1/M2 macrophage polarization markers in the spleen by western blotting. Then, we explored the regulatory effect of koumine on M1/M2 macrophage polarization and the effect on the PI3K/AKT signaling pathway in vitro. Finally, we verified the effects of koumine on macrophage polarization in CIA mice. RESULTS: We found that koumine alleviated symptoms, including relieving pain, reducing joint redness and swelling in AIA rats and restoring the M1/M2 macrophage balance in vivo. Interestingly, koumine had an inhibitory effect on both M1 and M2 macrophage polarization in vitro, but it had a stronger inhibitory effect on M1 macrophage. In a mixed polarization experiment, koumine mainly inhibited M1 macrophage polarization and had an inhibitory effect on the PI3K/AKT signaling pathway. Finally, we found that koumine had therapeutic effects on CIA mice, regulated macrophage polarization and inhibited the PI3K/AKT signaling pathway. CONCLUSIONS: Our results reveal that koumine regulates macrophage polarization through the PI3K/AKT signaling pathway. This may be one of the important mechanisms of its anti-RA effect, which provides a theoretical and scientific basis for the possible clinical application of koumine.

Pathogenetic characterization of a Micrococcus luteus strain isolated from an infant.

Purpose: To explore the clinical characteristics of Micrococcus luteus bloodstream infection in an infant and characterize the phenotype and genotype of the isolated strains, as well as seek suitable infection models for assessing virulence. Methods: Clinical data was collected from an infant patient diagnosed with M. luteus bloodstream infection. Metagenomic sequencing was performed on the isolated blood sample. The strain was isolated and underwent mass spectrometry, biochemical tests, antibiotic susceptibility assays, and whole-genome sequencing. The Galleria mellonella infection model was used to assess M. luteus virulence. Results: Patient responded poorly to cephalosporins, but recovered after Linezolid treatment. Metagenomic sequencing identified M. luteus as the predominant species in the sample, confirming infection. They were identified as M. luteus with a high confidence level of 98.99% using mass spectrometry. The strain showed positive results for Catalase, Oxidase, and Urea tests, and negative results for Mannose, Xylose, Lactose, Mannitol, Arginine, and Galactose tests, consistent with the biochemical profile of M. luteus reference standards. M. luteus susceptibility to 15 antibiotics was demonstrated and no resistance genes were detected. Predicted virulence genes, including clpB, were associated with metabolic pathways and the type VI secretion system. The infection model demonstrated dose-dependent survival rates. Conclusion: The infant likely developed a bloodstream infection with M. luteus due to compromised immunity. Although the isolated strain is sensitive to cephalosporin antibiotics and has low pathogenicity in infection models, clinical treatment with cephalosporins was ineffective. Linezolid proved to be effective, providing valuable guidance for future clinical management of such rare infections.

Expression of the ripAA Gene in the Soilborne Pseudomonas mosselii Can Promote the Control Efficacy against Tobacco Bacterial Wilt.

The environmental bacterium Pseudomonas mosselii produces antagonistic secondary metabolites with inhibitory effects on multiple plant pathogens, including Ralstonia solanacearum, the causal agent of bacterial wilt. In this study, an engineered P. mosselii strain was generated to express R. solanacearum ripAA, which determines the incompatible interactions with tobacco plants. The ripAA gene, together with its native promoter, was integrated into the P. mosselii chromosome. The resulting strain showed no difference in antimicrobial activity against R. solanacearum. Promoter-LacZ fusion and RT-PCR experiments demonstrated that the ripAA gene was transcribed in culture media. Compared with that of the wild type, the engineered strain reduced the disease index by 9.1% for bacterial wilt on tobacco plants. A transcriptome analysis was performed to identify differentially expressed genes in tobacco plants, and the results revealed that ethylene- and jasmonate-dependent defense signaling pathways were induced. These data demonstrates that the engineered P. mosselii expressing ripAA can improve biological control against tobacco bacterial wilt by the activation of host defense responses.

Artificial Intelligence-Assisted Score Analysis for Predicting the Expression of the Immunotherapy Biomarker PD-L1 in Lung Cancer.

Programmed cell death ligand 1 (PD-L1) is a critical biomarker for predicting the response to immunotherapy. However, traditional quantitative evaluation of PD-L1 expression using immunohistochemistry staining remains challenging for pathologists. Here we developed a deep learning (DL)-based artificial intelligence (AI) model to automatically analyze the immunohistochemical expression of PD-L1 in lung cancer patients. A total of 1,288 patients with lung cancer were included in the study. The diagnostic ability of three different AI models (M1, M2, and M3) was assessed in both PD-L1 (22C3) and PD-L1 (SP263) assays. M2 and M3 showed improved performance in the evaluation of PD-L1 expression in the PD-L1 (22C3) assay, especially at 1% cutoff. Highly accurate performance in the PD-L1 (SP263) was also achieved, with accuracy and specificity of 96.4 and 96.8% in both M2 and M3, respectively. Moreover, the diagnostic results of these three AI-assisted models were highly consistent with those from the pathologist. Similar performances of M1, M2, and M3 in the 22C3 dataset were also obtained in lung adenocarcinoma and lung squamous cell carcinoma in both sampling methods. In conclusion, these results suggest that AI-assisted diagnostic models in PD-L1 expression are a promising tool for improving the efficiency of clinical pathologists.

Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression.

HDL cholesterol (HDL-C) predicts risk of cardiovascular disease (CVD), but the factors regulating HDL are incompletely understood. Emerging data link CVD risk to decreased HDL-C in 8% of the world population and 40% of East Asians who carry an SNP of aldehyde dehydrogenase 2 (ALDH2) rs671, responsible for alcohol flushing syndrome; however, the underlying mechanisms remain unknown. We found significantly decreased HDL-C with increased hepatosteatosis in ALDH2-KO (AKO), ALDH2/LDLR-double KO (ALKO), and ALDH2 rs671-knock-in (KI) mice after consumption of a Western diet. Metabolomics identified ADP-ribose as the most significantly increased metabolites in the ALKO mouse liver. Moreover, ALDH2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor α (LXRα), leading to an upregulation of ATP-binding cassette transporter A1 (ABCA1) and HDL biogenesis. Conversely, AKO or ALKO mice exhibited lower HDL-C with ABCA1 downregulation due to increased nuclear PARP1 and upregulation of LXRα poly(ADP-ribosyl)ation. Consistently, PARP1 inhibition rescued ALDH2 deficiency-induced fatty liver and elevated HDL-C in AKO mice. Interestingly, KI mouse or human liver tissues showed ABCA1 downregulation with increased nuclear PARP1 and LXRα poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRα/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD.

Open chromatin interaction maps reveal functional regulatory elements and chromatin architecture variations during wheat evolution.

BACKGROUND: Bread wheat (Triticum aestivum) is an allohexaploid that is generated by two subsequent allopolyploidization events. The large genome size (16 Gb) and polyploid complexity impede our understanding of how regulatory elements and their interactions shape chromatin structure and gene expression in wheat. The open chromatin enrichment and network Hi-C (OCEAN-C) is a powerful antibody-independent method to detect chromatin interactions between open chromatin regions throughout the genome. RESULTS: Here we generate open chromatin interaction maps for hexaploid wheat and its tetraploid and diploid relatives using OCEAN-C. The anchors of chromatin loops show high chromatin accessibility and are concomitant with several active histone modifications, with 67% of them interacting with multiple loci. Binding motifs of various transcription factors are significantly enriched in the hubs of open chromatin interactions (HOCIs). The genes linked by HOCIs represent higher expression level and lower coefficient expression variance than the genes linked by other loops, which suggests HOCIs may coordinate co-expression of linked genes. Thousands of interchromosomal loops are identified, while limited interchromosomal loops (0.4%) are identified between homoeologous genes in hexaploid wheat. Moreover, we find structure variations contribute to chromatin interaction divergence of homoeologs and chromatin topology changes between different wheat species. The genes with discrepant chromatin interactions show expression alteration in hexaploid wheat compared with its tetraploid and diploid relatives. CONCLUSIONS: Our results reveal open chromatin interactions in different wheat species, which provide new insights into the role of open chromatin interactions in gene expression during the evolution of polyploid wheat.

Microscopic Volta potential difference on metallic surface promotes the osteogenic differentiation and proliferation of human mesenchymal stem cells.

Endogenous microscopic electric cues play an essential role in bone's remodeling and self-repair. Modulating the extracellular electrical environment, by means of external electric stimulation or changing surface potential of implants, was manifested to facilitate the osteointegration. The microscopic potential difference, originating from heterogeneous microstructures of materials, may mimic the endogenous electric signals to stimulate surrounding cells. In this study, the spark-plasma sintered Ti/Ta hybrid metal was fabricated and utilized to realize a surface microscopic potential difference at the same magnitude as endogenous potentials. Activated by the electric stimulation, the mesenchymal stem cells exhibited the anisotropic and polygonal cellular morphology on the Ti/Ta hybrid metal. The microscopic electric potential difference coordinated the cells proliferation on the subsequent days. Moreover, the results showed that the osteo-lineage differentiation on Ti/Ta hybrid metal were in vitro boosted over the control groups. Tailoring microstructures of material to obtain a reasonable electric microenvironment may be a necessary principle to achieve more favorable cell responses to implants, suggesting an extra degree of freedom in bone-repairing material design.

Fructose-1,6-Bisphosphate Aldolase B Depletion Promotes Hepatocellular Carcinogenesis Through Activating Insulin Receptor Signaling and Lipogenesis.

BACKGROUND AND AIMS: Insulin receptor (IR) transduces cell surface signal through phosphoinositide 3-kinase (PI3K)-AKT pathways or translocates to the nucleus and binds to the promoters to regulate genes associated with insulin actions, including de novo lipogenesis (DNL). Chronic activation of IR signaling drives malignant transformation, but the underlying mechanisms remain poorly defined. Down-regulation of fructose-1,6-bisphosphate aldolase (ALDO) B in hepatocellular carcinoma (HCC) is correlated with poor prognosis. We aim to study whether and how ALDOB is involved in IR signaling in HCC. APPROACH AND RESULTS: Global or liver-specific ALDOB knockout (L-ALDOB-/- ) mice were used in N-diethylnitrosamine (DEN)-induced HCC models, whereas restoration of ALDOB expression was achieved in L-ALDOB-/- mice by adeno-associated virus (AAV). 13 C6 -glucose was employed in metabolic flux analysis to track the de novo fatty acid synthesis from glucose, and nontargeted lipidomics and targeted fatty acid analysis using mass spectrometry were performed. We found that ALDOB physically interacts with IR and attenuates IR signaling through down-regulating PI3K-AKT pathways and suppressing IR nuclear translocation. ALDOB depletion or disruption of IR/ALDOB interaction in ALDOB mutants promotes DNL and tumorigenesis, which is significantly attenuated with ALDOB restoration in L-ALDOB-/- mice. Notably, attenuated IR/ALDOB interaction in ALDOB-R46A mutant exhibits more significant tumorigenesis than releasing ALDOB/AKT interaction in ALDOB-R43A, whereas knockdown IR sufficiently diminishes tumor-promoting effects in both mutants. Furthermore, inhibiting phosphorylated AKT or fatty acid synthase significantly attenuates HCC in L-ALDOB-/- mice. Consistently, ALDOB down-regulation is correlated with up-regulation of IR signaling and DNL in human HCC tumor tissues. CONCLUSIONS: Our study reports a mechanism by which loss of ALDOB activates IR signaling primarily through releasing IR/ALDOB interaction to promote DNL and HCC, highlighting a potential therapeutic strategy in HCC.

Acetaldehyde Dehydrogenase 2 regulates HMG-CoA reductase stability and cholesterol synthesis in the liver.

HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol biosynthesis and the target for cholesterol-lowering therapy. Acetaldehyde dehydrogenase 2 (ALDH2) is primarily responsible for detoxifying ethanol-derived acetaldehyde and endogenous lipid aldehydes derived from lipid peroxidation. Epidemiological and Genome Wide Association Studies (GWAS) have linked an inactive ALDH2 rs671 variant, responsible for alcohol flush in nearly 8% world population and 40% of Asians, with cholesterol levels and higher risk of cardiovascular disease (CVD) but the underlying mechanism remains elusive. Here we find that the cholesterol levels in the serum and liver of ALDH2 knockout (AKO) and ALDH2 rs671 knock-in (AKI) mice are significantly increased, consistent with the increase of intermediates in the cholesterol biosynthetic pathways. Mechanistically, mitochondrial ALDH2 translocates to the endoplasmic reticulum to promote the formation of GP78/Insig1/HMGCR complex to increase HMGCR degradation through ubiquitination. Conversely, ALDH2 mutant or ALDH2 deficiency in AKI or AKO mice stabilizes HMGCR, resulting in enhanced cholesterol synthesis, which can be reversed by Lovastatin. Moreover, ALDH2-regulated cholesterol synthesis is linked to the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). Together, our study has identified that ALDH2 is a novel regulator of cholesterol synthesis, which may play an important role in CVD.

Effect of attentional selection on working memory for depth in a retro-cueing paradigm.

Recent studies have shown that the temporary storage and manipulation of depth information (working memory for depth; WMd) is largely different from that of visual information in a 2D context (visual working memory; VWM). Although there has been abundant evidence on VWM showing that cueing a memory item during retention could bias attention to its internal representation and thus improves its memory performance (a retro-cue effect), it is unknown whether such an effect differs for WMd that is nested in a 3D context compared with that in a conventional 2D context. Here, we used a change detection task to investigate the effect of attentional selection on WMd by testing several types of retro-cue. The memory array consisted of items positioned at various stereoscopic depth planes, and a cue was presented during retention. Participants needed to make judgments on whether the depth position of target (one memory item) had changed. Our study showed reliable valid retro-cue benefits but no invalid retro-cue cost, indicating that the relational information may be registered in WMd to prevent a strategical removal of the unattended item. There was also a slight improvement in memory performance for cueing depth order compared with that for cueing other feature dimensions or 2D locations. The attentional effect on memory representation in a 3D context is different from that in a 2D context, and the divergence may suggest the distinctive nature of working memory for depth.

Dorsomorphin induces cancer cell apoptosis and sensitizes cancer cells to HSP90 and proteasome inhibitors by reducing nuclear heat shock factor 1 levels.

OBJECTIVE: Heat shock factor 1 (HSF1), a transcriptional regulator of heat shock proteins (HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far. METHODS: The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies. Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth. RESULTS: Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression. CONCLUSIONS: Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance. Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.

Fpr2 Deficiency Alleviates Diet-Induced Insulin Resistance Through Reducing Body Weight Gain and Inhibiting Inflammation Mediated by Macrophage Chemotaxis and M1 Polarization.

Obesity and related inflammation are critical for the pathogenesis of insulin resistance, but the underlying mechanisms are not fully understood. Formyl peptide receptor 2 (FPR2) plays important roles in host immune responses and inflammation-related diseases. We found that Fpr2 expression was elevated in the white adipose tissue of high-fat diet (HFD)-induced obese mice and db/db mice. The systemic deletion of Fpr2 alleviated HFD-induced obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis. Furthermore, Fpr2 deletion in HFD-fed mice elevated body temperature, reduced fat mass, and inhibited inflammation by reducing macrophage infiltration and M1 polarization in metabolic tissues. Bone marrow transplantations between wild-type and Fpr2-/- mice and myeloid-specific Fpr2 deletion demonstrated that Fpr2-expressing myeloid cells exacerbated HFD-induced obesity, insulin resistance, glucose/lipid metabolic disturbances, and inflammation. Mechanistic studies revealed that Fpr2 deletion in HFD-fed mice enhanced energy expenditure probably through increasing thermogenesis in skeletal muscle; serum amyloid A3 and other factors secreted by adipocytes induced macrophage chemotaxis via Fpr2; and Fpr2 deletion suppressed macrophage chemotaxis and lipopolysaccharide-, palmitate-, and interferon-γ-induced macrophage M1 polarization through blocking their signals. Altogether, our studies demonstrate that myeloid Fpr2 plays critical roles in obesity and related metabolic disorders via regulating muscle energy expenditure, macrophage chemotaxis, and M1 polarization.

Androgen alleviates neurotoxicity of ß-amyloid peptide (Aß) by promoting microglial clearance of Aß and inhibiting microglial inflammatory response to Aß.

AIMS: Lower androgen level in elderly men is a risk factor of Alzheimer's disease (AD). It has been reported that androgen reduces amyloid peptides (Aß) production and increases Aß degradation by neurons. Activated microglia are involved in AD by either clearing Aß deposits through uptake of Aß or releasing cytotoxic substances and pro-inflammatory cytokines. Here, we investigated the effect of androgen on Aß uptake and clearance and Aß-induced inflammatory response in microglia, on neuronal death induced by Aß-activated microglia, and explored underlying mechanisms. METHODS: Intracellular and extracellular Aß were examined by immunofluorescence staining and Western blot. Amyloid peptides (Aß) receptors, Aß degrading enzymes, and pro-inflammatory cytokines were detected by RT-PCR, real-time PCR, and ELISA. Phosphorylation of MAP kinases and NF-κB was examined by Western blot. RESULTS: We found that physiological concentrations of androgen enhanced Aß42 uptake and clearance, suppressed Aß42 -induced IL-1ß and TNFα expression by murine microglia cell line N9 and primary microglia, and alleviated neuronal death induced by Aß42 -activated microglia. Androgen administration also reduced Aß42 -induced IL-1ß expression and neuronal death in murine hippocampus. Mechanistic studies revealed that androgen promoted microglia to phagocytose and degrade Aß42 through upregulating formyl peptide receptor 2 and endothelin-converting enzyme 1c expression, and inhibited Aß42 -induced pro-inflammatory cytokines expression via suppressing MAPK p38 and NF-κB activation by Aß42 , in an androgen receptor independent manner. CONCLUSION: Our study demonstrates that androgen promotes microglia to phagocytose and clear Aß42 and inhibits Aß42 -induced inflammatory response, which may play an important role in reducing the neurotoxicity of Aß.

Extensive Causative Esophagitis Caused by Thermal Injury: A Case Report and Review of the Literature.

Esophagus thermal injury is a rare case that can be easily overlooked by practitioners. We herein present a case of thermally induced diffuse corrosive esophagitis with complaints of dysphagia and retrosternal chest pain after having steamed pork. A thorough disease course was demonstrated by serials of endoscopy images and video. A comprehensive review of articles and a concise overview of esophageal thermal injury clinical manifestation, disease process, typical endoscopy features, pharmacomanagement option, and outcomes will be conducted in this article.

Chronic Low-Dose Cadmium Exposure Impairs Cutaneous Wound Healing With Defective Early Inflammatory Responses After Skin Injury.

Impairment of the immune system is a developing concern in evaluating the toxicity of cadmium (Cd). In the present study, we investigated if Cd could impair cutaneous wound healing through interfering with inflammation after injury. We found that exposure of mice to CdCl2 through drinking water at doses of 10, 30, and 50 mg/l for 8 weeks significantly impaired cutaneous wound healing. Chronic 30 mg/l CdCl2 treatment elevated murine blood Cd level comparable to that of low dose Cd-exposed humans, had no effect on blood total and differential leukocyte counts, but reduced neutrophil infiltration, chemokines (CXCL1 and CXCL2), and proinflammatory cytokines (TNFα, IL-1ß, and IL-6) expression in wounded tissue at early stage after injury. Wounded tissue homogenates from CdCl2-treated mice had lower chemotactic activity for neutrophils than those from untreated mice. Mechanistic studies showed that chronic Cd treatment suppressed ERK1/2 and NF-κB p65 phosphorylation in wounded tissue at early stage after injury. Compared with neutrophils isolated from untreated mice, neutrophils from CdCl2 treated mice and normal neutrophils treated with CdCl2 invitro both had lower chemotactic response, calcium mobilization and ERK1/2 phosphorylation upon chemoattractant stimulation. Collectively, our study indicate that chronic low-dose Cd exposure impaired cutaneous wound healing by reducing neutrophil infiltration through inhibiting chemokine expression and neutrophil chemotactic response, and suppressing proinflammatory cytokine expression. Cd may suppress chemokine and proinflammatory expression through inactivating ERK1/2 and NF-κB, and inhibit neutrophil chemotaxis by attenuating calcium mobilization and ERK1/2 phosphorylation in response to chemoattractants.