Reactive oxygen species (ROS) modulate nitrogen signaling using temporal transcriptome analysis in foxtail millet.

Reactive oxygen species (ROS) is a chemically reactive chemical substance containing oxygen and a natural by-product of normal oxygen metabolism. Excessive ROS affect the growth process of crops, which will lead to the decrease of yield. Nitrogen, as a critical nutrient element in plants and plays a vital role in plant growth and crop production. Nitrate is the primary nitrogen source available to plants in agricultural soil and various natural environments. However, the molecular mechanism of ROS-nitrate crosstalk is still unclear. In this study, we used the foxtail millet (Setaria italica L.) as the material to figure it out. Here, we show that excessive NaCl inhibits nitrate-promoted plant growth and nitrogen use efficiency (NUE). NaCl induces ROS accumulation in roots, and ROS inhibits nitrate-induced gene expression in a short time. Surprisingly, low concentration ROS slight promotes and high concentration of ROS inhibits foxtail millet growth under long-term H2O2 treatment. These results may open a new perspective for further exploration of ROS-nitrate signaling pathway in plants.

Functional 2D Nanoplatforms Alleviate Eosinophilic Chronic Rhinosinusitis by Modulating Eosinophil Extracellular Trap Formation.

The therapeutic outcomes of patients with eosinophilic chronic rhinosinusitis (ECRS) remain unsatisfactory, largely because the underlying mechanisms of eosinophilic inflammation are uncertain. Here, it is shown that the nasal secretions of ECRS patients have high eosinophil extracellular trap (EET) and cell-free DNA (cfDNA) levels. Moreover, the cfDNA induced EET formation by activating toll-like receptor 9 (TLR9) signaling. After demonstrating that DNase I reduced eosinophilic inflammation by modulating EET formation, linear polyglycerol-amine (LPGA)-coated TiS2 nanosheets (TLPGA) as functional 2D nanoplatforms with low cytotoxicity, mild protein adsorption, and increased degradation rate is developed. Due to the more flexible linear architecture, TLPGA exhibited higher cfDNA affinity than the TiS2 nanosheets coated with dendritic polyglycerol-amine (TDPGA). TLPGA reduced cfDNA levels in the nasal secretions of ECRS patients while suppressing cfDNA-induced TLR9 activation and EET formation in vitro. TLPGA displayed exceptional biocompatibility, preferential nasal localization, and potent inflammation modulation in mice with eosinophilic inflammation. These results highlight the pivotal feature of the linear molecular architecture and 2D sheet-like nanostructure in the development of anti-inflammation nanoplatforms, which can be exploited for ECRS treatment.

Conducting Polymer Nanoparticles with Intrinsic Aqueous Dispersibility for Conductive Hydrogels.

Conductive hydrogels are promising materials with mixed ionic-electronic conduction to interface living tissue (ionic signal transmission) with medical devices (electronic signal transmission). The hydrogel form factor also uniquely bridges the wet/soft biological environment with the dry/hard environment of electronics. The synthesis of hydrogels for bioelectronics requires scalable, biocompatible fillers with high electronic conductivity and compatibility with common aqueous hydrogel formulations/resins. Despite significant advances in the processing of carbon nanomaterials, fillers that satisfy all these requirements are lacking. Herein, intrinsically dispersible acid-crystalized PEDOT:PSS nanoparticles (ncrys-PEDOTX ) are reported which are processed through a facile and scalable nonsolvent induced phase separation method from commercial PEDOT:PSS without complex instrumentation. The particles feature conductivities of up to 410 S cm-1 , and when compared to other common conductive fillers, display remarkable dispersibility, enabling homogeneous incorporation at relatively high loadings within diverse aqueous biomaterial solutions without additives or surfactants. The aqueous dispersibility of the ncrys-PEDOTX particles also allows simple incorporation into resins designed for microstereolithography without sonication or surfactant optimization; complex biomedical structures with fine features (< 150 µm) are printed with up to 10% particle loading . The ncrys-PEDOTX particles overcome the challenges of traditional conductive fillers, providing a scalable, biocompatible, plug-and-play platform for soft organic bioelectronic materials.

DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug.

Hand-foot syndrome (HFS) is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes. Even though the cause and pathophysiology of HFS are relatively widely reported, how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied. Additionally, prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce. In our study, we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS. Mechanistically, DNA damage, as the primary cytotoxic cause, in keratinocytes induces cell cycle arrest, activates the cGAS-STING signaling pathway, and subsequently mediates cellular senescence, ultimately fueling a robust secondary inflammatory response that results in HFS. More importantly, the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence. These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.

IL-17A exacerbates psoriasis in a STAT3 overexpressing mouse model.

Background: Psoriasis is an autoimmune skin disease characterized by immunocyte activation, excessive proliferation, and abnormal differentiation of keratinocytes. Signal transducers and activators of transcription 3 (STAT3) play a crucial role in linking activated keratinocytes and immunocytes during psoriasis development. T helper (Th) 17 cells and secreted interleukin (IL)-17A contribute to its pathogenesis. IL-17A treated STAT3 overexpressing mouse model might serve as an animal model for psoriasis. Methods: In this study, we established a mouse model of psoriasiform dermatitis by intradermal IL-17A injection in STAT3 overexpressing mice. Transcriptome analyses were performed on the skin of wild type (WT), STAT3, and IL-17A treated STAT3 mice. Bioinformatics-based functional enrichment analysis was conducted to predict biological pathways. Meanwhile, the morphological and pathological features of skin lesions were observed, and the DEGs were verified by qPCR. Results: IL-17A treated STAT3 mice skin lesions displayed the pathological features of hyperkeratosis and parakeratosis. The DEGs between IL-17A treated STAT3 mice and WT mice were highly consistent with those observed in psoriasis patients, including S100A8, S100A9, Sprr2, and LCE. Gene ontology (GO) analysis of the core DEGs revealed a robust immune response, chemotaxis, and cornified envelope, et al. The major KEGG enrichment pathways included IL-17 and Toll-like receptor signaling pathways. Conclusion: IL-17A exacerbates psoriasis dermatitis in a STAT3 overexpressing mouse.

Construction of CpG Delivery Nanoplatforms by Functionalized MoS2 Nanosheets for Boosting Antitumor Immunity in Head and Neck Squamous Cell Carcinoma.

Despite the promising achievements of immune checkpoint blockade (ICB) therapy for tumor treatment, its therapeutic effect against solid tumors is limited due to the suppressed tumor immune microenvironment (TIME). Herein, a series of polyethyleneimine (Mw = 0.8k, PEI0.8k )-covered MoS2 nanosheets with different sizes and charge densities are synthesized, and the CpG, a toll-like receptor-9 agonist, is enveloped to construct nanoplatforms for the treatment of head and neck squamous cell carcinoma (HNSCC). It is proved that functionalized nanosheets with medium size display similar CpG loading capacity regardless of low or high PEI0.8k coverage owing to the flexibility and crimpability of 2D backbone. CpG-loaded nanosheets with medium size and low charge density (CpG@MM -PL ) could promote the maturation, antigen-presenting capacity, and proinflammatory cytokines generation of bone marrow-derived dendritic cells (DCs). Further analysis reveals that CpG@MM -PL effectively boosts the TIME of HNSCC in vivo including DC maturation and cytotoxic T lymphocyte infiltration. Most importantly, the combination of CpG@MM -PL and ICB agents anti-programmed death 1 hugely improves the tumor therapeutic effect, inspiring more attempts for cancer immunotherapy. In addition, this work uncovers a pivotal feature of the 2D sheet-like materials in nanomedicine development, which should be considered for the design of future nanosheet-based therapeutic nanoplatforms.

Liangxue Jiedu formula improves imiquimod-induced psoriasiform dermatitis with circadian desynchrony by regulating Th17 cell differentiation based on network pharmacological analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Liangxue Jiedu formula (LXJDF) is an effective traditional Chinese medicine (TCM) formula for treating psoriasis of blood-heat syndrome and has been used in clinics for decades. AIM OF THE STUDY: This study aimed to discover the mechanism of LXJDF in psoriasis and the circadian clock by network pharmacology and experimental studies. MATERIALS AND METHODS: The compounds of LXJDF were obtained from the TCMSP and BATMAN-TCM databases. The genes related to psoriasis and circadian rhythm/clock were identified by the OMIM and GeneCards databases. Then, target genes were integrated by Venn and analyzed by the String, CytoNCA, DAVID (GO and KEGG) databases, and the network was constructed using Cytoscape. Mice were raised under light disturbance for fourteen days. On the eighth day, mouse dorsal skin was shaved and smeared with 62.5 mg 5% imiquimod at 8:00 (ZT0) for six successive days. Mice were randomly divided into the model, LXJDF-H (49.2 g/kg·bw), LXJDF-L (24.6 g/kg·bw), and positive drug (dexamethasone) groups. Other mice were smeared with Vaseline under the normal light cycle as the control. The drug of each group was administered at 10:00 (ZT2) and 22:00 (ZT14). The skin lesions were observed, and PASI was scored daily. HE and immunofluorescence were used to measure pathological morphology. Th17 cytokines in serum and skin were measured by flow cytometry and qPCR. Circadian clock gene and protein expression levels were determined by qPCR and Western blotting. RESULTS: We found 34 potential targets of LXJDF in the treatment of psoriasis and circadian rhythm and confirmed their importance by topology analysis. KEGG pathway analysis revealed that the two major pathways were Th17 cell differentiation and the HIF-1 signaling pathway. At ZT2 and ZT14, LXJDF improved IMQ-induced light disturbance mouse skin lesions, including alleviating scales, erythema, and infiltration, reducing PASI, and inhibiting keratinocyte hyperproliferation and parakeratosis. LXJDF reduced IL-17A, IL-17F, TNF-α, and IL-6 in serum at ZT2 and increased IL-10 at ZT2 and ZT14. LXJDF downregulated the expression of IL-17A and IL-17F in skin. At ZT2, LXJDF significantly upregulated CLOCK and REV-ERBα expression and downregulated HIF-1α expression. At ZT14, LXJDF decreased HIF-1α and RORγt expression and significantly increased REV-ERBα expression. CONCLUSION: LXJDF improves psoriasis dermatitis with circadian rhythm disorders by regulating Th17 cell differentiation.

Capecitabine induces hand-foot syndrome through elevated thymidine phosphorylase-mediated locoregional toxicity and GSDME-driven pyroptosis that can be relieved by tipiracil.

BACKGROUND: Hand-foot syndrome (HFS) is a serious dose-limiting cutaneous toxicity of capecitabine-containing chemotherapy, leading to a deteriorated quality of life and negative impacts on chemotherapy treatment. The symptoms of HFS have been widely reported, but the precise molecular and cellular mechanisms remain unknown. The metabolic enzyme of capecitabine, thymidine phosphorylase (TP) may be related to HFS. Here, we investigated whether TP contributes to the HFS and the molecular basis of cellular toxicity of capecitabine. METHODS: TP-/- mice were generated to assess the relevance of TP and HFS. Cellular toxicity and signalling mechanisms were assessed by in vitro and in vivo experiments. RESULTS: TP-/- significantly reduced capecitabine-induced HFS, indicating that the activity of TP plays a critical role in the development of HFS. Further investigations into the cellular mechanisms revealed that the cytotoxicity of the active metabolite of capecitabine, 5-DFUR, was attributed to the cleavage of GSDME-mediated pyroptosis. Finally, we demonstrated that capecitabine-induced HFS could be reversed by local application of the TP inhibitor tipiracil. CONCLUSION: Our findings reveal that the presence of elevated TP expression in the palm and sole aggravates local cell cytotoxicity, further explaining the molecular basis underlying 5-DFUR-induced cellular toxicity and providing a promising approach to the therapeutic management of HFS.

Mingmu Xiaoyao granules regulate the PI3K/Akt/mTOR signaling pathway to reduce anxiety and depression and reverse retinal abnormalities in rats.

Objective: To investigate the effects of Mingmu Xiaoyao granules (MMXY) on the morphology and function of the retina and the mechanism of PI3K/Akt/mTOR pathway-related proteins in rats with anxiety and depression induced by chronic unpredictable mild stress (CUMS). Methods: Fifty-two male Sprague Dawley rats were randomly allocated to either a control (n = 14) or a simulated CUMS group (n = 38). The CUMS model was established successfully at 4 weeks. Six rats in each group were randomly selected to be sacrificed and their retinas isolated for histological examination. At 5 weeks, rats in the CUMS group were randomly allocated to the following groups: Model (CUMS + pure water), MMXY-H (CUMS + MMXY 7.2 g/kg/d), MMXY-L (CUMS + MMXY 3.6 g/kg/d), and CBZ (CUMS + Carbamazepine 20 mg/kg/d), with eight rats in each group. All rats were given the relevant intervention once a day. At 12 weeks, sucrose preference and open field tests were performed to evaluate the anxiety and depression status of rats. In live rats, optical coherence tomography angiography was used to measure retinal thickness and blood flow, while electroretinograms (ERGs) and visual evoked potentials (VEPs) were used to evaluate retinal function. The next day, the specimens were sacrificed for serological, histological, immunofluorescence, Western blot and transmission electron microscopy examinations to explore the mechanism of MMXY in CUMS rats. Results: MMXY improved the anxiety and depression-like behavior of rats. Results of optical coherence tomography angiography showed that MMXY improved retinal inner thickness and blood flow in CUMS rats. MMXY improved the amplitude of a- and b-waves in the scotopic and photopic ERG, as well as N2 and P2 peak time and amplitude in the flash-VEP in CUMS rats. Retinal histological staining and transmission electron microscopy showed that MMXY reversed retinal morphology and ultrastructure in CUMS rats. MMXY reduced the expression of Beclin1 and LC3I/II proteins, regulated the PI3K/Akt/mTOR pathway, inhibited autophagy, and had a protective effect on the retina in CUMS rats. Conclusion: MMXY may effectively improve retinal morphology and function as well as anxiety and depression-like behaviors in CUMS rats by regulating the PI3K/Akt/mTOR signaling pathway.

Prophylactic Effect of Nitric Oxide Donors on Rat Models of EGFR Inhibitor‒Induced Cutaneous Toxicities.

EGF receptor (EGFR) inhibitors have been established as first-line standard-of-care therapies for nonsmall cell lung cancer but are frequently accompanied by adverse dermatological effects, in particular, acneiform rash. There is no effective clinical intervention, partially because of its poorly understood etiology. In this study, we show that inhibition of EGFR initiated keratinocyte HaCaT cell cycle arrest and apoptosis, which fueled a robust secondary inflammatory response. Rats gavaged with EGFR inhibitor showed a phenotype similar to that of clinical patients, which was in line with the interrupted functions observed in HaCaT keratinocytes. We found that a nitric oxide donor, nitroglycerin, was a feasible treatment alternative for EGFR inhibitor‒induced rash. Restoration of epidermal extracellular signal‒regulated kinase and a reduction in signal transducer and activator of transcription 3 signaling through nitroglycerin treatment rescued the cellular functions that had been damaged in vitro and further ameliorated the rash in rat models. In addition, the efficacy of nitroglycerin was superior to that of existing clinical interventions. These data highlighted the importance of epidermal EGFR signaling and led to the identification of a small-molecule nitric oxide donor as a mediator that can maintain EGFR pathway functions during anti-EGFR therapies, providing a therapeutic anchor point for adverse EGFRI-induced skin effects.

Serum Intestinal Metabolites are Raised in Patients with Psoriasis and Metabolic Syndrome.

Purpose: Psoriasis is an immune-mediated chronic inflammatory disease. Metabolic syndrome (MetS) is characterized by central obesity, hypertension, dyslipidemia, diabetes and insulin resistance (IR). Increasing evidence indicates that psoriasis is associated with MetS. This study aimed to explore some metabolite indexes which could evaluate the severity or predict the risk of psoriasis patients associated with MetS. Patients and methods: It was a case-control study conducted in Beijing Hospital of Traditional Chinese Medicine. Sixty healthy volunteers (HC), 100 patients with psoriasis (Ps), 100 patients with MetS (MetS) and 80 patients with both psoriasis and MetS (Ps+MetS) were entered between January 2016 and December 2018. Blood samples were taken after at least 12 hours fasting and the contents of trimethylamine N-oxide (TMAO), carnitine, choline and betaine in serum were measured by Liquid Chromatography Mass Spectrometry (LC-MS/MS). Besides, the serum levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol (CHO), triglyceride (TG), blood glucose (BG), creatinine (Cr), urea nitrogen (BUN), uric acid (UA) were determined. Results: The non-healthy groups had different degrees of dyslipidemia, Ps-MetS> Ps >MetS. Compared with HC, the Ps had a higher level of TG; The MetS had the lowest level of HDL; The Ps+Mets had the highest level of TG and CHO. The Ps and Ps+MetS both had high level of UA, but there was no difference between the two groups. As for intestinal metabolites, the Ps had significant differences in TMAO, carnitine, and betaine in comparison with HC. The MetS had the highest level of TMAO. There was positive correlation between PASI and TMAO and betaine. Conclusions: TMAO and betaine could serve as indexes reflecting the severity of psoriasis. TG, CHO, LDL and UA could serve as risk factors of MetS in psoriatic patients.

Impaired AT2 to AT1 cell transition in PM2.5-induced mouse model of chronic obstructive pulmonary disease.

BACKGROUND: Particular matter 2.5 (PM2.5) is one of the most important air pollutant, and it is positively associated with the development of chronic obstructive pulmonary disease (COPD). However, the precise underlying mechanisms through which PM2.5 promotes the development of COPD remains largely unknown. METHODS: Mouse alveolar destruction were determined by histological analysis of lung tissues and lung function test. Alveolar type II cells (AT2) to alveolar type I cells (AT1) transition in PM2.5-induced COPD mouse model was confirmed via immunofluorescence staining and qPCR analysis. The differentially expressed genes in PM2.5-induced COPD mouse model were identified by RNA-sequencing of alveolar epithelial organoids and generated by bioinformatics analysis. RESULTS: In this study, we found that 6 months exposure of PM2.5 induced a significantly decreased pulmonary compliance and resulted in pulmonary emphysema in mice. We showed that PM2.5 exposure significantly reduced the AT2 to AT1 cell transition in vitro and in vivo. In addition, we found a reduced expression of the intermediate AT2-AT1 cell process marker claudin 4 (CLDN4) at day 4 of differentiation in mouse alveolar organoids treated with PM2.5, suggesting that PM2.5 exposure inhibited AT2 cells from entering the transdifferentiation process. RNA-sequencing of mouse alveolar organoids showed that several key signaling pathways that involved in the AT2 to AT1 cell transition were significantly altered including the Wnt signaling, MAPK signaling and signaling pathways regulating pluripotency of stem cells following PM2.5 exposure. CONCLUSIONS: In summary, these data demonstrate a critical role of AT2 to AT1 cell transition in PM2.5-induced COPD mouse model and reveal the signaling pathways that potentially regulate AT2 to AT1 cell transition during this process. Our findings therefore advance the current knowledge of PM2.5-induced COPD and may lead to a novel therapeutic strategy to treat this disease.

In vitro characterization of Haemonchus contortus trehalose-6-phosphate phosphatase and its immunomodulatory effects on peripheral blood mononuclear cells (PBMCs).

BACKGROUND: Trehalose-6-phosphate phosphatase (TPP6) is a key enzyme in the trehalose biosynthesis pathway. The accumulation of TPP6 inside the body is harmful to the pathogen, but almost nothing is currently known about the function of TPP6 from Haemonchus contortus (CRE-GOB-1). METHODS: The H. contortus CRE-GOB-1 (HcGOB) gene was cloned and recombinant protein of GOB (rHcGOB) was expressed; transcription of the HcGOB gene at different developmental stages of H. contortus was then studied. The spatial expression pattern of the HcGOB gene in adult female and male worms was determined by both quantitative real-time PCR (qPCR) and immunofluorescence. The binding of the rHcGOB protein to goat PBMCs was assessed by immunofluorescence assay. The immunomodulatory impacts of rHcGOB on cell proliferation, nitric oxide generation and cytokine secretion were assessed by co-culture of rHcGOB protein with goat PBMCs. RESULTS: The HcGOB protein was transcribed in eggs, infective third-stage larvae (iL3s) and adults of H. contortus, with the highest transcript levels found in the egg stage. The transcript levels were significantly elevated in iL3s after manual desheathing. HcGOB was widely distributed in adult worms where it was mainly localized in the gut and gonads. rHcGOB was observed to bind to PBMCs and also to be recognized by sera collected from a goat infected with H. contortus. rHcGOB significantly activated the interleukin-10/transforming growth factor ß/signal transducer and activator of transcription 3 (IL-10/TGF-ß/STAT3) pathway in PBMCs while suppressing the transcription and expression of IL-4 and IL-17. CONCLUSIONS: These results suggest that the HcGOB gene plays an important role in the development, parasitism and reproduction of H. contortus. The rHcGOB protein affected the immunomodulatory function of PBMCs in the in vitro study, suggesting that this protein would be a promising vaccine target.

Huiyang Shengji Extract Improve Chronic Nonhealing Cutaneous through the TGF-ß1/Smad3 Signaling Pathway.

Chronic nonhealing cutaneous wounds are a thorny problem in the field of surgery because of their prolonged and unhealed characteristics. Huiyang Shengji extract (HSE) is an extract of traditional Chinese medicine prescription for treating chronic wounds. This study aims to investigate the regulation of M1 macrophages on fibroblast proliferation and secretion and the intervention mechanism of Huiyang Shengji extract. We found that the effects of HSFs stimulated with paracrine factors from M1 macrophages were as follows: the proliferation of HSFs was reduced, the expression of MKI-67 was downregulated, and the content and gene expression of the inflammation factors and fibroblast MMPs were increased, while the content and gene expression of TIMP-1 are decreased, the content of human fibroblasts secreting type I collagen (COL1A1) and type III collagen (COL3A1) was decreased, and the TGF-ß1/Smad3 signaling pathway was inhibited. Interestingly, HSE inhibited these effects of M1 macrophages on human fibroblasts after the intervention, and the inhibitory effect was related to the concentration. In conclusion, M1 macrophages caused changes in HSFs and secretion, while HSE has a specific regulatory effect on the proliferation and secretion of fibroblasts caused by M1 macrophages.

Inhibition of the Wnt/ß-catenin signaling pathway reduces autophagy levels in complement treated podocytes.

In idiopathic membranous nephropathy, the complement membrane attack complex, more commonly referred to as complement 5b-9 (C5b-9), induces glomerular epithelial cell injury and proteinuria. C5b-9 can also activate numerous mechanisms that restrict or facilitate injury. Recent studies suggest that autophagy and the canonical Wnt signaling pathway serve an important role in repairing podocyte injury. However, the effect of C5b-9 on these pathways and the relationship between them remains unclear. The aim of the present study was to show the effect of C5b-9 on the Wnt/ß-catenin signaling pathway and autophagy in podocytes in vitro. Levels of relevant indicators were detected by immunofluorescence staining and capillary western immunoassay. C5b-9 serum significantly activated the Wnt/ß-catenin signaling pathway and promoted autophagy. Treatment with Dickkopf-related protein 1 (DKK1), a Wnt/ß-catenin pathway blocker, protected podocytes from injury and significantly inhibited autophagy. The results indicated that inhibition of the Wnt/ß-catenin pathway physiologically activated autophagy. The results indicated that C5b-9 resulted in a decrease in Akt in podocytes. However, the podocytes preincubated with DKK1 and then attacked by C5b-9 showed an increase in Akt levels. This may explain the observation that blocking the Wnt/ß-catenin signaling pathway attenuated C5b-9 podocyte damage, while inhibiting autophagy. The results of the present study also suggest that regulation of these two pathways may serve as a novel method for the treatment of idiopathic membranous nephropathy.

Liangxue Jiedu Formula Improves Psoriasis and Dyslipidemia Comorbidity via PI3K/Akt/mTOR Pathway.

The pathological mechanism of psoriasis and dyslipidemia comorbidity is unclear, and there are few reports on therapy. By establishing an animal model of ApoE-/- mice induced by imiquimod (IMQ), we explored the effects of Liangxue Jiedu formula (LXJDF), a traditional Chinese herb medicine, on psoriasis and dyslipidemia comorbidity through PI3K/Akt/mTOR pathway. The experiment was divided into a control group, a model group, an LXJDF high-dose group, an LXJDF low-dose group, and a positive drug (atorvastatin) group. Each group of mice was given continuous oral administration once a day. After 3 weeks, the mice dorsal skins were smeared with 62.5 mg of 5% IMQ cream for five consecutive days and continued to be given the corresponding drugs. We observed the effects of LXJDF on skin lesion changes, PASI score, pathological characteristics, blood lipid levels (TC, TG, LDL, HDL, and oxLDL), liver pathology, inflammatory factors in the skin, and the protein expression of PI3K/Akt/mTOR pathway in both the skin and liver. The results showed that LXJDF could significantly improve the psoriasiform skin lesions of IMQ-induced ApoE-/- mice, including the reduction of PASI, thinning of epidermal thickness, inhibition of hyperkeratosis and parakeratosis, and inflammatory infiltration in the dermis, and reduce lipid accumulation in the epidermal. LXJDF could regulate blood lipid levels, reduce liver inflammation, and protect the liver. LXJDF could significantly decrease the gene expressions of inflammatory factors IL-17A, IL-23, IL-6, and TNF-α in the skin. LXJDF showed specific inhibition of PI3K, Akt, mTOR protein, and its phosphorylation expressions. In conclusion, LXJDF exerts an intervention effect on psoriasis and dyslipidemia comorbidity via PI3K/Akt/mTOR and its phosphorylation pathway.

Association of Waist-to-Height Ratio, Metabolic Syndrome, and Carotid Atherosclerosis in Individuals with a High Risk of Stroke: A Cross-Sectional Study of 9605 Study Participants.

Background: To determine the association of waist-to-height ratio (WHtR), metabolic syndrome (MetS), and carotid atherosclerosis (CAS) in individuals with a high risk of stroke. Methods: We performed a cross-sectional analysis of 9605 study responders from eight urban area communities in Northern China. Height, weight, waist circumference, blood pressure (BP), and blood lipid were measured. Information of population characteristics, smoking status, alcohol consumption, physical activity, and diet were determined by validated questionnaire. Results: A total of 9605 study responders were included in this study. The average age was 60 ± 9 years with 5911 (61.5%) patients being females. The prevalence of MetS and CAS was 26.2% and 75.1%, respectively. WHtR was significantly associated with CAS using our final adjusted model [odds ratio (OR): 1.233, 95% confidence interval (CI): 1.096-1.378]. The association of CAS with hypertension and hyperglycemia were statistically significant among factors that constitute MetS. Additional risk factors affecting the development of CAS included age, previous stroke, and smoking history (P < 0.05). Conclusion: WHtR was determined to perform better compared with other traditional indicators for correlating CAS. We believe that WHtR is a better indicator for the early identification of CAS in individuals with a high risk of stroke. This will facilitate the early detection and intervention of CAS.

Paeonol inhibits the development of 1­chloro­2,4­dinitrobenzene­induced atopic dermatitis via mast and T cells in BALB/c mice.

Our previous studies suggested that paeonol, the active constituent of the traditional Chinese medicine Cortex Moutan, may be an effective treatment for inflammatory disorders. In the present study, the therapeutic potential of paeonol on atopic dermatitis (AD) was investigated using animal and cell experiments. AD­like lesions were induced by repeated application of 1­chloro­2,4­dinitrobenzene (DNCB) to the shaved dorsal skin of BALB/c mice, and P815 cells were used for in vitro assays. The skin lesions, serum and spleens of the mice were analyzed using lesion severity scoring, histological analysis, flow cytometry, reverse transcription­quantitative polymerase chain reaction, western blotting and ELISA, in order to investigate the anti­AD effects of paeonol. In addition, western blotting and ELISA were conducted for in vitro analysis of P815 cells. The results demonstrated that oral administration of paeonol inhibited the development of DNCB­induced AD­like lesions in the BALB/c mice by reducing severity of the lesions, epidermal thickness and mast cell infiltration; this was accompanied by reduced levels of immunoglobulin E and inflammatory cytokines [interleukin (IL)­4, histamine, IL­13, IL­31 and thymic stromal lymphopoietin], along with regulation of the T helper (Th) cell subset (Th1/Th2) ratio. Application of paeonol also reduced the protein expression levels of phosphorylated (p)­p38 and p­extracellular signal­regulated kinase (ERK) in skin lesions. In vitro, paeonol reduced the expression levels of tumor necrosis factor­α and histamine in P815 cells, and inhibited p38/ERK/mitogen­activated protein kinase signaling. The present findings indicated that paeonol may relieve dermatitis by acting on cluster of differentiation 4+ T and mast cells; therefore, paeonol may represent a potential therapeutic strategy for the treatment of allergic inflammatory conditions via immunoregulation.

Hesperidin inhibits keratinocyte proliferation and imiquimod-induced psoriasis-like dermatitis via the IRS-1/ERK1/2 pathway.

AIMS: To evaluate the therapeutic benefits of Hesperidin (Hes) using an imiquimod (IMQ)-induced psoriasis-like mouse model and human immortalized keratinocytes (HaCaT) cells stimulated with lipopolysaccharide (LPS). METHODS: Mice were treated with IMQ and orally administered Hes (125-500 mg/kg/day), methotrexate (MTX) 1 mg/kg/day or distilled water. HaCaT cells were stimulated with LPS (1 µg/mL) and relevant indices were measured after administration with different concentrations of Hes (5-20 µg/mL) for 24 h. Inflammatory skin lesions in IMQ mice were evaluated using the psoriasis area severity index (PASI) and pathological staining. Proteins in the IRS-1/ERK1/2 pathway and inflammatory factors were assessed using western blotting or quantitative real-time PCR. In addition, factors related to IRS-1 secretion levels were assessed by enzyme-linked immunosorbent assays. Extracellular flux (XF) analysis was used to assess cellular metabolic levels. KEY FINDINGS: Hes significantly improved psoriasis-like skin lesions of IMQ-treated mice and inhibited LPS-induced HaCaT cell proliferation. In addition, Hes remarkably decreased PASI scores, reduced epidermal thickness, decreased proliferation and differentiation of epidermal cells, inhibited mRNA expression of inflammatory factors, reduced local skin lesions and serum insulin and glucose levels. Furthermore, Hes modulated the secretion levels of serum Leptin, Adiponectin and Resistin, and inhibited the activation of the IRS-1/ERK1/2 signaling pathway and regulated HaCaT cells metabolism. SIGNIFICANCE: This study demonstrated that Hes administration could have significant therapeutic value for the prevention and clinical treatment of psoriasis.

Identification and Characterization of Neuropeptides by Transcriptome and Proteome Analyses in a Bivalve Mollusc Patinopecten yessoensis.

Neuropeptides play essential roles in regulation of reproduction and growth in marine molluscs. But their function in marine bivalves - a group of animals of commercial importance - is largely unexplored due to the lack of systematic identification of these molecules. In this study, we sequenced and analyzed the transcriptome of nerve ganglia of Yesso scallop Patinopecten yessoensis, from which 63 neuropeptide genes were identified based on BLAST and de novo prediction approaches, and 31 were confirmed by proteomic analysis using the liquid chromatography-tandem mass spectrometry (LC-MS/MS). Fifty genes encode known neuropeptide precursors, of which 20 commonly exist in bilaterians and 30 are protostome specific. Three neuropeptides that have not yet been reported in bivalves were identified, including calcitonin/DH31, lymnokinin and pleurin. Characterization of glycoprotein hormones, insulin-like peptides, allatostatins, RFamides, and some reproduction, cardioactivity or feeding related neuropeptides reveals scallop neuropeptides have conserved molluscan neuropeptide domains, but some (e.g., GPB5, APGWamide and ELH) are characterized with bivalve-specific features. Thirteen potentially novel neuropeptides were identified, including 10 that may also exist in other protostomes, and 3 (GNamide, LRYamide, and Vamide) that may be scallop specific. In addition, we found neuropeptides potentially related to scallop shell growth and eye functioning. This study represents the first comprehensive identification of neuropeptides in scallop, and would contribute to a complete understanding on the roles of various neuropeptides in endocrine regulation in bivalve molluscs.