Cholesterol metabolism has been linked to immune functions, but the mechanisms by which cholesterol biosynthetic signaling orchestrates inflammasome activation remain unclear. Here, we have shown that NLRP3 inflammasome activation is integrated with the maturation of cholesterol master transcription factor SREBP2. Importantly, SCAP-SREBP2 complex endoplasmic reticulum-to-Golgi translocation was required for optimal activation of the NLRP3 inflammasome both in vitro and in vivo. Enforced cholesterol biosynthetic signaling by sterol depletion or statins promoted NLPR3 inflammasome activation. However, this regulation did not predominantly depend on changes in cholesterol homeostasis controlled by the transcriptional activity of SREBP2, but relied on the escort activity of SCAP. Mechanistically, NLRP3 associated with SCAP-SREBP2 to form a ternary complex which translocated to the Golgi apparatus adjacent to a mitochondrial cluster for optimal inflammasome assembly. Our study reveals that, in addition to controlling cholesterol biosynthesis, SCAP-SREBP2 also serves as a signaling hub integrating cholesterol metabolism with inflammation in macrophages.

Controlling the biodistribution of nanoparticles upon intravenous injection is the key to achieving target specificity. One of the impediments in nanoparticle-based tumor targeting is the inability to limit the trafficking of nanoparticles to liver and other organs leading to smaller accumulated amounts in tumor tissues, particularly via passive targeting. Here we overcome both these challenges by designing nanoparticles that combine the specificity of antibodies with favorable particle biodistribution profiles, while not exceeding the threshold for renal filtration as a combined vehicle. To that end, ultrasmall silica nanoparticles are functionalized with anti-human epidermal growth factor receptor 2 (HER2) single-chain variable fragments to exhibit high tumor-targeting efficiency and efficient renal clearance. This ultrasmall targeted nanotheranostics/nanotherapeutic platform has broad utility, both for imaging a variety of tumor tissues by suitably adopting the targeting fragment and as a potentially useful drug delivery vehicle.

Neuroinflammation plays an important role in secondary injury after traumatic brain injury (TBI). Andrographolide (Andro), a diterpenoid lactone isolated from Andrographis paniculata, has been demonstrated to exhibit anti-inflammatory activity in neurodegenerative disorders. This study therefore aimed to investigate the potential neuroprotective effects of Andro after TBI and explore the underlying mechanisms. In our study, we used a weight-dropped model to induce TBI in Sprague-Dawley rats, the neurological deficits were assessed using modified neurological severity scores, Fluoro-Jade B (FJB) and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining were employed to examine neuronal degeneration and apoptosis after TBI, immunofluorescence was designed to investigate microglial activation. Quantitative Real-time PCR and ELISA were conducted to detect the expression levels of pro-inflammatory cytokines, Western blot was used to examine the expression level of proteins of relative signaling pathway. Our results showed that after Andro administration, the neurological deficit was attenuated, and the cerebral edema and apoptosis in brain tissues were also decreased following TBI. Both microglial activation and the expression of pro-inflammatory cytokines were significantly inhibited by Andro after TBI. Moreover, Andro inhibited NF-κB p65 subunit translocation and decreased the expression levels of phosphorylated extracellular signal regulated kinase (ERK) and p38 MAPK after TBI. Altogether, this study suggests that Andro could improve neurobehavioral function by inhibiting NF-κB and MAPK signaling pathway in TBI, which might provide a new approach for treating brain injury.

G4C14-A4T14 polymorphism of TP73 gene has been reported with a potential association in cancer risks through affected cell homeostasis; however the results were not consistent. We performed a comprehensive meta-analysis to explore the associations between G4C14-A4T14 polymorphism and cancer susceptibility. Extensive retrieve was performed in PubMed, EMBASE, Google Scholar, Web of Science, Wanfang database and CNKI database up to May 20, 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were conducted to evaluate the overall strength of the associations in five genetic models, as well as in subgroup analyses. Q-test, false-positive report probability analysis and trial sequential analysis, Egger's test and Begg's funnel plot were applied to evaluate the robustness of the results. In silico analysis was managed to demonstrate the relationship of TP73 expression correlated with cancer tissues. Finally, 36 case-control studies with a total of 9493 cancer cases and 13,157 healthy controls were enrolled into the meta-analysis. The pooled results present a significantly higher risk of G4C14-A4T14 polymorphism in all the five genetic models, as well as in the subgroups of Caucasian, cervical cancer, colorectal cancer, H-B subgroup and comfort to Hardy-Weinberg equilibrium subgroup. In silico analysis revealed that the expression of TP73 in cervical cancer tissue is higher than it in corresponding normal tissue, as well as in cervical cancer. All in all, TP73 G4C14-A4T14 polymorphism causes an upgrade cancer risk, especially in Caucasian population. G4C14-A4T14 polymorphism might be a potential biomarker for judging the tumorigenesis of cervical cancer and colorectal cancer.

Infra-pyloric artery (IPA) is an important anatomical landmark in treatment of gastric cancer and is the key vessel for pylorus-preserving gastrectomy and subgroup of infra-pyloric lymph nodes. However, its anatomical variation is not thoroughly understood. Our study aimed to clarify the origination of the IPA.

Matrix metalloproteinase 1 (MMP-1) is a member of the zinc-dependent endopeptidase family, which cleaves the extracellular matrix. The present study investigated the functional role of MMP-1 in breast cancer ex vivo and in vitro in order to determine the underlying molecular mechanisms. The levels of MMP-1 were analyzed in 99 breast cancer specimens using immunohistochemistry and western blotting. A stable short hairpin RNA (shRNA) knockdown of MMP-1 expression was performed in MCF-7 and MDA-MB-231 breast cancer cells, and the effects were examined using MTT and colony formation assays, as well as migration and invasion assays, while western blotting was used to detect the activation of intracellular signaling. The MMP-1 protein was more highly expressed in triple-negative breast cancer tissues than in estrogen receptor(+) and human epidermal growth factor 2 receptor(3+) breast cancer tissues (P<0.05). Furthermore, the MMP-1 levels were significantly higher in the tumor and tumor stromal cells of lymph node metastatic breast cancer tissues than in those of non-metastatic tissues. The knockdown of MMP-1 expression in MCF-7 and MDA-MB-231 cells using MMP-1 shRNA significantly inhibited cell proliferation, migration and invasion, and the expression of the Myc proto-oncogene protein, phosphorylated and total RAC-α serine/threonine-protein kinase 1, and B-cell lymphoma 2, but increased the protein levels of apoptosis regulator BAX and caspase 3. In conclusion, the data suggest that MMP-1 serves an important role in breast cancer development and metastasis. Future studies should assess MMP-1 as a prognostic marker for patients with breast cancer and its inhibition as a novel strategy for controlling breast cancer.

Autistic spectral disorder (ASD) is a prevalent neurodevelopmental disease that affects multiple brain regions. Both clinical and animal studies have revealed the possible involvement of the cerebellum in ASD pathology. In this study, we generated a rodent ASD model through a single prenatal administration of valproic acid (VPA) into pregnant mice, followed by cerebellar morphological and functional studies of the offspring. Behavioral studies showed that VPA exposure led to retardation of critical motor reflexes in juveniles and impaired learning in a tone-conditioned complex motor task in adults. These behavioral phenotypes were associated with premature migration and excess apoptosis of the granular cell (GC) precursor in the cerebellar cortex during the early postnatal period, and the decreased cell density and impaired dendritic arborization of the Purkinje neurons. On acute cerebellar slices, suppressed synaptic transmission of the Purkinje cells were reported in the VPA-treated mice. In summary, converging evidence from anatomical, electrophysiological and behavioral abnormalities in the VPA-treated mice suggest cerebellar pathology in ASD and indicate the potential values of motor dysfunction in the early diagnosis of ASD.

Background and Objective: Increasing evidence suggested that polymorphisms in genes of PI3K/Akt pathway were closely related to prostate cancer (PCa) risk. Nevertheless, these results are controversial and inconclusive. Here, we conducted a comprehensive updated meta-analysis and systematic review to precisely illustrate the association between polymorphisms in genes of PI3K/Akt signaling pathway and PCa risk. Materials and Methods: The gene set of PI3K/Akt pathway was referenced from the Kyoto Encyclopedia of Genes and Genomes (KEGG) website. Relevant studies were identified by the systematically researching on PubMed, Web of Science and Google Scholar databases up to October 1, 2017. The odds ratios (ORs) with a corresponding 95% confidential intervals (95%CIs) were applied to test their associations. All the analyses were conducted by using Stata 12.0 (Stata Corporation, USA). Results: Finally, 38 articles comprising 62 case-control studies were enrolled for 13 polymorphisms in genes of PI3K/Akt pathway. However, overall results failed to present a positive association between polymorphisms in genes of PI3K/Akt pathway and PCa risk. Nevertheless, in the subgroup analysis by ethnicity, we identified that IL-6-rs1800795 polymorphism was associated with an increased risk of PCa for Caucasian individuals in dominant model (MM + MW vs. WW: OR = 1.245, 95%CI = 1.176-1.318, P < 0.001). Conclusion: Our work suggests that polymorphisms in genes of PI3K/Akt Signaling Pathway are not risk factor for PCa. Further well-designed studies with larger samples and precise designs are demanded to corroborate our findings.

Sleep deprivation affects the pathophysiology of immune-inflammatory skin diseases such as psoriasis. Increasing efforts are directed toward exploring potential mechanisms involving sleep deprivation and immune responses. However, studies focusing on the effects of different timing of sleep deprivation on skin inflammation are lacking. This study thus investigated the immunomodulatory effects of paradoxical sleep (PS) deprivation at different timing of psoriasiform process on skin inflammation in the psoriasis-like mouse model. Male adult C57BL/6 mice were divided into 5 groups (each n = 5): control group (CON), IMQ-S2 group [treating with 31.25 mg imiquimod (IMQ) per day for 5 days with 48 h of PS deprivation on the fourth and fifth day], S2-IMQ group (treating with 31.25 mg IMQ per day for 5 days with 48 h of PS deprivation on the first and second day), 31.25 group (treating with 31.25 mg IMQ per day for 5 days) and 62.5 group (treating with 62.5 mg IMQ per day for 5 days). Compared with IMQ-S2 group and 31.25 group, S2-IMQ group mice had significant increase of IL-17A mRNA level in skin lesions and lymph nodes, and more severe cutaneous inflammation. However, IMQ-S2 group had the highest IL-1β mRNA level in skin lesions and the highest IL-6 mRNA level in lymph nodes among the three groups. Results of flow cytometry showed that frequencies of γδT cell, IL-17A+γδT cell, dendritic cell (DC) and MHCⅡ+ DC in lymph nodes of S2-IMQ group were significantly higher than IMQ-S2 group and 31.25 group, so was the frequency of γδT cells in skin lesions. However, the frequency of DCs in skin lesions of S2-IMQ group was significantly lower than IMQ-S2 group. These data suggest that PS deprivation at the early stage rather than the late stage of psoriasiform process exacerbates the skin inflammation through modulation of the immune system, which may involve that IL-1β and IL-6 stimulated by PS deprivation in turn increasing IL-17 expression through activation and proliferation of γδT cells and DCs migration.

Septic brain injury is a severe disease of the central nervous system and involves alteration of the cell death pathway due to sepsis. Increasing evidence indicates that Toll-like receptor 4 (TLR4) plays a key role in the development of sepsis. Cell death is also thought to contribute to septic brain injury. However, the mechanism that regulates cell death pathways in response to TLR4 in neurons exposed to septic brain injury is unclear. Here, we established a rat model of septic brain injury to evaluate the effect of TLR4 inhibition on cell death pathways. Furthermore, primary neurons with and those without TLR4 inhibition were exposed to lipopolysaccharide (LPS). We found that septic brain injury induction by cecum ligation and puncture evoked autophagy, induced high-mobility group box-1(HMGB1) translocation and increased TLR4 expression. Inhibition of TLR4 also enhanced autophagy and increased nuclear HMGB1 levels in the sepsis-injured rat brain cortex. After LPS treatment in vitro, HMGB1 was released from neurons. This release of HMGB1 could be inhibited using a TLR4 inhibitor. Collectively, these results indicate that modulation of TLR4 may result in the regulation of neuron cell death pathways by regulating autophagy in cortical tissues. Thus, it may represent a potential therapeutic strategy for neuronal protection in septic brain injury.

Microcalcification is a very important diagnostic information in breast cancer. The purpose of this study was to determine the relationship of clinicopathological features and prognosis of breast cancer with microcalcification and to detect biomarkers related to the possible mechanisms of microcalcifications.

Ling-gui-zhu-gan decoction (LGZG), a classic traditional Chinese medicine formula, has been confirmed to be effective in improving steatosis in non-alcoholic fatty liver disease (NAFLD). However, the mechanism under the efficacy remains unclear. Hence, this study was designed to investigate the mechanisms of LGZG on alleviating steatosis.

The purpose of this study was to assess the effect of proximal fibular osteotomy (PFO) on ankle joint. 49 patients or 53 lower limbs were included and followed-up with a minimum of one year in the study prospectively. Patients were evaluated radiographically and clinically. The questionnaires of the American Knee Society Score (KSS), the Ankle-Hindfoot Scale of the American Orthopedic Foot and Ankle Society (AOFAS), Visual Analogue Scale/Score (VAS) were used to assess the patients clinically. Radiographic evaluations were measured by the hip-knee-ankle angle (HKA), the femoro-tibial angle (FTA), tibial inclination (TI), distal tibial articural surface (TAS), talar tilt (TT), length of fibular (FL), and hind foot alignment such as hindfoot alignment view angle (HAVA), hindfoot alignment ratio (HAR), and hindfoot moment arm (HMA). Of the 53 subjects, no significant differences were exhibited in AOFAS, VAS scores and FL in ankle joint, but a significant differences were demonstrated in KSS score, HKA, FTA, TI, TT, HAVA, HAR and HMA after PFO. Due to the structural improvements of ankle joint, PFO not only improves joint function but also the alignment of ankle joint radiographically, and is still recommended as a safe surgery in treating medial compartment osteoarthritis of knee.

In current study, a bioinformatic-based network pharmacology was used to identify the osteosarcoma (OGS)-pathological targets and formononetin (FN)-treated targets before the main core predictive biotargets were screened. In addition, all core targets were selected through a number of bioinformatic databases, followed by identification of predominant biological processes and signalling pathways of FN anti-OGS. Further, top three core targets of FN anti-OGS were determined as oestrogen receptor 1 (ESR1), tumour protein p53 (TP53), receptor tyrosine-protein kinase erbB-2 (ERBB2) respectively. In clinical biochemical data, the plasma samples of OGS showed the increased trends of alkaline phosphatase, triglyceride, blood glucose, lactate dehydrogenase, high-sensitive C-reactive protein and some immune cell counts when referenced to medical criteria. In clinicopathological examination, histological OGS sections resulted in increased positive cell counts of neoplastic ESR1, TP53, ERBB2. To further validate these corn proteins in experimental study in vivo, FN-treated tumour-bearing nude mice showed intracellular reductions of ESR1, TP53, ERBB2 positive expressions, accompanied with visibly reduced tumour weights. Collectively, our bioinformatic and experimental findings disclosed main core targets, biological processes and signalling pathways of FN anti-OGS. Interestingly, the top core targets were representatively validated following FN treatment in vivo. Therefore, we reasoned that these predictive targets might be the potential biomarkers for screening and treating osteosarcoma.

Triple-negative breast cancer (TNBC) harbors genetic heterogeneity and generally has more aggressive clinical outcomes. As such, there is urgency in identifying new prognostic targets and developing novel therapeutic strategies. In this study, miR-224 was overexpressed in breast cancer cell lines and TNBC primary cancer samples. Knockdown of miR-224 in MDA-MB-231 cancer cells reduced cell proliferation, migration, and invasion. Through integrating in silico prediction algorithms with KEGG pathway and Gene Ontology analyses, CASP9 was identified to be a potential target of miR-224. miR-224 knockdown significantly increased CASP9 transcript and protein levels. Furthermore, luciferase reporter assays confirmed a direct interaction of miR-224 with CASP9. Our findings have demonstrated that the miR-224/CASP9 axis plays an important role in TNBC progression, providing evidence in support of a promising therapeutic strategy for this disease.

Crop emergence and canopy cover are important physiological traits for potato (Solanum tuberosum L.) cultivar evaluation and nutrients management. They play important roles in variety screening, field management and yield prediction. Traditional manual assessment of these traits is not only laborious but often subjective.

Auxin signalling plays an essential role in regulating plant development. Auxin response factors (ARFs), which are critical components of auxin signalling, modulate the expression of early auxin-responsive genes by binding to auxin response factor elements (AuxREs). However, there has been no comprehensive characterization of this gene family in cotton. Here, we identified 56 GhARF genes in the assembled Gossypium hirsutum genome. This gene family was divided into 17 subfamilies, and 44 members of them were distributed across 21 chromosomes. GhARF6 and GhARF11 subfamily genes were predominantly expressed in vegetative tissues, whereas GhARF2 and GhARF18 subfamily genes were highly expressed during seed fibre cell initiation. GhARF2-1 and GhARF18-1 were exclusively expressed in trichomes, organs similar to cotton seed fibre cells, and overexpression of these genes in Arabidopsis enhances trichome initiation. Comparative transcriptome analysis combined with AuxRE prediction revealed 11 transcription factors as potential target genes of GhARF2 and GhARF18. Six of these genes were significantly expressed during seed fibre cell initiation and were bound by GhARF2-1 and GhARF18-1 in yeast one-hybrid assays. Our results suggest that GhARF2 and GhARF18 genes may be key regulators of cotton seed fibre initiation by regulating the expression of several transcription factor genes. This study deepens our understanding of auxin-mediated initiation of cotton seed fibre cells and helps us in breeding better cotton varieties in the future.

To investigate the efficacy and safety of saffron in the treatment of major depressive disorder (MDD) in comparison to placebo and synthetic antidepressants.

Nanobubble (NB), a newly developed nanoscaled ultrasound contrast agent (UCA) for molecular imaging, has been widely researched for these years. Targeting it with functional molecule, nanobubble can adhere selectively to cellular epitopes and receptors outside the vasculature via enhanced permeability and retention (EPR) effect of tumor blood vessel. To enhance the targeting rate of our previous prepared NBs-Affibody for HER2 (+) breast cancer imaging, we introduced a near-infrared fluorescent (NIRF) dye, IR783, in this study to enhance tumor-specific targeting rate and provide a promising modality for dual-mode imaging. The prepared IR783-NBs-Affibody presented a uniform nanoscale size around 482.7 ± 54.3 nm, good biosecurity, and stability over time. The encapsulation efficiency (EE) of IR-783 was 15.09% in the conjugates leading to a successful NIR fluorescence and ultrasound enhancement imaging ex vivo. IR783-NBs-Affibody was able to automatically accumulate on BT474 cells with a highly increased targeting rate of 85.4% compared with previous NBs-Affibody of 26.6%, while Affibody-guided HER2 binding was only found in HER2-positive cell lines (BT474 and T-47D). The newly developed IR783-NBs-Affibody is characterized with favorable HER2 targeting ability and bimodal imaging capability for breast cancer. Thus, IR783-NBs-Affibody holds great potential in molecular diagnosis for patients with breast cancer.

Chicken embryonic stem cells (cESCs) obtained from stage X embryos provide a novel model for the study of avian embryonic development. A new way to maintain cESCs for a long period in vitro still remains unexplored. We found that the cESCs showed stem cell-like properties in vitro for a long term with the support of DF-1 feeder and basic culture medium supplemented with human basic fibroblast growth factor (hbFGF), mouse stem cell factor (mSCF), and human leukemia inhibitory factor (hLIF). During the long culture period, the cESCs showed typical ES cell morphology and expressed primitive stem cell markers with a relatively stable proliferation rate and high telomerase activity. These cells also exhibited the capability to differentiate into cardiac myocytes, smooth muscle cells, neural cells, osteoblast, and adipocyte in vitro. Chimera chickens were produced by cESCs cultured for 25 passages with this new culture system. The experiments showed that DF-1 was the optimal feeder and hbFGF was an important factor for maintaining the pluripotency of cESCs in vitro.