Tandem Ene/[4 + 2] Cycloaddition Reaction for the Synthesis of 9-Benzylphenanthrenes from Arynes and α-(Bromomethyl)styrenes.

A tandem reaction for the synthesis of phenanthrenes from arynes and α-(bromomethyl)styrenes is reported. The transformation proceeds via an ene reaction of α-(bromomethyl)styrenes with arynes, followed by a [4 + 2] cycloaddition reaction. The reaction generates 9-benzylphenanthrene derivatives in moderate to excellent yields.

Role of Treg/Th17 Imbalance, Microbiota and miRNAs in Pancreatic Cancer: Therapeutic Options.

Pancreatic cancer is one of the most lethal kinds of cancer; numerous patients die from it every year all over the word. Fewer than 5% of people with pancreatic cancer survive death and recover. Recent evidence suggests that inflammation parameters, such as Th17 cells and Tregs, affect the progression and even the diagnosis and treatment of pancreatic cancer. In the inflammation process, T lymphocytes play an essential role in inflammation intensity, and related cytokines modulate immune responses in the tumor microenvironment. Their function is to establish a balance between destructive inflammation and defense against tumor cells via immune system, and Treg/Th17 imbalance is a common problem in this cancer. The role of microbiota in the development of some cancers is clear; microbiota may also be involved in the pancreatic cancer development. All risk factors for pancreatic cancer, such as chronic pancreatitis-related to microbiota, influence the acute or chronic immune response. Some evidence has been presented regarding the role of the immune response in carcinogenesis. In addition, miRNAs are very important in suppressing and stimulating the growth of cancer cells, and a variety of them have been identified. Some miRNAs are abnormally expressed in many cancers and have main roles as post-transcriptional regulators. They show oncogenic or tumor-suppressive functions by binding to marked mRNAs. In this review, we highlight recent findings regarding the role of Treg/Th17 imbalance, microbiota functions, and miRNAs performance in pancreatic cancer. We also present the evidence regarding therapeutic options.

The roles of tumor-associated macrophages in tumor angiogenesis and metastasis.

Tumor associated macrophages (TAMs) are the most frequent immune cells within tumor microenvironment (TME). There is growing evidence that TAMs are involved in tumor progression via multiple mechanisms. TAMs create an immunosuppressive TME by producing growth factors, chemokines, and cytokines which modulate recruitment of immune cells and inhibit anti-tumor responses. They also serve as angiogenesis promoting cells by production of pro-angiogenic factors and matrix metalloproteinases (MMPs) and vascular constructing which guarantee supplying oxygen and nutrients to solid tumor cells. Furthermore, TAMs play important functions in tumor metastasis through contributing to invasion, extravasation, survival, intravasation, and colonization of tumor cells. In this review, we summarized macrophage classification, TAMs polarization, and mechanisms underlying TAM-promoting angiogenesis and metastasis.

Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.

Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.

Degradation of perineuronal nets in the medial prefrontal cortex promotes extinction and reduces reinstatement of methamphetamine-induced conditioned place preference in female mice.

The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories.

Advances in electrically driven light-emitting diodes based on lead-free metal halides.

The emerging lead halide perovskites show great potential for their use as emitters in electrically driven light-emitting diodes (LEDs) with external quantum efficiency (EQE) over 25%. While the toxicity of lead and inferior device stability are the main obstacles for their commercialization, replacing Pb2+ with low- or non-toxic metal ions to form low- or zero-dimensional structures provides an alternative approach to effectively tackle these issues. Recently, luminescent lead-free metal halides have been increasingly developed toward eco-friendly and highly efficient electroluminescence. In this feature article, we give a brief overview of recent advances in luminescent lead-free metal halides and their applications in electrically driven LEDs. The challenges and prospects in this field are outlined at the end.

DNA methylation of DKK-1 may correlate with pathological bone formation in ankylosing spondylitis.

OBJECTIVE: To investigate DNA methylation (DNAm) status of dickkopf-associated protein 1 (DKK-1) in ossified hip capsule synovium and serum among patients with ankylosing spondylitis (AS). METHODS: Western blot was applied to detect the level of DKK-1 protein expression in hip joint capsule tissues from four patients with AS as well as four patients with femoral neck fracture (FNF) caused by trauma as control. DKK-1 gene promoter methylation (GPM) was examined by methylation-specific polymerase chain reaction. Reverse transcription-polymerase chain reaction was performed to examine the messenger RNA (mRNA) levels of DKK-1, ß-catenin, and Wnt3a in both tissue and serum. The DNAm status of serum DKK-1 was measured among 36 patients with AS and syndesmophytes (AS + syndesmophytes group), 40 patients with AS but no syndesmophyte (AS group), and 42 healthy individuals (control group). Also, the serum levels of DKK-1 were measured by enzyme-linked immunosorbent assay. The modified New York criteria (mNYC) together with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) were adopted to examine the radiographic progression of AS. The receiver operating characteristic (ROC) curve was applied to investigate the diagnostic value of the methylation rate of DKK-1 with regard to radiographic progression. RESULTS: The expressions of DKK-1 protein and mRNA in hip joint capsule tissues of AS patients were significantly lower, while DKK-1 GPM rate, ß-catenin mRNA, and Wnt3a mRNA were markedly higher when compared with FNF group. For serum samples, the DKK-1 methylation rate was significantly higher in AS+ syndesmophytes group in contrast to AS group and healthy controls. Serum levels of DKK-1 protein and mRNA in AS with syndesmophytes group were markedly decreased, while ß-catenin mRNA and Wnt3a mRNA expressions were significantly increased than AS with no syndesmophyte group and the healthy control group. AS patients in Grade 4 showed a significantly higher serum DKK-1 GPM rate than those in Grade 3 based on mNYC. Serum DKK-1 GPM level was markedly and positively correlated with mSASSS. Serum levels of DKK-1 in AS+ syndesmophytes group were markedly lower compared with AS but no syndesmophyte group and healthy controls. ROC curve analysis indicated that serum DKK-1 methylation rate serves as a decent indicator for AS radiographic progression. CONCLUSION: DNAm of DKK-1 may correlate with pathological bone formation in AS, which may provide new strategies for the treatment of AS abnormal bone formation.

Electrophysiological evidence for the characteristics of implicit self-schema and other-schema in patients with major depressive disorder: An event-related potential study.

Background: The significance of implicit self-schema and other-schema in major depressive disorder (MDD) is highlighted by both cognitive theory and attachment theory. The purpose of the current study was to investigate the behavioral and event-related potential (ERP) characteristics of implicit schemas in MDD patients. Methods: The current study recruited 40 patients with MDD and 33 healthy controls (HCs). The participants were screened for mental disorders using the Mini-International Neuropsychiatric Interview. Hamilton Depression Rating Scale-17 and Hamilton Anxiety Rating Scale-14 were employed to assess the clinical symptoms. Extrinsic Affective Simon Task (EAST) was conducted to measure the characteristics of implicit schemas. Meanwhile, reaction time and electroencephalogram data were recorded. Results: Behavioral indexes showed that HCs responded faster to positive self and positive others than negative self (t = -3.304, p = 0.002, Cohen's d = 0.575) and negative others (t = -3.155, p = 0.003, Cohen's d = 0.549), respectively. However, MDD did not show this pattern (p > 0.05). The difference in other-EAST effect between HCs and MDD was significant (t = 2.937, p = 0.004, Cohen's d = 0.691). The ERP indicators of self-schema showed that under the condition of positive self, the mean amplitude of LPP in MDD was significantly smaller than that in HCs (t = -2.180, p = 0.034, Cohen's d = 0.902). The ERP indexes of other-schema showed that HCs had a larger absolute value of N200 peak amplitude for negative others (t = 2.950, p = 0.005, Cohen's d = 0.584) and a larger P300 peak amplitude for positive others (t = 2.185, p = 0.033, Cohen's d = 0.433). The above patterns were not shown in MDD (p > 0.05). The comparison between groups found that under the condition of negative others, the absolute value of N200 peak amplitude in HCs was larger than that in MDD (t = 2.833, p = 0.006, Cohen's d = 1.404); under the condition of positive others, the P300 peak amplitude (t = -2.906, p = 0.005, Cohen's d = 1.602) and LPP amplitude (t = -2.367, p = 0.022, Cohen's d = 1.100) in MDD were smaller than that in HCs. Conclusion: Patients with MDD lack positive self-schema and positive other-schema. Implicit other-schema might be related to abnormalities in both the early automatic processing stage and the late elaborate processing stage, while the implicit self-schema might be related only to the abnormality in the late elaborate processing stage.

Roles of lncRNAs in cancer: Focusing on angiogenesis.

Approximately 98% of the human genome consists of non-coding sequences that are classified into two classes by size: small non-coding RNAs (≤200 nucleotides) and long non-coding RNAs (≥200 nucleotides). Long non-coding RNAs (lncRNAs) are involved in various cellular events and act as guides, signals, decoys, and dynamic scaffolds. Due to their oncogenic and tumor suppressive roles, lncRNAs are important in cancer development and growth. LncRNAs play their roles by modulating cancer hallmarks, including DNA damage, metastasis, immune escape, cell stemness, drug resistance, metabolic reprogramming, and angiogenesis. Angiogenesis is vital for solid tumors which guarantees their growth beyond 2 mm3. Tumor angiogenesis is a complex process and is regulated through interaction between pro-angiogenic and anti-angiogenic factors within the tumor microenvironment. There are accumulating evidence that different lncRNAs regulate tumor angiogenesis. In this paper, we described the functions and mechanisms of lncRNAs in tumor angiogenesis.

Nanomedicine and Early Cancer Diagnosis: Molecular Imaging using Fluorescence Nanoparticles.

Incorporating nanotechnology into fluorescent imaging and magnetic resonance imaging (MRI) has shown promising potential for accurate diagnosis of cancer at an earlier stage than the conventional imaging modalities. Molecular imaging (MI) aims to quantitatively characterize, visualize, and measure the biological processes or living cells at molecular and genetic levels. MI modalities have been exploited in different applications including noninvasive determination and visualization of diseased tissues, cell trafficking visualization, early detection, treatment response monitoring, and in vivo visualization of living cells. High-affinity molecular probe and imaging modality to detect the probe are the two main requirements of MI. Recent advances in nanotechnology and allied modalities have facilitated the use of nanoparticles (NPs) as MI probes. Within the extensive group of NPs, fluorescent NPs play a prominent role in optical molecular imaging. The fluorescent NPs used in molecular and cellular imaging can be categorized into three main groups including quantum dots (QDs), upconversion, and dyedoped NPs. Fluorescent NPs have great potential in targeted theranostics including cancer imaging, immunoassay- based cells, proteins and bacteria detections, imaging-guided surgery, and therapy. Fluorescent NPs have shown promising potentials for drug and gene delivery, detection of the chromosomal abnormalities, labeling of DNA, and visualizing DNA replication dynamics. Multifunctional NPs have been successfully used in a single theranostic modality integrating diagnosis and therapy. The unique characteristics of multifunctional NPs make them potential theranostic agents that can be utilized concurrently for diagnosis and therapy. This review provides the state of the art of the applications of nanotechnologies in early cancer diagnosis focusing on fluorescent NPs, their synthesis methods, and perspectives in clinical theranostics.