The etiology of allergic rhinitis (AR) is complicated. Traditional therapy of AR still has challenges, such as low long-term treatment compliance, unsatisfactory therapeutic outcomes, and a high financial burden. It is urgent to investigate the pathophysiology of allergic rhinitis from different perspectives and explore brand-new possible preventative or treatment initiatives.

To explore the correlations between the expression of zinc finger protein 521 (ZNF521) with immune invasion and prognosis of gastric cancer.

Ginkgolide is a unique terpenoid natural compound in Ginkgo biloba, and it has an important medicinal value. Proper selenium has been reported to promote plant growth and development, and improve plant quality, stress resistance, and disease resistance. In order to study the effects of exogenous selenium (Se) on the physiological growth and the content of terpene triolactones (TTLs) in G. biloba seedlings, the seedlings in this work were treated with Na2SeO3. Then, the physiological indexes, the content of the TTLs, and the expression of the related genes were determined. The results showed that a low dose of Na2SeO3 was beneficial to plant photosynthesis as it promoted the growth of ginkgo seedlings and increased the root to shoot ratio. Foliar Se application significantly increased the content of soluble sugar and protein and promoted the content of TTLs in ginkgo leaves; indeed, it reached the maximum value of 7.95 mg/g in the ninth week, whereas the application of Se to the roots inhibited the synthesis of TTLs. Transcriptome analysis showed that foliar Se application promoted the expression levels of GbMECPs, GbMECT, GbHMGR, and GbMVD genes, whereas its application to the roots promoted the expression of GbDXS and GbDXR genes. The combined analysis results of metabolome and transcriptome showed that genes such as GbDXS, GbDXR, GbHMGR, GbMECPs, and GbCYP450 were significantly positively correlated with transcription factors (TFs) GbWRKY and GbAP2/ERF, and they were also positively correlated with the contents of terpene lactones (ginkgolide A, ginkgolide B, ginkgolide M, and bilobalide). Endogenous hormones (MeJA-ILE, ETH, and GA7) were also involved in this process. The results suggested that Na2SeO3 treatment affected the transcription factors related to the regulation of endogenous hormones in G. biloba, and further regulated the expression of genes related to the terpene synthesis structure, thus promoting the synthesis of ginkgo TTLs.

Prolonged exposure to low-level noise has often been used scientifically as well as clinically to induce neuroplastic changes within the central auditory pathway in order to reduce central gain, suppress tinnitus and hyperacusis, and modulate different features of central auditory processing. A fundamental assumption underling these studies is that the noise exposure levels are so low that they have no effect on the neural output of the cochlea. Therefore, functional changes occurring in the central auditory pathway must be the results of central rather than peripheral changes. In an attempt to identify long-term noise exposures that did not cause peripheral changes, we measured the compound action potential (CAP) input/output functions from control rats and rats exposed for 6-weeks to 18-24 kHz noise presented at 25, 45, 55, 65, 75 or 85 dB SPL. Exposures >65 dB SPL significantly increased CAP thresholds; the critical intensity (Ct) below which no threshold shift occurred was estimated to be 55 dB SPL. Exposures >55 dB SPL significantly reduced suprathreshold CAP amplitudes; the critical intensity (Ca) below which no amplitude change was predicted to occur was a remarkably low level of 19 dB SPL. These results demonstrate that even extremely low-intensity long duration exposures can disrupt the neural output of the cochlea; these peripheral modifications are likely to contribute to the extensive compensatory changes observed at multiple levels of the central auditory pathway, neural network changes aimed at re-establishing homeostasis.

Lycopene, a natural carotenoid, has potential chemopreventive effects in many cancers. This study aimed to examine the effects of lycopene on regulating the inflammation and apoptosis of N-nitrosomethylbenzylamine(NMBzA) induced esophageal cancer in F344 rats. After the rats were fed normal diets containing different concentrations of lycopene for 25 weeks (10, 25, 50 mg/kg·d of lycopene, respectively), the incidence of tumors in the rats treated with lycopene was significantly lower than that in the simple exposed group (P < 0.05). The antioxidant activity of lycopene was exerted by measuring the levels of GSH-PX, SOD and MDA activity by oxidative stress kits. Furthermore, through western blotting analysis lycopene intervention was found to have significantly improved apoptosis cytokines by increasing the protein expression levels of PPARγ and caspase-3, and also significantly reduced inflammatory cytokines by decreasing the protein expression of NF-κB and COX-2 in the esophagus tissue, especially in the 25 mg/kg of lycopene intervention group (all P < 0.05). These results demonstrated that appropriate dose of lycopene intervention could inhibit the carcinogenesis of esophageal in F344 rats through the possible mechanisms of anti-inflammatory and pro-apoptosis.

Osteosarcoma (OS) is a primary malignant bone tumor with a high fatality rate. Circular RNAs (circRNAs) are a type of endogenous noncoding RNA that have been verified to participate in cancer pathophysiological processes. We aim to investigate the roles of circRNAs in osteosarcoma tumorigenesis. In the present study, we showed that hsa_circ_0003732 was up-regulated in OS tissues and elevated level of hsa_circ_0003732 was linked to poor prognosis of OS patients. Functional investigation indicated that hsa_circ_0003732 promoted proliferation of OS cells. Furthermore, we identified miR-545 as the hsa_circ_0003732-associated microRNA and CCNA2 was a direct target of miR-545. In addition, hsa_circ_0003732 could elevate CCNA2 expression via miR-545, resulting in the promotion of OS cells proliferation. Altogether, our findings demonstrate that hsa_circ_0003732 promotes OS cells proliferation via miR-545/CCNA2 axis and imply hsa_circ_0003732 may be a potential prognosis biomarker and therapeutic target for OS.

Recently, mineralocorticoid receptors (MR) were identified in peripheral nociceptive neurons, and their acute antagonism was responsible for immediate and short-lasting (non-genomic) antinociceptive effects. The same neurons were shown to produce the endogenous ligand aldosterone by the enzyme aldosterone synthase.

Acute myeloid leukemia (AML) is a malignant disease originating from hematopoietic stem cells (HSC). Chemotherapy and/or HSC transplantation is unsatisfactory due to serious side effects, multidrug resistance, and high relapse rate. Thus, alternative strategies are urgently needed to develop more effective therapies. Liriope muscari baily saponins C (DT-13) is a novel compound isolated from Liriope muscari (Decne.) Baily, and exhibited a potent cytotoxicity against several solid tumors. However, the anti-AML activity of DT-13 and the potential mechanisms are still unknown. This study is the first to demonstrate that DT-13 had preferential cytotoxicity against AML cells, and remarkably inhibited proliferation and colony forming ability. Moreover, DT-13 induced the death receptor pathway-dependent apoptosis of HL-60 and Kasumi-1 cells by up-regulating Fas, FasL, DR5 and TRAIL as well as promoted the cleavage of caspase 8, caspase 3 and PARP. Meanwhile, DT-13 induced the differentiation with morphological change related to myeloid differentiation, elevated NBT and α-NAE positive cell rates, differentiation markers CD11b and CD14 as well as level of transcription factors C/EBPα and C/EBPβ. RNA-sequencing analysis revealed that KLF2 may be one of the potential targets regulated by DT-13. Further studies indicated that KLF2 played a critical role in DT-13-induced apoptosis and differentiation. Moreover, activation of AMPK-FOXO was proved to be the upstream of KLF2 pathway that contributed to the induction of apoptosis and differentiation by DT-13. Additionally, restoration of KLF2 by DT-13 was highly correlated with the AMPK-related histone acetylation mechanisms. Finally, DT-13 exhibited an obvious anti-AML effect in NOD/SCID mice with the engraftment of HL-60 cells. Our study suggests that DT-13 may serve as a novel agent for AML by AMPL-KLF2-mediated apoptosis and differentiation.

To systematically evaluate the efficacy and safety of tanshinone for chronic kidney disease (CKD).

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by chronic synovitis, bone erosion, and bone loss. Erzhi Pill (EZP), a classic Chinese patent medicine, is often used to treat osteoporosis and shows a capacity for bone metabolism regulation. Methotrexate (MTX), an essential drug for RA treatment, has been reported to inhibit generalized bone loss in RA patients. However, the combined therapeutic effects and mechanism of EZP and MTX in RA have not been fully elucidated. The aim of this study was to investigate the synergistic effect of EZP and MTX on RA and to explore the underlying mechanism through network pharmacological prediction and experimental verification. Chemical compounds of EZP, human target proteins of EZP and MTX, and RA-related human genes were identified in the Encyclopedia of Traditional Chinese Medicine database, PubChem database, and NCBI database, respectively. The molecular network of EZP and MTX in RA was generated and analyzed with Ingenuity Pathway Analysis software according to the datasets. Then, MTX monotherapy, EZP monotherapy, and combined MTX and EZP therapy were administered to collagen-induced arthritis rats, followed by assessment of pathological score, bone damage, bone alkaline phosphatases (BALP), and tartrate-resistant acid phosphatase (TRACP), and of gene levels related to the Wnt1/LRP5/β-catenin pathway according to network pharmacological analysis. Finally, serum samples from MTX-, EZP- and MTX+EZP-treated rats were used to treat the rat osteoblast (OB)-like UMR-106 cell line to evaluate gene levels related to Wnt1/LRP5/β-catenin. Network pharmacological analysis showed that the Wnt/β-catenin signaling pathway was the top signaling pathway shared among MTX, EZP, and RA. The results from in vivo experiments indicated that EZP combined with MTX reduced arthritis severity, alleviated ankle bone damage, increased BALP and decreased TRACP serum levels, and regulated the mRNA expression of Wnt1, LRP5, β-catenin, Runx2, BALP, and BGP in the ankles. In vitro experiments showed that EZP combined with MTX could also improve the expression of genes related to the Wnt1/LRP5/β-catenin pathway. This study demonstrated that EZP in combination with MTX played a synergistic role in regulating OBs in RA, which was connected to the modulatory effect of EZP and MTX on the Wnt1/LRP5/β-catenin signaling pathway.

Ataxia-telangiectasia mutated (ATM) is an apical kinase of the DNA damage response following DNA double-strand breaks (DSBs); however, the mechanisms of ATM activation are not completely understood. Long noncoding RNAs (lncRNAs) are a class of regulatory molecules whose significant roles in DNA damage response have started to emerge. However, how lncRNA regulates ATM activity remains unknown. Here, we identify an inhibitor of ATM activation, lncRNA HITT (HIF-1α inhibitor at translation level). Mechanistically, HITT directly interacts with ATM at the HEAT repeat domain, blocking MRE11-RAD50-NBS1 complex-dependent ATM recruitment, leading to restrained homologous recombination repair and enhanced chemosensitization. Following DSBs, HITT is elevated mainly by the activation of Early Growth Response 1 (EGR1), resulting in retarded and restricted ATM activation. A reverse association between HITT and ATM activity was also detected in human colon cancer tissues. Furthermore, HITTs sensitize DNA damaging agent-induced cell death both in vitro and in vivo. These findings connect lncRNA directly to ATM activity regulation and reveal potential roles for HITT in sensitizing cancers to genotoxic treatment.

Four new thiodiketopiperazine alkaloids, namely, 5'-hydroxy-6'-ene-epicoccin G (1), 7-methoxy-7'-hydroxyepicoccin G (2), 8'-acetoxyepicoccin D (3), and 7'-demethoxyrostratin C (4), as well as a pair of new enantiomeric diketopiperazines, (±)-5-hydroxydiphenylalazine A (5), along with five known analogues (6-10), were isolated and identified from the culture extract of Epicoccum nigrum SD-388, a fungus obtained from deep-sea sediments (-4500 m). Their structures were established on the basis of detailed interpretation of the NMR spectroscopic and mass spectrometric data. X-ray crystallographic analysis confirmed the structures and established the absolute configurations of compounds 1-3, while the absolute configurations for compounds 4 and 5 were determined by ECD calculations. Compounds 4 and 10 showed potent activity against Huh7.5 liver tumor cells, which were comparable to that of the positive control, sorafenib, and the disulfide bridge at C-2/C-2' is likely essential for the activity.

Angiotensin II (AngII) serves an important inflammatory role in cardiovascular disease; it can induce macrophages to differentiate into the M1‑type, produce inflammatory cytokines and resist pathogen invasion, and can cause a certain degree of damage to the body. Previous studies have reported that connexin 43 (Cx43) and NF‑κB (p65) are involved in the AngII‑induced inflammatory pathways of macrophages; however, the mechanisms underlying the effects of Cx43 and NF‑κB (p65) on AngII‑induced macrophage polarization have not been determined. Thus, the present study aimed to investigate the effects of Cx43 and NF‑κB (p65) on the polarization process of AngII‑induced macrophages. The macrophage polarization‑related proteins and mRNAs were examined by flow cytometry, western blotting, immunofluorescence, ELISA and reverse transcription‑quantitative PCR analyses. RAW264.7 macrophages were treated with AngII to simulate chronic inflammation and it was subsequently found that AngII promoted RAW 264.7 macrophage polarization towards the M1‑type by such effects as the release of inducible nitric oxide synthase (iNOS), tumour necrosis factor (TNF)‑α, IL‑1β, the secretion of IL‑6, and the expression of M1‑type indicators, such as CD86. Simultaneously, compared with the control group, the protein expression levels of Cx43 and phosphorylated (p)‑p65 were significantly increased following AngII treatment. The M1‑related phenotypic indicators, iNOS, TNF‑α, IL‑1β, IL‑6 and CD86, were inhibited by the NF‑κB (p65) signalling pathway inhibitor BAY117082. Similarly, the Cx43 inhibitors, Gap26 and Gap19, also inhibited the expression of M1‑related factors, and the protein expression levels of p‑p65 in the Gap26/Gap19 groups were significantly decreased compared with the AngII group. Altogether, these findings suggested that AngII may induce the polarization of RAW264.7 macrophages to the M1‑type through the Cx43/NF‑κB (p65) signalling pathway.

Epidemiology suggests that adverse environmental exposure during pregnancy may predispose children to hypercholesterolemia in adulthood. This study aimed to demonstrate hypercholesterolemia induced by prenatal dexamethasone exposure (PDE) in adult male offspring rats and explore the intrauterine programming mechanisms. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0, 0.1, 0.2, and 0.4 mg/kg∙d) from gestational days (GD) 9 to 21, and the serum and liver of the male offsprings were collected at GD21, postnatal week (PW) 12 and 28. Furthermore, the effects of dexamethasone on the expression of low-density lipoprotein receptor (LDLR) and its epigenetic mechanism was confirmed in the bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and continuous hepatocyte line. PDE could reduce the birth weight of male offsprings, increase the serum total cholesterol (TCH) level in adult rats, and decrease the liver low-density lipoprotein receptor (LDLR) expression. Serum TCH level and liver LDLR expression were decreased in PDE male fetuses in utero (GD21). Moreover, PDE increased the translocation of the glucocorticoid receptor (GR) in the fetal liver, the expression of DiGeorge syndrome critical region 8 gene (DGCR8), the pre- and post-natal expression of miR-148a. The results of PDE offspring in vivo and in vitro exhibited similar changes. These changes could be reversed by overexpressing LDLR, inhibiting miR-148a or GR. PDE caused hypercholesterolemia in male adult offspring rats, which was mediated via dexamethasone activated intrauterine hepatic GR, enhanced the expression of DGCR8 and miR-148a, thereby reducing the expression of LDLR, leading to impaired liver cholesterol reverse transport function, and finally causing hypercholesterolemia in adult rats.

Individuals infected with hepatitis B virus (HBV) are often coinfected with human immunodeficiency virus (HIV). However, individuals with chronic HBV infection living with acute HIV infection have a significantly lower HBV viral load, along with higher HBeAg and HBsAg loss than HBV-infected individuals alone. Here, we investigated the possible role of natural killer cells (NK cell) function in this progressive course to explore the relationship between phenotypic/functional changes in NK cells during acute HIV infection and HBV clearance in patients with HIV/HBV coinfection.Peripheral blood NK cells from 38 patients with primary HIV infection, including 20 with untreated HIV infection and 18 treatment-naïve patients with HIV/HBV coinfection and 16 patients with chronic HBV infection, were enrolled in this study.We found that the HIV/HBV-coinfected individuals had higher levels of NK cells than the HBV-infected individuals, due to expansion of the CD56 NK cell population. The proportion of NK cells in CD56 and CD56 NK subsets was not found significant difference between HIV/HBV-coinfected and HBV-infected individuals. However, NKG2C levels on NK cells and subsets were significantly higher in HIV/HBV-coinfected individuals than in HBV-infected individuals, whereas NKG2A levels were unaffected or decreased. In addition, the levels of degranulation CD107a, cytotoxicity and IFN-γ production of NK cells were increased in HIV/HBV-coinfected individuals than in HBV-infected individuals. The level of IL-10 production of NK cells was decreased in HIV/HBV-coinfected individuals than in HBV-infected individuals. Furthermore, the level of HBV-DNA was inversely correlated with the proportion of NKG2C and NKG2CNKG2A NK cells, while positively correlated with the proportion of NKG2A and NKG2CNKG2A NK cells. IFN-γ production was inversely correlated with levels of HBV-DNA, but the CD107a expression and IL-10 production of NK cells were not correlated with HBV-DNA levels.These results demonstrate that the upregulation of NKG2C expression, but not of NKG2A expression on the surface of NK cells increases cytolytic capacity and the amounts of cytokines produced and may play a crucial role in HBV clearance during HIV/HBV-coinfection.

Ruxolitinib is an inhibitor of Janus kinases (JAK) 1/2. It was authorised recently by the U.S. Food and Drug Administration (FDA) as a new Myelofibrosis treatment. In this study, we identified ruxolitinib as a new inhibitor of nitric oxide (NO) production in response to lipopolysaccharide (LPS)stimulation of RAW 264.7 cells.

Glehnia littoralis is an important medicinal halophyte-the dried root of which is used as Chinese herbal medicine. However, the use, selection and stability of reference genes are rarely verified in studies of G. littoralis, which hampers investigation of its salt tolerance and metabolism. In this study, we selected 13 candidate reference genes from the transcriptome data of G. littoralis-serine/threonine-protein phosphatase PP2A (PP2A), polyubiquitin 10 (UBQ10), actin (ACT), elongation factor 1-α (EF1-α), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), α-tubulin (α-TUB), β-tubulin (β-TUB), polypyrimidine tract-binding protein 1 (PTBP1), expressed protein 1 (EXP1), expressed protein 2 (EXP2), TIP41-like (TIP41), SAND family (SAND), and cyclophilin 2 (CYP2), and used qRT-PCR to analyse their expression levels in roots of G. littoralis treated with NaCl, polyethylene glycol (PEG), abscisic acid (ABA), and methyl jasmonate (MeJA), as well as in various organs of G. littoralis. The ΔCt, geNorm, NormFinder, and BestKeeper algorithms were used to assess the expression stability of the candidate reference genes and the results were then used to generate a comprehensive rank list with the RankAggreg R package. The most stable reference genes for normalisation were EXP1 and PP2A in response to NaCl, EXP2 and PP2A in response to ABA, CYP2 and α-TUB in response to MeJA, and ACT and EXP1 in the PEG and the organ subsets. GAPDH, β-TUB, and UBQ10 exhibited low stability and so were unsuitable for normalisation. This study is the first systematic analysis of candidate reference genes in G. littoralis and will facilitate further investigation of normalisation of gene expression in G. littoralis.

Circular RNAs (circRNAs) are thought to play essential roles in multiple biological processes, including apoptosis, an important process in antral follicle atresia. We aimed to investigate the potential involvement of circRNAs in granulosa cell apoptosis and thus antral follicle atresia. CircRNA expression profiles were generated from porcine granulosa cells isolated from healthy antral (HA) and atretic antral (AA) follicles. Over 9632 circRNAs were identified, of which 62 circRNAs were differentially expressed (DE-circRNAs). Back-splicing, RNase R resistance, and stability of DE-circRNAs were validated, and miRNA binding sites and related target genes were predicted. Two exonic circRNAs with low false discovery rate (FDR) high fold change, miRNA binding sites, and relevant biological functions-circ_CBFA2T2 and circ_KIF16B-were selected for further characterization. qRT-PCR and linear regression analysis confirmed expression and correlation of the targeted genes-the antioxidant gene GCLC (potential target of circ_CBFA2T2) and the apoptotic gene TP53 (potential target of circ_KIF16B). Increased mRNA content of TP53 in granulosa cells of AA follicles was further confirmed by strong immunostaining of both p53 and its downstream target pleckstrin homology like domain family a member 3 (PHLDA3) in AA follicles compared to negligible staining in granulosa cells of HA follicles. Therefore, we concluded that aberrantly expressed circRNAs presumably play a potential role in antral follicular atresia.

Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized.

In order to discover novel derivatives in the anti-tumor field, reported anti-tumor pharmacophores (uridine, uracil, and thymine) were combined with 2-methoxyestradiol, which has been characterized as having excellent biological properties in terms of anti-tumor activity. Thus, 20 hybrids were synthesized through etherification at the 17β-OH or 3-phenolic hydroxyl group of 2-methoxyestradiol, and evaluated for their biological activities against the human breast adenocarcinoma MCF-7 cell lines, human breast cancer MDA-MB-231 cell lines, and the normal human liver L-O2 cell lines. As a result, all the uridine derivatives and single-access derivatives of uracil/thymine possessed good anti-proliferative activity against tested tumor cells (half maximal inhibitory concentration values from 3.89 to 19.32 µM), while only one dual-access derivative (21b) of thymine possessed good anti-proliferative activity (half maximal inhibitory concentration ≈ 25 µM). Among them, the uridine derivative 11 and the single-access derivative of uracil 12a possessed good anti-proliferative selectivity against tested tumor cells. Furthermore, basic mechanism studies revealed that hybrids 11 and 12a could induce apoptosis in MCF-7 cells through mitochondrial pathway. These hybrids induced morphological changes in MCF-7 cells, causing mitochondrial depolarization. These two hybrids also had the following effects: arrest of the cell cycle at the G2 phase; upregulation of Apaf-1, Bax, and cytochrome c; downregulation of Bcl-2 and Bcl-xL for both mRNA and protein; and increase of the expression for caspase-8 and -9. Finally, apoptotic effector caspase-3 was increased, which eventually caused nuclear apoptosis at least through an intrinsic pathway in the mitochondria. Additionally, hybrids 11 and 12a could specifically bind to estradiol receptor alpha in a dose-dependent manner.