Melanoma is a potentially fatal form of skin cancer with great metastatic potential. THOC2 plays a vital role in human biological progression, however, the roles of THOC2 in melanoma tumorigenesis are still unknown. In the present study, our data demonstrated that THOC2 expression was significantly increased in melanoma tissues, and high THOC2 expression was associated with poor overall survival of melanoma patients. THOC2 reduction repressed melanoma cell proliferation and invasion, and induced cell apoptosis in vitro. Microarray data revealed that the cAMP signaling pathway was significantly downregulated in A375 cells transfected with si-THOC2, which was further confirmed by RT-qPCR and bioinformatics analysis. In conclusion, our data indicated that THOC2 might act as an oncogene in melanoma progression through cAMP signaling pathway regulation, which may offer a therapeutic target for melanoma treatment.

The aim of the study was to investigate the independent and combined effects of the cortisol-to-cortisone ratio (F/E) and 11-deoxycortisol on prediabetes and type 2 diabetes mellitus (T2DM) among different genders.

This study was designed to explore the regulation mechanism of miR-450 in the development of hepatocarcinoma, and the effects of overexpression of miR-450 on biological behaviors such as proliferation, migration, and invasion of hepatoma cells.

Emerging evidence suggests that circular RNAs (circRNAs) are linked to the development and progression of human cancers. Nevertheless, their contribution to breast cancer (BC) is still largely unknown. In the current study, we screened and identified a novel circRNA, circ-UBE2D2, which was highly expressed in BC cell lines and tissues and was closely related to aggressive clinical features and dismal prognosis. Small interfering RNA (siRNA)-mediated circ-UBE2D2 silencing notably inhibited the proliferation, migration and invasion of BC cells, whereas circ-UBE2D2 overexpression displayed opposite effects. Mechanistically, circ-UBE2D2 was able to simultaneously function as molecular sponges of miR-1236 and miR-1287 to regulate the expression of their respective target genes. Moreover, circ-UBE2D2-induced tumor-promoting effects could be effectively blocked by miR-1236 or miR-1287 in BC cells. More importantly, therapeutic delivery of cholesterol-conjugated si-circ-UBE2D2 oligonucleotides significantly delayed tumor growth in vivo. Overall, our findings indicate that circ-UBE2D2 plays an essential oncogenic role in BC, and targeting circ-UBE2D2 may be a feasible treatment for BC patients.

Mesenchymal stem cells (MSCs) show protective effects on ischemia/reperfusion- (I/R-) induced endothelial cell (EC) injury and vascular damage. Stem cell-released exosomes (EXs) could modulate target cell functions by delivering their cargos, and exert therapeutic effects as their mother cells. miR-126 is an important regulator of EC functions and angiogenesis. In this study, we determined whether EXs released from MSC-EXs provided beneficial effects on hypoxia/reoxygenation- (H/R-) injured ECs by transferring miR-126. MSCs were transfected with a miR-126 mimic or miR-126 short hairpin RNA to obtain miR-126-overexpressing MSC-EXs (MSC-EXsmiR-126) and miR-126 knockdown MSC-EXs (MSC-EXsSimiR-126). For functional studies, H/R-injured ECs were coincubated with various MSC-EXs. The viability, migration, tube formation ability, and apoptosis of ECs were measured. miR-126 and proangiogenic/growth factor (VEGF, EGF, PDGF, and bFGF) expressions were detected by qRT-PCR. Akt, p-Akt, p-eNOS, and cleaved caspase-3 expressions were examined by western blot. The PI3K inhibitor (LY294002) was used in pathway analysis. We found that overexpression/knockdown of miR-126 increased/decreased the proliferation of MSCs, as well as miR-126 expression in their derived MSC-EXs. MSC-EXsmiR-126 were more effective in promoting proliferation, migration, and tube formation ability of H/R-injured ECs than MSC-EXs. These effects were associated with the increase in p-Akt/Akt and p-eNOS, which could be abolished by LY294002. Besides, MSC-EXsmiR-126 were more effective than MSC-EXs in reducing the apoptosis of ECs, coupled with the decrease in cleaved caspase-3. Moreover, compared to MSC-EXs, MSC-EXsmiR-126 significantly upregulated the level of VEGF, EGF, PDGF, and bFGF in H/R-injured ECs. Downregulation of miR-126 in MSC-EXs inhibited these effects of MSC-EXs. The results suggest that MSC-EXs could enhance the survival and angiogenic function of H/R-injured ECs via delivering miR-126 to ECs and subsequently activate the PI3K/Akt/eNOS pathway, decrease cleaved caspase-3 expression, and increase angiogenic and growth factors.

Wnt1-inducible signaling pathway protein 1 (WISP1) is upregulated in several types of human cancer, and has been implicated in cancer progression. However, its clinical implications in gastric cancer (GC) remain unclear.

α-Linolenic acid (ALA) is a plant-derived omega-3 unsaturated fatty acid that is rich in flaxseed oil (FO). The effect of FO on bone health is controversial. This study aims to evaluate the effect of FO on bone damage induced by a high-fat diet (HFD) and to explore the possible mechanism.

To report the clinical results and surgical tactics of spinal osteotomy for ankylosing spondylitis (AS) kyphosis based on the experiences of 428 patients.

Immune checkpoint inhibitors against PD-1/PD-L1 yield improved survival rates of KRAS-mutant NSCLC patients, who conferred a poor prognosis without effective targeted therapy until now. Yet, the underlying association between KRAS mutations and immune responses remains unclear. We performed an integrated analysis of the data from publicly available repositories and from clinical center cohorts to explore the association between KRAS mutation status and tumor immunity-associated features, including PD-L1 expression, CD8+ tumor-infiltrating lymphocytes (TILs) and tumor mutational burden (TMB). Our results revealed that KRAS mutations are correlated with an inflammatory tumor microenvironment and tumor immunogenicity, resulting in superior patient response to PD-1/PD-L1 inhibitors. Meanwhile, three-pool analysis further confirmed that KRAS-mutant NSCLC patients show remarkable clinical benefit from anti-PD-1/PD-L1 immunotherapy. In addition, a KRAS-mutant lung adenocarcinoma mouse model was established to estimate the relative efficacy of anti-PD-L1 monoclonal antibody monotherapy or combination treatment with docetaxel versus docetaxel alone. Most surprisingly, we found that PD-L1 blockade combined with docetaxel did not promote an anti-tumor response. These findings uncover that PD-1/PD-L1 blockade monotherapy may be the optimal therapeutic schedule in NSCLC patients harboring KRAS mutations.

Sub-acute ruminal acidosis (SARA) [1] is one of the most common problems of dairy animals causing great economical loss due to decreased milk production. Here we determined the antioxidant effect of sodium butyrate (NaB) [2] in experimentally induced SARA and its effects on mammary epithelial tissues of goat. Goats (n = 12) were equally divided into two groups: high-concentrate (HC) as control group fed with HC diet (concentrate: forage = 6:4) whereas HC + NaB as treatment group fed HC diet with NaB at 1% by weight for 24 weeks. Mammary epithelial tissue samples were analyzed for the expression of genes and proteins responsible for oxidative stress as well as biochemical markers of antioxidant activity in the form of Reactive Oxygen Species (ROS). The total antioxidant capacity (T-AOC) of antioxidant enzymes was also calculated. Butyrate induced antioxidant effect by increasing mRNA and protein abundance of antioxidants in mammary gland of HC + NaB group compared to HC group. Likewise, the total antioxidant capacity (T-AOC) was significantly increased and Malondialdehyde (MDA) concentration was decreased in HC + NaB group compared to HC group. It is concluded that oxidative stress in mammary gland of goats induced by high concentrate diet was alleviated by NaB supplementation.

The NEO-CLASSIC study provided valuable insight for the clinical efficacy and tolerability profiles of perioperative chemotherapy with oxaliplatin and capecitabine, plus gastrectomy, in patients with localized resectable gastric cancer.The study was designed to explore the potential survival benefits of an eight-cycle, perioperative oxaliplatin and capecitabine (XELOX) schedule in the above-mentioned setting and to explore the feasibility of prolonging the cycles of preoperative chemotherapy. The projected endpoint was not met.

A hydrophilic interaction liquid chromatography (HILIC)-ultra high-pressure liquid chromatography (UHPLC) coupled with tandem mass spectrometry (MS/MS) method was developed and applied to profile metabolite changes in human Huh-7 cells exposed to the potent aryl hydrocarbon receptor (AHR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Comparisons of sensitivity (limit of detection as low as 0.01 µM) and reproducibility (84% of compounds had an interday relative standard deviation (RSD) less than 10.0%; 83% of compounds had an intraday RSD less than 15.0%) were assessed for all the metabolites. The exposure of Huh-7 cells to the hepatotoxic carcinogen TCDD at low doses (1 nM and 10 nM for 4 h and 24 h, respectively) was reflected by the disturbance of amino acid metabolism, energy metabolism (glycolysis, TCA cycle), and nucleic acid metabolism. TCDD caused a significant decrease in amino acids such as serine, alanine, and proline while promoting an increase in arginine levels with 24 h treatment. Energy metabolism intermediates such as phosphoenolpyruvate and acetyl-CoA and nucleosides such as UMP, XMP, and CMP were also markedly decreased. These results support the application of HILIC-UHPLC-MS/MS for robust and reliable analysis of the cellular response to environmentally relevant toxicants at lower doses.

Liver transplantation (LT) is currently considered an important method in treating hepatocellular carcinoma (HCC) and an alternative treatment for other liver malignancies. Here, we demonstrated that the graft-versus-tumor (GVT) effect exists in allogeneic liver transplantation (allo LT). Recipient-derived T cells played a critical role in the GVT process of allo LT, as demonstrated by extensive infiltration and significant activation of recipient T cells in the tumor after surgery. Moreover, this process was related to donor-derived T/B cells by improving the immune microenvironment in the tumor, as demonstrated by elevated levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-6, IL-16, chemokine (C-X-C motif) ligand 10 (CXCL10), and CXCL11 and decreased levels of IL-10 and IL-4 at tumor sites. Additionally, tacrolimus (FK506) treatment inhibited the GVT effect on allo LT. Donor liver-derived T/B cells infiltrate extrahepatic tumors to trigger a strong T-cell-mediated immune response and thus improve the tumor immune microenvironment.

Neutrophil extracellular traps (NETs) are one of the most powerful and specific tools for neutrophils to clean up extracellular microbes, but the mechanisms of NETosis under infection are scarcely studied. In this study, by examining the neutrophils from human peripheral blood and mouse abdomen, we demonstrated that PRAK dysfunction resulted in a significantly reduced NET formation and elevated apoptotic cells. Furthermore, PRAK dysfunction could lead to impaired NET-mediated antibacterial activity and shorten the survival of mice with CLP-induced sepsis. Mechanism studies revealed that attenuated NET formation in PRAK dysfunctional neutrophils correlated with overproduction of reactive oxygen species (ROS), which triggered apoptosis through excessive autophagy. The imbalance of NET formation and apoptosis was further regulated by treatment with lower ROS in hypoxia. Here, we propose a novel candidate, PRAK, which can sense the oxidative stress and regulate the releasing of ROS, may be the master molecular switch to regulate the NETosis-apoptosis axis of neutrophils.

Psoriasis is a common autoimmune disease. Acupuncture-related techniques have been widely used to treat psoriasis since its ability to engage neuronal function, the immune system, and other systems is well documented. This study aimed to investigate and compare the effects of three common acupuncture-related techniques in psoriasis-like skin inflammatory responses and explore the possible involved mechanisms. Imiquimod (IMQ)-induced psoriasis-like mice were treated with acupuncture needling, electroacupuncture, or fire acupuncture. Methotrexate (MTX) was applied as a positive control. Scoring by the psoriasis area and severity index (PASI) evaluated skin lesion changes. Keratinocyte proliferation and inflammatory cell infiltration were investigated using pathological staining. The secretion levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay. The expression levels of neuropeptides were assessed by Western immunoblotting. We found that acupuncture needling, electroacupuncture, and fire acupuncture all ameliorated skin lesions, reduced epidermal thickness, inhibited keratinocyte proliferation, and reduced CD3+ T cell infiltration. The aforementioned acupuncture techniques also decreased inflammatory cytokine secretion, including IL-1β, IL-17A, and IL-23p40. Among them, electroacupuncture showed the best curative effects. Additionally, electroacupuncture downregulated the expression levels of Neurokinin A (NKA), which was positively associated with decreased inflammatory cytokine levels in local lesions. In conclusion, acupuncture needling, electroacupuncture, and fire acupuncture alleviated IMQ-induced psoriasis-like lesions. By contrast, electroacupuncture was more beneficial in reducing the inflammatory response, which might be related to locally dampened neuropeptide levels. Observations support the therapeutic effect of acupuncture for psoriasis and indicate a neuromodulatory mechanism in treating psoriasis by electroacupuncture.

Strawberry is often subjected to cold stress in temperate regions when insulation measures are not strictly applied in protected cultivation. Cold stress adversely influences plant growth and development by triggering a massive change to the transcriptome. To provide the potential strategies in improving strawberry cold tolerance and give a glimpse into the understanding of the complex cold signaling pathways in plants, this study identified attractive candidate genes and revealed diverse regulatory networks that responded to cold stress in strawberry (Fragaria×ananassa) by a transcriptomic analysis. Totally, there were 2397 differentially expressed genes (DEGs) under cold stress treatment (T1) vs. normal treatment (CK). Of these, 1180 DEGs were upregulated, while 1217 DEGs were downregulated. Functional enrichment analysis showed that DEGs were significantly (adjusted P value < 0.05) overrepresented in six pathways including plant hormone signal transduction, flavonoid biosynthesis, mitogen-activated protein kinase (MAPK) signaling, starch and sucrose metabolism, circadian rhythm, and alpha-linolenic acid metabolism. The cold signaling initiated expression of downstream cold-responsive (COR) genes with cis-acting element ABRE or CRT/DRE in the ABA-independent or ABA-dependent pathway to impel plant defense against the stress. Strikingly, GIGANTEA (gene id 101308922), two-component response regulator-like PRR95 (gene id 101295449), and ethylene-responsive transcription factor ERF105-like (gene id 101295082) were dramatically induced under low-temperature treatment, indicating that they played an important role in response to cold stress in strawberry.

Main conclusion Among 247 RsAP2/ERF identified, the majority of the 21 representatives were preferably expressed under drought and heat while suppressed under heavy metals, indicating their potential roles in abiotic stress responses and tolerance. APETALA2/Ethylene-Responsive factor (AP2/ERF) transcription factor (TF) is one of the largest gene families in plants that play a fundamental role in growth and development as well as biotic and/or abiotic stresses responses. Although AP2/ERFs have been extensively characterized in many plant species, little is known about this family in radish, which is an important root vegetable with various medicinal properties. The available genome provides valuable opportunity to identify and characterize the global information on AP2/ERF TFs in radish. In this study, a total of 247 ERF family genes were identified from the radish genome, and sequence alignment and phylogenetic analyses classified the AP2/ERF superfamily into five groups (AP2, ERF, DREB, RAV and soloist). Motif analysis showed that other than AP2/ERF domains, other conserved regions were selectively distributed among different clades in the phylogenetic tree. Chromosome location analysis showed that tandem duplication may result in the expansion of RsAP2/ERF gene family. The RT-qPCR analysis confirmed that a proportion of AP2/ERF genes were preferably expressed under drought and heat stresses, whereas they were suppressed under the ABA and heavy metal stresses. These results provided valuable information for further evolutionary and functional characterization of RsAP2/ERF genes, and contributed to genetic improvement of stress tolerances in radish and other root vegetable crops.

Adriamycin(ADR) is still considered to be one of the most effective agents in the treatment of breast cancer (BrCa), its efficacy is compromised by intrinsic resistance or acquire characteristics of multidrug resistance. At present, there are few genetic alterations that can be exploited as biomarkers to guide targeted use of ADR in clinical. Therefore, exploring the determinants of ADR sensitivity is pertinent for their optimal clinical application. TP53 is the most frequently mutated gene in human BrCa, p53 mutation has been reported to be closely related to ADR resistance, whereas the underlying mechanisms that cause endogenous ADR resistance in p53-mutant BrCa cells are not completely understood. The aim of the present study was to investigate the potential roles of miRNA in the response to ADR in p53-mutated breast cancer. Here, we report that BrCa cells expressing mutp53 are more resistant to ADR than cells with wild-type p53 (wtp53). The DNA repair protein- Fanconi anemia complementation group F protein (FANCF) and the translesion synthesis DNA polymerase REV1 protein is frequently abundant in the context of mutant p53 of BrCa. By targeting two key factors, miR-30c increases the sensitivity of BrCa cells to ADR. Furthermore, p53 directly activates the transcription of miR-30c by binding to its promoter. Subsequent analyses revealed that p53 regulates REV1 and FANCF by modulating miR-30c expression. Mutation of the p53 abolished this response. Consistently, reduced miR-30c expression is highly correlated with human BrCa with p53 mutational status and is associated with poor survival. We propose that one of the pathways affected by mutant p53 to increase intrinsic resistance to ADR involves miR-30c downregulation and the consequent upregulation of FANCF and REV1. The novel miRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies.

Inhibin α (INHA) is a candidate gene controlling ovulation in poultry. As the functional center of inhibin, INHA is a molecular marker associated with egg-laying performance. The objective of the current study was to analyze the expression differences of INHA in reproductive system and single nucleotide polymorphisms (SNPs) associations with reproductive traits in chickens. A total of 260 LuHua chickens (barred-feather chicken) were adopted. Twelve SNPs were detected in INHA gene. Among the exonic SNPs, three (g. 22177991A>G, g. 22178249G>C, and g. 22178414G>A) were missense mutations, resulting in the amino acid substitutions Val→Ala, Ala→Gly, and Ala→Gly, respectively. Four SNPs in the 3＇ untranslated region of INHA were predicted to either disturb or create microRNA-target interactions. Five SNPs (g. 22176870T>C, g. 22177100T>C, g. 22177149T>C, g. 22177991A>G, and g. 22178975G>A) were significantly associated with the number of eggs at 300 d of age (EN) (P < 0.05). Birds carrying GA genotype exhibited more EN than those with AA genotype (P < 0.01). In addition, quantitative real-time PCR revealed that INHA is mainly expressed in follicles on d 300 in chickens. Firstly, INHA expression increased and then decreased. The highest INHA mRNA abundance was found in the fifth largest preovulatory follicle (F5) (P < 0.01). In the prehierarchical follicles, INHA mRNA expression increased dramatically in small yellow follicles (SYF) (P < 0.01). Western blotting analysis showed that the INHA protein expression profile in the follicle was similar to its mRNA counterpart with greater expression in F5 and SYF follicles and lowest expression in F1 follicles (P < 0.05). These results suggest that INHA is a potential candidate gene improving reproductive traits in chickens.

Cryoablation is moderately effective against prostate cancer. Of note, the off-target or enlarged therapeutic effect after cryoablation is reported in routine clinical practice. To uncover it, we constructed a bilateral inguinal transplantation model of prostate cancer. All the mice were randomly subdivided into three groups: Group A (Control group), Group B (Surgery group), and Group C (Cryoablation group). All the procedures in three groups were conducted only for tumors in the target region (right groin). The tumors in untargeted region (left groin) received no treatment. We measured the growth of untargeted tumors and lung metastasis rate, and then explored the changes in a series of immune cells and danger signals. First, our results revealed the protective effect of cryoablation treatment against the abscopal tumor. The possible mechanism was mediated by an increase in the number of CD4+ T cells, CD8+ T cells, ratio T helper 1 (Th1)/Th2, the killing activity of cytotoxic T lymphocytes and NK cells. Hsp70 may be involved in the modulation of the immune response. The combination of weakened Ki67 activity and activated immune response delayed spectator tumor growth, decreased the pulmonary metastasis rate, and prolonged animal survival, with an inducible abscopal effect.