Ovarian cancer has a unique tumor microenvironment (TME) that enables cancer-associated fibroblasts (CAFs) to interact with cellular and matrix constituents and influence tumor development and ...migration into the peritoneal cavity. Collagen type XI alpha 1 (COL11A1) is overexpressed in CAFs; therefore this study examines its role during CAF activation in epithelial ovarian cancer (EOC). Coculturing human ovarian fibroblasts (HOFs) with high COL11A1-expressing EOC cells or exposure to the conditioned medium of these cells prompted the expression of COL11A1 and CAF phenotypes. Conversely, coculturing HOFs with low COL11A1-expressing EOC cells or COL11A1-knockdown abrogated COL11A1 overexpression and secretion, in addition to CAF activation. Increased p-SP1 expression attributed to COL11A1-mediated extracellular signal-regulated kinase activation (ERK) induced p65 translocation into the nucleus and augmented its binding to the insulin-like growth factor binding protein 2 (IGFBP2) promoter, ultimately inducing TGF-β3 activation. The CAF-cancer cell crosstalk triggered interleukin-6 release, which in turn promoted EOC cell proliferation and invasiveness. These in vitro results were confirmed by in vivo findings in a mouse model, showing that COL11A1 overexpression in EOC cells promoted tumor formation and CAF activation, which was inhibited by TGF-β3 antibody. Human tumors with high TGF-β3 levels showed elevated expression of COL11A1 and IGFBP2, which was associated with poor survival. Our findings suggest the possibility that anti-TGF-β3 treatment strategy may be effective in targeting CAFs in COL11A1-positive ovarian tumors.
Hepatitis B virus infection is a major social and economic burden in developing countries, especially in China. We aimed to evaluate the effects of hepatitis B surface antigen (HBsAg) positive status ...on the pregnancy outcomes in the Chinese population.
This retrospective cohort study was performed using data from the Medical Birth Registry of Xiamen, China, from January 2011 to March 2018. Multivariate logistic regression analysis was used to assess the association between the HBsAg status and pregnancy outcomes.
This study included 3,789 HBsAg-positive women and 29, 648 non-exposed women. The HBsAg-positive pregnant women were slightly older in age (29.3±4.3 vs. 28.9±4.4, P< 0.001). Additionally, pregnant women with a positive HBsAg status had higher odds of gestational diabetes mellitus (GDM) (adjusted odds ratio aOR, 1.13; 95% confidence interval CI, 1.03-1.23), and cesarean delivery (aOR, 1.12; 95%CI, 1.03-1.21). The risk of infants being large or small-for-gestational age, having low-birth weight, and of macrosomia, preterm birth, and stillbirth did not differ significantly between the HBsAg-positive and-negative women.
In Xiamen, China, the slightly higher risk of GDM and cesarean section in women positive for HBsAg should not be neglected. Further studies should be conducted to evaluate the effects of HBsAg positivity on the pregnancy outcomes in different ethnic populations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The poor efficiency and low immunogenicity of photodynamic therapy (PDT), and the immunosuppressive tumor microenvironment (ITM) lead to tumor recurrence and metastasis. In this work, TCPP‐TER‐Zn@RSV ...nanosheets (TZR NSs) that co‐assembled from the endoplasmic reticulum (ER)‐targeting photosensitizer TCPP‐TER‐Zn nanosheets (TZ NSs for short) and the autophagy promoting and indoleamine‐(2, 3)‐dioxygenase (IDO) inhibitor‐like resveratrol (RSV) are fabricated to enhance antitumor PDT. TZR NSs exhibit improved therapeutic efficiency and amplified immunogenic cancer cell death (ICD) by ER targeting PDT and ER autophagy promotion. TZR NSs reversed the ITM with an increase of CD8+ T cells and reduce of immunosuppressive Foxp3 regulatory T cells, which effectively burst antitumor immunity thus clearing residual tumor cells. The ER‐targeting TZR NSs developed in this paper presents a simple but valuable reference for high‐efficiency tumor photodynamic immunotherapy.
TCPP‐TER‐Zn@RSV nanosheets (TZR NSs) exhibit excellent tumor‐killing effect by precisely targeting the endoplasmic reticulum (ER) and generating reactive oxygen species (ROS) in situ, promoting oxidative stress to induce lethal ER‐phagy and induce strong immunogenic cancer cell death (ICD) effects, which promotes the maturation of dendritic cells (DCs) in vitro and in vivo. TZR NSs regulate abundance of T cells in the tumor microenvironment (TME) and evoked T cells‐mediated immune responses, thereby significantly enhancing antitumor efficacy.
The antioxidant defense system in malignant cells, which involves antioxidant enzymes and antioxidant molecules, is an innate barrier to photodynamic therapy (PDT). Because of the complexity of the ...endogenous antioxidant mechanisms of these cells, simply inhibiting individual antioxidant pathways has a limited effect on improving the lethality of ROS. To enhance the efficacy of PDT for tumor treatment, a versatile nanoparticle (NP)‐based drug is developed, which the authors call PZB NP, containing the glutathione inhibitor l‐buthionine sulfoximine (BSO) and the heme oxygenase 1 (HO‐1) inhibitor protoporphyrin zinc(II) (ZnPP) to suppress the innate antioxidant defense system of cancer cells in a two‐pronged manner. BSO reduces intracellular glutathione levels to minimize ROS elimination and protein protection during PDT, and ZnPP inhibits the ROS‐stimulated upregulation of the antioxidant HO‐1, thus preventing ROS removal by cells after PDT. Thus, BSO and ZnPP synergistically suppress the antioxidant defense systems of cancer cells both during and after protoporphyrin‐IX‐mediated PDT in a two‐pronged manner, resulting in tumor cell death through excess oxidative pressure. The results demonstrate that the construction of nanodrugs having dual antioxidation defense suppression properties is a promising route for the development of highly efficient ROS‐based therapies.
A simple and versatile nanodrug, PZB nanoparticle, is developed to enhance PDT efficacy using a two‐pronged antioxidant suppression strategy. In short, the nanoparticle‐loaded BSO reduces the existing intracellular antioxidant (glutathione) concentration before PDT. Subsequently, the loaded protoporphyrin zinc(II) (ZnPP) inhibits ROS‐stimulated antioxidant enzymes (heme oxygenase 1) after PDT. These significantly enhance intracellular oxidative stress, leading to increased cancer cell death.
Acute kidney injury (AKI) is a common clinical problem, characterized by a sudden loss of renal function, a high risk of death, and the eventual development of renal fibrosis and renal failure. ...Cordyceps cicadae is a traditional Chinese medicine with the potential function of kidney protection. We analyze two sputum extracts, a water extract (WCC), and an ethanol extract (ECC), to assess the potential of treating AKI in an animal model of kidney injury induced by cisplatin. A nephrotoxic mouse model was first established by intraperitoneal injection of cisplatin. Subsequently, WCC and ECC were orally administered in these mice. The results show that WCC and ECC significantly alleviated cisplatin-induced AKI renal histological changes, serum creatinine (CRE) and blood urea nitrogen (BUN) production, and the levels of NO, TNF-α, IL-1β, and IL-6. The levels of malondialdehyde (MDA) and glutathione (GSH) were suppressed by administration of WCC and ECC. However, WCC treatment prevented these changes significantly better than ECC treatment. In addition, Western blot data showed that WCC attenuated the cisplatin-induced protein expression of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), as well as inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation in the kidney tissues. Furthermore, WCC greatly inhibited the expression of Toll-like receptor 4 (TLR4) and cisplatin-induced NF-κB activation, as well as dramatically increasing the production of antioxidative enzymes (i.e., superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1)), silent information regulator T1 (Sirt1), and p-AMP-activated protein kinase (AMPK) in the kidney tissues. In addition, we found that WCC increased the expression levels of the autophagy-related proteins LC3B and Beclin-1; proapoptotic proteins, including cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) 1; and organic anion transporters 1 (OAT1) and 3 (OAT3) in the kidney tissues. Finally, WCC, ECC, and two bioactive compounds—adenosine and N6-(2-hydroxyethyl) adenosine (HEA)—inhibited the production of nitrite oxide (NO) and intracellular reactive oxygen species (ROS) triggered by lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophages in vitro. Collectively, WCC could provide a potential therapeutic candidate for the prevention of cisplatin-induced kidney injury through the inhibition of oxidative stress and inflammation.
Tissue inhibitor of metalloproteinases-3 (TIMP3) is vital in regulating several biological processes. TIMP3 exerts antitumour effects via matrix metalloproteinase (MMP)-dependent and MMP-independent ...pathways. Due to promoter methylation and miRNA binding, TIMP3 expression has been observed to decrease in various cancers. Consequently, the migration and invasion of cancer cells increases. Conflicting results have reported that expression levels of TIMP3 in primary and advanced cancers are higher than those in healthy tissues. Therefore, the role of TIMP3 in cancer biology and progression needs to be elucidated. This review provides an overview of TIMP3, from its biological function to its effects on various cancers. Moreover, gynaecological cancers are discussed in detail. TIMP3 has been associated with cervical adenocarcinoma as well as cancer development in serous ovarian cancer and breast cancer metastasis. However, the relationship between TIMP3 and endometrial cancers remains unclear. TIMP3 may be a useful biomarker for gynaecological cancers and is a potential target for future cancer therapy.
Mitochondria dysfunction is the major characteristic of mitophagy, which is essential in mitochondrial quality control. However, excessive mitophagy contributes to cell death in a number of diseases, ...including ischemic stroke and hepatotoxicity. Insulin‐like growth factor II (IGF‐II) and its receptor (IGF‐IIR) play vital roles in the development of heart failure during hypertension. We found that IGF‐II triggers IGF‐IIR receptor activation, causing mitochondria dysfunction, resulting in mitophagy, and cardiomyocyte cell death. These results indicated that IGF‐IIR activation triggers mitochondria fragmentation, leading to autophagosome formation, and loss of mitochondria content. These results are associated with Parkin‐dependent mitophagy. Additionally, autophagic proteins Atg5, and Atg7 deficiency did not suppress IGF‐IIR‐induced mitophagy. However, Rab9 knockdown reduced mitophagy and maintained mitochondrial function. These constitutive mitophagies through IGF‐IIR activation trigger mitochondria loss and mitochondrial ROS accumulation for cardiomyocyte viability decrease. Together, our results indicate that IGF‐IIR predominantly induces mitophagy through the Rab9‐dependent alternative autophagy.
These results found that IGF‐IIR signaling activation triggered mitochondria fragmentation, leading to autophagosome formation, and loss of mitochondria content. Our results indicate that IGF‐IIR predominantly induces mitophagy through the Rab9‐dependent alternative autophagy.
Scholars and researchers generally believe that scientific inquiry is an important activity for cultivating students' applied knowledge and high‐level thinking ability. The process of scientific ...inquiry can promote students' learning motivation and trigger their higher‐order thinking ability. However, students may not have enough prior knowledge or they may lack inquiry experience, which may influence the effectiveness of their inquiry learning. Besides, in a scientific inquiry environment assisted by technology, students must face abundant and diverse learning resources, and may not effectively organize and carry out advanced cogitation to solve problems. Therefore, this research proposed an integrated concept mapping and image recognition (IR) approach to help students effectively acquire and organize knowledge in the process of scientific inquiry. This study applied a quasi‐experimental design to verify the effect of this proposed approach. The experimental group conducted the concept mapping‐based IR (CM‐IR) learning approach, whilst the control group conducted the conventional IR‐based learning approach to evaluate the students' performance in terms of their learning motivation and learning achievements. The participants were two classes of 10th‐grade students in northern Taiwan. One was the experimental group with 22 students, whilst the other was the control group with 22 students. The experimental results show that the students learning with the CM‐IR learning approach had better learning achievement, attitudes and intrinsic motivation, as well as higher mental load than those learning with the conventional IR‐based learning approach. Accordingly, several suggestions are provided for future research in this field.
Practitioner notes
What is already known about this topic
With the development of information technology, AI has attracted the attention of researchers.
Image recognition (IR) is one of the AI applications, and has been used to support learning in various educational fields.
Researchers have indicated that concept mapping is an effective instructional strategy and promotes students' knowledge construction.
What this paper adds
A concept mapping‐based IR (CM‐IR) learning approach is proposed to improve students' scientific inquiry performance.
A quasi‐experimental design was conducted with 10th‐grade students on the ‘Plant identification’ unit of the scientific inquiry course.
The experimental results show that the proposed approach can significantly improve students' learning achievement, learning motivation and learning attitude.
Implications for practice and/or policy
The CM‐IR learning approach could be an effective method to facilitate students' learning performances and motivation in scientific inquiry.
It is worth promoting the CM‐IR learning approach in school settings since it is low‐cost and enables learning anywhere using mobile devices.
Scholars and educators are encouraged to work on how AI technologies applications can be applied to support learning.
Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance.
To screen drugs that target CSCs ...to improve the current treatment outcome and overcome drug resistance in patients with lung cancer.
We used publicly available embryonic stem cell and CSC-associated gene signatures to query the Connectivity Map for potential drugs that can, at least in part, reverse the gene expression profile of CSCs. High scores were noted for several phenothiazine-like antipsychotic drugs, including trifluoperazine. We then treated lung CSCs with different EGFR mutation status with trifluoperazine to examine its anti-CSC properties. Lung CSCs resistant to epidermal growth factor receptor-tyrosine kinase inhibitor or cisplatin were treated with trifluoperazine plus gefitinib or trifluoperazine plus cisplatin. Animal models were used for in vivo validation of the anti-CSC effect and synergistic effect of trifluoperazine with gefitinib.
We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazine inhibited Wnt/β-catenin signaling in gefitinib-resistant lung cancer spheroids. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models.
Using in silico drug screening by Connectivity Map followed by empirical validations, we repurposed an existing phenothiazine-like antipsychotic drug, trifluoperazine, as a potential anti-CSC agent that could overcome epidermal growth factor receptor-tyrosine kinase inhibitor and chemotherapy resistance.
In adiposity, immune cells infiltrate adipose tissues, especially macrophages, forming chronic inflammation. This study aimed to investigate the mechanism of lunasin regulating immune functions of ...RAW264.7 macrophages in obesity-related conditions. Lipopolysaccharide (LPS) triggered an acute inflammation, and adipocyte-conditioned medium (Ad-CM) and co-cultures of RAW264.7 macrophages and 3T3-L1 adipocytes were used to mimic obese microenvironments. Lunasin protected the vitality of RAW cells and suppressed leptin secretion in Ad-CM. In LPS, lunasin reduced 47% of 2′,7′-dichlorodihydrofluorescein diacetate (DCF-DA) staining, 28% of nitric oxide production, and 27% of tumor necrosis factor-α secretion in LPS-stimulated co-culture, while there were opposing effects in Ad-CM and co-culture without LPS. Moreover, LPS-stimulated migration was inhibited at 44% by lunasin, while Ad-CM-declined 49% of migration. Lunasin increased 21% and 42% of phagocytosis in LPS and Ad-CM challenges. Overall, the study first revealed that lunasin exerted immunomodulation in macrophages against LPS-stimulated inflammation but boosted immune functions in obesity-related microenvironments.
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