Thyroid Nodules: Emerging Trends in Detection and Visualization based on Citespace.

BACKGROUND: Thyroid nodule (TN) is a highly prevalent clinical endocrine disease. Many countries have formed guidelines on the prevention and treatment of TN based on extensive research. However, there is a scarcity of TN-related literature based on bibliometrics. OBJECTIVES: This study aimed to evaluate the scientific achievements and progress of TN research from a global perspective by investigating the literature for 20 years through bibliometrics. METHODS: We searched the literature on TN in the core collection of the Web of Science database from 2002 to 2021 and used the Citespace software to analyze the co-authorship, co-citation, and co-occurrence of countries, institutions, authors, keywords, and co-cited literature. RESULTS: We retrieved 12319 documents related to TN. The literature on TN has been growing since 2002. The United States has contributed the largest proportion of TN papers (20.64%), followed by China, Italy, and South Korea. The United States ranked first in terms of centrality (0.38). Haugen BR, Gharib H, and Cibas ES are the top three most cited authors. The papers published in Thyroid were cited most frequently (7952 times). The most prominent keywords were management, cancer, fine needle aspiration, diagnosis, malignant tumor, thyroid cancer, ultrasound, biopsy, benign, surgery, ablation, and cytology. All keywords could be divided into three categories: diagnosis stratification, treatment, and cancer. As far as potential hot spots are concerned, the keywords that have recently burst strongly and are still continuing are: "Association Guideline" (2018-2021), "Radiofrequency Ablation" (2017-2021), "Classification" (2019-2021), and "Data System" (2017-2021). CONCLUSION: Based on the current trends, the number of publications on TN will continue to increase. The United States is the most active contributor to research in this field. Previous literature focused on stratification, cancer, surgery, and ablation, and there were different opinions on the stratification of diagnosis. There were relatively few studies on pathogenesis and treatment using medicine. More focus will be placed on association guidelines, radiofrequency ablation, classification, and data system, which may be the next popular topics in TN research.

Brain-Penetrating Peptide Shuttles across the Blood-Brain Barrier and Extracellular-like Space.

Systemic delivery of therapeutics into the brain is greatly impaired by multiple biological barriers─the blood-brain barrier (BBB) and the extracellular matrix (ECM) of the extracellular space. To address this problem, we developed a combinatorial approach to identify peptides that can shuttle and transport across both barriers. A cysteine-constrained heptapeptide M13 phage display library was iteratively panned against an established BBB model for three rounds to select for peptides that can transport across the barrier. Using next-generation DNA sequencing and in silico analysis, we identified peptides that were selectively enriched from successive rounds of panning for functional validation in vitro and in vivo. Select peptide-presenting phages exhibited efficient shuttling across the in vitro BBB model. Two clones, Pep-3 and Pep-9, exhibited higher specificity and efficiency of transcytosis than controls. We confirmed that peptides Pep-3 and Pep-9 demonstrated better diffusive transport through the extracellular matrix than gold standard nona-arginine and clinically trialed angiopep-2 peptides. In in vivo studies, we demonstrated that systemically administered Pep-3 and Pep-9 peptide-presenting phages penetrate the BBB and distribute into the brain parenchyma. In addition, free peptides Pep-3 and Pep-9 achieved higher accumulation in the brain than free angiopep-2 and may exhibit brain targeting. In summary, these in vitro and in vivo studies highlight that combinatorial phage display with a designed selection strategy can identify peptides as promising carriers, which are able to overcome the multiple biological barriers of the brain and shuttle different-sized molecules from small fluorophores to large macromolecules for improved delivery into the brain.

The role and mechanism of NADPH oxidase in the development and progression of thyroid carcinoma.

Thyroid cancer is the fastest increasing cancer in both men and women and is the most common endocrine cancer. Researchers have gradually intensified their research on the mechanism of thyroid cancer development. Within this realm, Oxidative stress is often believed to play a causal and contributory role in thyroid cancer development. NADPH oxidase is one of the important sources of reactive oxygen species for tumor cell growth and is involved in the biological processes of thyroid tumor cell proliferation, migration, invasion and epithelial-to-mesenchymal transition. However, the mechanism of NADPH oxidase in the pathogenesis of thyroid cancer is still not very clear at present. Clarifying the role and mechanism of NADPH oxidase in the pathogenesis of thyroid cancer will help to develop new strategies for the prevention and treatment of thyroid cancer as early as possible, and improve the survival rates of thyroid tumor patients. This article reviews the research progress on the mechanism of NADPH oxidase in thyroid cancer.

Application and Development Prospect of Nanoscale Iron Based Metal-Organic Frameworks in Biomedicine.

Metal-organic frameworks (MOFs) are coordination polymers that comprise metal ions/clusters and organic ligands. MOFs have been extensively employed in different fields (eg, gas adsorption, energy storage, chemical separation, catalysis, and sensing) for their versatility, high porosity, and adjustable geometry. To be specific, Fe2+/Fe3+ exhibits unique redox chemistry, photochemical and electrical properties, as well as catalytic activity. Fe-based MOFs have been widely investigated in numerous biomedical fields over the past few years. In this study, the key index requirements of Fe-MOF materials in the biomedical field are summarized, and a conclusion is drawn in terms of the latest application progress, development prospects, and future challenges of Fe-based MOFs as drug delivery systems, antibacterial therapeutics, biocatalysts, imaging agents, and biosensors in the biomedical field.

Role of NLRP3 inflammasome activation in HCC cell progression.

Hepatocellular carcinoma (HCC) is a globally prevalent and fatal malignancy worldwide, and identifying therapeutic strategies is time-consuming. Numerous reports have suggested the involvement of the NLRP3 inflammasome in the progression of various cancers. However, the detailed mechanisms underlying the role of NLRP3 inflammasome in HCC progression remain unclear. In this study, we observed low expression levels of the NLRP3 inflammasome in a subset of HCC cells. Furthermore, we demonstrated that the NLRP3 inflammasome can be activated by LPS + ATP through the nuclear factor kappa B signaling pathway, as confirmed by western blotting and immunofluorescence staining. To assess the impact of NLRP3 inflammasome activation on HCC cell behavior, we employed Edu staining, cell cycle assay, Annexin V/PI staining, and wound healing assay. Our results revealed that NLRP3 inflammasome activation inhibited the proliferation of Bel-7402 and SMMC-7721 cells, arrested the cell cycle at the G1 phase, and suppressed cell migration, while apoptosis remained unaffected. In summary, our findings suggest that targeting the NLRP3 inflammasome could have therapeutic potential for HCC.

Identification and analysis of anti-tumor effective substances in Yangzheng Mixture.

Yangzheng Mixture is a traditional Chinese medicine used in clinical practice as an adjuvant therapy for tumors. However, little is known about its active components in tumor treatment. The purpose of this study was to explore the potential anti-tumor components of Yangzheng Mixture to better promote its clinical application. Using LC-MS/MS, 43 components were detected in concentrated Yangzheng Mixture. Six components, comprising astragaloside, calycosin, formononetin, isoquercitrin, ononin, and calycosin-7-O-ß-D-glucoside, were identified in rat plasma. The cancer cell absorption assay showed that the intracellular concentration of four components, calycosin, calycosin-7-O-ß-D-glucoside, formononetin, and ononin, increased with extended incubation time and demonstrated potential anti-tumor effects. The MTT assay results confirmed that Yangzheng Mixture inhibited different tumor cells proliferation. Additionally, the colony formation assay, flow cytometry analysis and wound healing displayed that Yangzheng Mixture and a combination of four components could inhibit colony formation, arrest the cell cycle and impair cell migration of tumor cells, including HCT-116, MHCC-97L, MCF-7 and NCI-H1299. In summary, our study highlighted the plausible application of Yangzheng Mixture as a potential adjuvant treatment for tumors. Furthermore, it identified effective anti-tumor components and provided evidences for the further clinical application of Yangzheng Mixture.

Albendazole exerts an anti-hepatocellular carcinoma effect through a WWOX-dependent pathway.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related deaths. The WW-domain containing oxidoreductase (WWOX) protein suppresses carcinogenesis and its absence is closely related to aggressive HCC phenotypes. In this study, by using SPR analysis, cell viability assay and xenograft mice models, we found that albendazole (ABZ), a safe and effective anthelmintic drug, exhibited the binding affinity with WWOX protein and potential inhibition effect on HCC cells in vitro and in vivo. Overexpression and knockdown of WWOX confirmed that the suppression of HCC by ABZ. Flow cytometric analysis, western blotting analysis and Co-IP were conducted to study the mechanism of ABZ. Our data showed that ABZ regulated the interaction between WWOX and its binding proteins including p53 and C-MYC. Furthermore, ABZ triggered p53-induced intrinsic apoptosis and suppressed EMT-mediated migration by C-MYC/Fibronectin axis. In addition, ∆NP73 expression was significantly inhibited by ABZ, which further sensitized p53-induced intrinsic apoptosis and cell cycle arrest. In summary, ABZ could suppress the proliferation and migration of HCC cells by regulating WWOX-dependent signaling pathway.

Targeting mitochondrial dysfunctions in pancreatic cancer evokes new therapeutic opportunities.

Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity of this cancer urgently demand the exploration of novel approaches for the development of effective therapeutic measures. Metabolic derangement is one of the hallmarks of cancers which restructures mitochondrial activities and biological pathways. Apart from their bioenergetic and biosynthetic functions, mitochondria are also implicated in a myriad of cellular functions including proliferation, differentiation, apoptosis, senescence, homeostasis, and other cell regulatory mechanisms. It has been noted that PC, like other types of cancers, exploits these activities in favor of tumor growth and survival by inducing mitochondrial dysfunctions such as mitochondrial-DNA mutation, metabolic enzyme modification, ROS generation, mitophagy, evasion of apoptosis, and mitochondrial biogenesis. During pancreatic carcinogenesis, a large number of onco-factors including Bcl-2 family proteins, NF-κB, HIFs, NRF2, NOX, MFNs, DRP1, DUSP6, Cyp-D, PARKIN, and others are dysregulated, resulting into reprogramming of metabolic pathways and cellular kinetics. Hence, targeted interventions in these metabolic derangements may present some effective anticancer approaches. The current review gives an insight into various mitochondrial disorders and their targetable molecules in PC which may provide certain novel opportunities in the pursuit of therapeutic development. Furthermore, we have also discussed certain treatment perspectives in PC based on specific mitochondrial activities.

Shuanghua decoction exerts anticancer activity by activating NLRP3 inflammasome via ROS and inhibiting NF-κB signaling in hepatocellular carcinoma cells.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major subtype of liver cancer, with a high mortality rate, and close relation to chronic hepatitis. The components of the NLRP3 inflammasome are poorly expressed or even lost in HCC. Downregulation of the NLRP3 inflammasome expression significantly affects the clinical stages and pathological grade of HCC. According to previous research, Shuanghua decoction (SHD), a traditional folk prescription, has an inhibitory effect on nasopharyngeal cancer. PURPOSE: This study aimed to reveal the therapeutic potential of the traditional folk recipe, SHD and its demolition recipe for HCC, and to explore the underlying mechanism. METHODS: The effect of SHD and its demolition recipe on HCC cell biological behaviors was assessed using the MTT assay, colony formation, LDH release assay, KFluor-Edu staining, annexin V-FITC/PI staining assay, Hoechst staining, wound-healing assay, transwell assay, reactive oxygen species (ROS) release assay, HPLC, nude mice model, HE staining, IHC, western blot, and immunofluorescence staining in vitro and in vivo. RESULTS: SHD was found to inhibit HCC, and Oldenlandia and OP (Oldenlandia: Prunella spike = 2.5:1) were identified as the main ingredients that inhibited the proliferation and migration of HCC cells via the activation of the ROS-mediated NLRP3 inflammasome and inhibition of the NF-κB signaling pathway in vitro and in vivo. CONCLUSION: Overall, Chinese medicine theory and pharmacology research revealed that SHD, Oldenlandia and OP may be promising traditional Chinese medicine for the treatment of HCC.

Targeting NOX4 disrupts the resistance of papillary thyroid carcinoma to chemotherapeutic drugs and lenvatinib.

Advanced differentiated thyroid cancer cells are subjected to extreme nutritional starvation which contributes to develop resistance to treatments; however, the underlying mechanism remains unclear. Cells were subjected to serum deprivation by culture in medium containing 0.5% fetal bovine serum. A CCK8 assay, cell death Detection ELISAPLUS kit, and PI staining were conducted to determine cell viability, cell apoptosis, and cell cycle, respectively. NADPH oxidase 4 (NOX4) knockdown-stable cell lines were generated by lentivirus-mediated shRNA knockdown in BCPAP cells and TPC-1 cells. Etoposide and doxorubicin, two chemotherapeutic drugs, as well as lenvatinib were utilized to determine the effect of NOX4 on drug resistance. Lenvatinib-resistant BCPAP cells (LRBCs) were established to confirm this effect. The underlining mechanisms of NOX4 under starvation were explored using western blot. Finally, GLX351322, an inhibitor targeting NOX4, was used to inhibit NOX4-derived ROS in vitro and detect its effect on drug resistance of tumor cells in vivo. NOX4 is overexpressed under serum deprivation in BCPAP or TPC-1 cells. NOX4 knockdown impairs cell viability, increases cell apoptosis, extends G1 phase during cell cycle and modulates the level of energy-associated metabolites in starved cells. When the starved cells or LRBCs are treated with chemotherapeutic drugs or Lenvatinib, NOX4 knockdown inhibits cell viability and aggravates cell apoptosis depending on NOX4-derived ROS production. Mechanistically, starvation activates TGFß1/SMAD3 signal, which mediates NOX4 upregulation. The upregulated NOX4 then triggers ERKs and PI3K/AKT pathway to influence cell apoptosis. GLX351322, a NOX4-derived ROS inhibitor, has an inhibitory effect on cell growth in vitro and the growth of BCPAP-derived even LRBCs-derived xenografts in vivo. These findings highlight NOX4 and NOX4-derived ROS as a potential therapeutic target in resistance to PTC.

Controlled loading of albumin-drug conjugates ex vivo for enhanced drug delivery and antitumor efficacy.

To harness the intrinsic transport properties of albumin yet improve the therapeutic index of current in situ albumin-binding prodrugs, we developed albumin-drug conjugates with a controlled loading that achieved better antitumor efficacy. Here, model drug monomethyl auristatin E (MMAE) was conjugated ex vivo to Cys34 of albumin via a cathepsin B-sensitive dipeptide linker to ensure that all drug would be bound specifically to albumin. The resulting albumin-drug conjugate with a drug to albumin ratio (DAR) of 1 (ALDC1) retained the native secondary structure of albumin compared to conjugate with a higher DAR of 3 (ALDC3). ALDC1 exhibited improved drug release and cytotoxicity compared to ALDC3 in vitro. Slower plasma clearance and increased drug exposure over time of ALDC1 were observed compared to ALDC3 and MMAE prodrug. In single dose studies with MIA PaCa2 xenografts, cohorts treated with ALDC1 had the highest amount of MMAE drug in tumor tissues compared to other treatment arms. After multiple dosing, ALDC1 significantly delayed the tumor growth compared to control treatment arms MMAE, MMAE-linker conjugate and ALDC3. When dosed with the maximum tolerated dose of ALDC1, there was complete eradication of 83.33% of the tumors in the treatment group. Ex vivo conjugated ALDC1 also significantly inhibited tumor growth in an immunocompetent syngeneic mouse model that better recapitulates the phenotype and clinical features of human pancreatic cancers. In summary, site-specific loading of drug to albumin at 1:1 ratio allowed the conjugate to better maintain the native structure of albumin and its intrinsic properties. By conjugating the drug to albumin prior to administration minimized premature cleavage and instability of the drug in plasma and enabled higher drug accumulation in tumors compared to in situ albumin-binding prodrugs. This strategy to control drug loading ex vivo ensures complete drug binding to the albumin carrier and achieves excellent antitumor efficacy, and it has the potential to greatly improve the outcomes of anticancer therapy.

Peptides as surface coatings of nanoparticles that penetrate human cystic fibrosis sputum and uniformly distribute in vivo following pulmonary delivery.

Therapeutic delivery of drug and gene delivery systems have to traverse multiple biological barriers to achieve efficacy. Mucosal administration, such as pulmonary delivery in cystic fibrosis (CF) disease, remains a significant challenge due to concentrated viscoelastic mucus, which prevents drugs and particles from penetrating the mucus barrier. To address this problem, we used combinatorial peptide-presenting phage libraries and next-generation sequencing (NGS) to identify hydrophilic, net-neutral charged peptide coatings that enable penetration through human CF mucus ex vivo with ~600-fold better penetration than control, improve uptake into lung epithelial cells compared to uncoated or PEGylated-nanoparticles, and exhibit enhanced uniform distribution and retention in the mouse lung airways. These peptide coatings address multiple delivery barriers and effectively serve as excellent alternatives to standard PEG surface chemistries to achieve mucus penetration and address some of the challenges encountered using these chemistries. This biomolecule-based strategy can address multiple delivery barriers and hold promise to advance efficacy of therapeutics for diseases like CF.

Identification of peptide coatings that enhance diffusive transport of nanoparticles through the tumor microenvironment.

In solid tumors, increasing drug penetration promotes their regression and improves the therapeutic index of compounds. However, the heterogeneous extracellular matrix (ECM) acts as a steric and interaction barrier that hinders effective transport of therapeutics, including nanomedicines. Specifically, the interactions between the ECM and surface physicochemical properties of nanomedicines (e.g. charge, hydrophobicity) affect their diffusion and penetration. To address the challenges using existing surface chemistries, we used peptide-presenting phage libraries as a high-throughput approach to screen and identify peptides as coatings with desired physicochemical properties that improve diffusive transport through the tumor microenvironment. Through iterative screening against the ECM and identification by next-generation DNA sequencing and analysis, we selected individual clones and quantify their transport by diffusion assays. Here, we identified a net-neutral charge, hydrophilic peptide P4 that facilitates significantly higher diffusive transport of phage than negative control through in vitro tumor ECM. Through alanine mutagenesis, we confirmed that the hydrophilicity, charge, and spatial ordering impact diffusive transport. The P4 phage clone exhibited almost 200-fold improved uptake in ex vivo pancreatic tumor xenografts compared to the negative control. Nanoparticles coated with P4 exhibited ∼40-fold improvement in diffusivity in pancreatic tumor tissues, and P4-coated particles demonstrated less hindered diffusivity through the ECM compared to functionalized control particles. By leveraging the power of molecular diversity using phage display, we can greatly expand the chemical space of surface chemistries that can improve the transport of nanomedicines through the complex tumor microenvironment to ultimately improve their efficacy.

Quantitative PCR of T7 Bacteriophage from Biopanning.

This protocol describes the use of quantitative PCR (qPCR) to enumerate T7 phages from phage selection experiments (i.e., "biopanning"). qPCR is a fluorescence-based approach to quantify DNA, and here, it is adapted to quantify phage genomes as a proxy for phage particles. In this protocol, a facile phage DNA preparation method is described using high-temperature heating without additional DNA purification. The method only needs small volumes of heat-treated phages and small volumes of the qPCR reaction. qPCR is high-throughput and fast, able to process and obtain data from a 96-well plate of reactions in 2-4 h. Compared to other phage enumeration approaches, qPCR is more time-efficient. Here, qPCR is used to enumerate T7 phages identified from biopanning against in vitro cystic fibrosis-like mucus model. The qPCR method can be extended to quantify T7 phages from other experiments, including other types of biopanning (e.g., immobilized protein binding, in vivo phage screening) and other sources (e.g., water systems or body fluids). In summary, this protocol can be modified to quantify any DNA-encapsulated viruses.

Peptides as drug delivery vehicles across biological barriers.

Peptides are small biological molecules that are attractive in drug delivery and materials engineering for applications including therapeutics, molecular building blocks and cell-targeting ligands. Peptides are small but can possess complexity and functionality as larger proteins. Due to their intrinsic properties, peptides are able to overcome the physiological and transport barriers presented by diseases. In this review, we discuss the progress of identifying and using peptides to shuttle across biological barriers and facilitate transport of drugs and drug delivery systems for improved therapy. Here, the focus of this review is on rationally designed, phage display peptides, and even endogenous peptides as carriers to penetrate biological barriers, specifically the blood-brain barrier(BBB), the gastrointestinal tract (GI), and the solid tumor microenvironment (T). We will discuss recent advances of peptides as drug carriers in these biological environments. From these findings, challenges and potential opportunities to iterate and improve peptide-based approaches will be discussed to translate their promise towards the clinic to deliver drugs for therapeutic efficacy.

Human umbilical cord mesenchymal stem cells attenuate cisplatin-induced acute and chronic renal injury.

Mesenchymal stem cell is becoming a promising candidate in acute kidney injury (AKI). We first reported that human umbilical cord mesenchymal stem cells (hucMSCs) could ameliorate renal function in ischemic/reperfusion AKI rats, but the role of hucMSCs in cisplatin-induced acute and chronic injury has been demonstrated. More specifically, it is still unknown whether hucMSCs halt renal interstitial fibrosis. In this study, we investigated the effect of hucMSCs in cisplatin-induced kidney injury and explored the mechanism of action. Blood urea nitrogen (BUN) and creatinine (Cr) analyses showed amelioration of functional parameters in hucMSC-treated rats at early damage. Transplantation with hucMSCs promoted renal cell regeneration, inhibited cell apoptosis, abrogated inflammatory responses and protected mitochondria. Moreover, Masson's trichrome staining demonstrated reduced levels of fibrosis in kidney tissues of hucMSC-treated rats at six and eight weeks after cisplatin injection. These results were corroborated by reduced collagen deposit, the ratio of Bax to Bcl-2 and transforming growth factor ß mRNA expression. Furthermore, hucMSCs prevented the epithelial-mesenchymal transition (EMT) in injury renal tissues, leading to the attenuation of chronic renal interstitial fibrosis. Taken together, our findings suggested that hucMSCs could decrease the kidney from development of later renal interstitial fibrosis by amelioration of early AKI.

Human umbilical cord mesenchymal stem cells attenuate cisplatin-induced acute and chronic renal injury.

Mesenchymal stem cell is becoming a promising candidate in acute kidney injury (AKI). We first reported that human umbilical cord mesenchymal stem cells (hucMSCs) could ameliorate renal function in ischemic/reperfusion AKI rats, but the role of hucMSCs in cisplatin-induced acute and chronic injury has been demonstrated. More specifically, it is still unknown whether hucMSCs halt renal interstitial fibrosis. In this study, we investigated the effect of hucMSCs in cisplatin-induced kidney injury and explored the mechanism of action. Blood urea nitrogen (BUN) and creatinine (Cr) analyses showed amelioration of functional parameters in hucMSC-treated rats at early damage. Transplantation with hucMSCs promoted renal cell regeneration, inhibited cell apoptosis, abrogated inflammatory responses and protected mitochondria. Moreover, Masson's trichrome staining demonstrated reduced levels of fibrosis in kidney tissues of hucMSC-treated rats at six and eight weeks after cisplatin injection. These results were corroborated by reduced collagen deposit, the ratio of Bax to Bcl-2 and transforming growth factor ß mRNA expression. Furthermore, hucMSCs prevented the epithelial-mesenchymal transition (EMT) in injury renal tissues, leading to the attenuation of chronic renal interstitial fibrosis. Taken together, our findings suggested that hucMSCs could decrease the kidney from development of later renal interstitial fibrosis by amelioration of early AKI.

Contribution of organic cation transporter 3 to cisplatin cytotoxicity in human cervical cancer cells.

This study was conducted to investigate whether drug transporters play a role in determination of cisplatin resistance in cervical cancer cells. The transcript levels of the transporter genes previously associated with cisplatin transport and/or resistance were compared between the cisplatin-sensitive cervical adenocarcinoma KB-3-1 and its derivative cisplatin-resistant KB-CP20 cells. The expression of the efflux transporter gene multidrug resistance-associated protein 2 (MRP2) was significantly reduced in KB-CP20 cells, in support of previous studies indicating that MRP2 is unlikely responsible for cisplatin resistance in these cells. We observed that the expression of the uptake transporter organic cation transporter 3 (OCT3) was extremely downregulated in KB-CP20 compared with KB-3-1 cells. Consistently, the transport function for organic cations in the former was considerably low. OCT3 overexpression significantly increased cisplatin cellular accumulation and cytotoxicity in KB-3-1 cells, while its downregulation by short hairpin RNA or chemical inhibition increased the resistance. Interestingly, there was no effect of OCT3 overexpression on cisplatin accumulation and cytotoxicity in human embryonic kidney 293 cells. The present study indicates that OCT3 partially contributes to the sensitivity of cervical adenocarcinoma cells to cisplatin cytotoxicity. Further studies are required to determine OCT3 activity in cervical cancer tissues of different cisplatin chemoresponses and to elucidate the underlying mechanisms of different OCT3 function in different cell types.

5-Azacytidine induces cardiac differentiation of human umbilical cord-derived mesenchymal stem cells by activating extracellular regulated kinase.

5-Azacytidine (5-Aza) induces differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes. However, the underlying mechanisms are not well understood. Our previous work showed that 5-Aza induces human bone marrow-derived MSCs to differentiate into cardiomyocytes. Here, we demonstrated that 5-Aza induced cardiac differentiation of human umbilical cord-derived MSCs (hucMSCs) and explored the potential signaling pathway. Our results showed that hucMSCs had cardiomyocyte phenotypes after 5-Aza treatment. In addition, myogenic cells differentiated from hucMSCs were positive for mRNA and protein of desmin, ß-myosin heavy chain, cardiac troponin T, A-type natriuretic peptide, and Nkx2.5. Human diploid lung fibroblasts treated with 5-Aza expressed no cardiac-specific genes. 5-Aza did not induce hucMSCs to differentiate into osteoblasts. Further study revealed that 5-Aza treatment activated extracellular signal related kinases (ERK) in hucMSCs, but protein kinase C showed no response to 5-Aza administration. U0126, a specific inhibitor of ERK, could inhibit 5-Aza-induced expression of cardiac-specific genes and proteins in hucMSCs. Increased phosphorylation of signal transducers and activators of transcription 3, and up-regulation of myocyte enhancer-binding factor-2c and myogenic differentiation antigen in 5-Aza-treated hucMSCs were also suppressed by U0126. Taken together, these results suggested that sustained activation of ERK by 5-Aza contributed to the induction of the differentiation of hucMSCs into cardiomyocytes in vitro.

Hepatocyte growth factor modification promotes the amelioration effects of human umbilical cord mesenchymal stem cells on rat acute kidney injury.

Human umbilical cord-derived mesenchymal stem cells (hucMSCs) are particularly attractive cells for cellular and gene therapy in acute kidney injury (AKI). Adenovirus-mediated gene therapy has been limited by immune reaction and target genes selection. However, in the present study, we investigated the therapeutic effects of hepatocyte growth factor modified hucMSCs (HGF-hucMSCs) in ischemia/reperfusion-induced AKI rat models. In vivo animal models were generated by subjecting to 60 min of bilateral renal injury by clamping the renal pedicles and then introduced HGF-hucMSCs via the left carotid artery. Our results revealed that serum creatinine and urea nitrogen levels decreased to the baseline more quickly in HGF-hucMSCs-treated group than that in hucMSCs- or green fluorescent protein-hucMSCs-treated groups at 72 h after injury. The percent of proliferating cell nuclear antigen-positive cells in HGF-hucMSCs-treated group was higher than that in the hucMSCs or green fluorescent protein-hucMSCs-treated groups. Moreover, injured renal tissues treated with HGF-hucMSCs also exhibited less hyperemia and renal tubule cast during the recovery process. Immunohistochemistry and living body imaging confirmed that HGF-hucMSCs localize to areas of renal injury. Real-time polymerase chain reaction result showed that HGF-hucMSCs also inhibited caspase-3 and interleukin-1ß mRNA expression in injured renal tissues. Western blot also showed HGF-hucMSCs-treated groups had lower expression of interleukin-1ß. Terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate (dUTP) nick end labeling method indicated that HGF-hucMSCs-treated group had the least apoptosis cells. In conclusion, our findings suggest that HGF modification promotes the amelioration of ischemia/reperfusion-induced rat renal injury via antiapoptotic and antiinflammatory mechanisms; thus, providing a novel therapeutic application for hucMSCs in AKI.