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Background: Gastric cancer (GC) is a common tumor found worldwide, and cisplatin is the first-line agent for the treatment of GC. However, the resistance to cisplatin is an obstacle. Here, we aim to explore the biological mechanism of long noncoding RNA regulator of reprogramming (ROR) in the cisplatin resistance of GC. Materials and Methods: ROR, miR-519d-3p, and high mobility group protein A2 (HMGA2) expression in GC tissues and cells were measured by quantitative real-time polymerase chain reaction and Western blot. Cell viability, migration, invasion, and apoptosis were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, transwell assay, and flow cytometry, respectively. The relative protein expression was detected by Western blot. The interactions between miR-519d-3p and ROR, HMGA2 were predicted using miRcode and starBase v2.0 online database, and then verified by dual luciferase reporter assay and RNA immunoprecipitation assay. In addition, the xenograft tumor mouse model was constructed to verify the biological role of ROR in vivo. Results: The levels of ROR, HMGA2 were significantly upregulated, and miR-519d-3p was apparently downregulated in GC tissues and cells. The miRcode and starBase v2.0 online websites and dual luciferase reporter assay validated that miR-519d-3p directly interacted with ROR and HMGA2. Furthermore, ROR knockdown downregulated HMGA2 to restrain cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and cisplatin resistance in GC cells by targeting miR-519d-3p. In addition, the depletion of ROR repressed the xenograft tumor growth in vivo. Conclusion: In conclusion, we first found the ROR/miR-519d-3p/HMGA2 regulatory network to regulate cell proliferation, migration, invasion, EMT, and cisplatin resistance in GC, and this may shed light on the GC tumorigenesis.

Background Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a high mortality rate and poor prognosis. miR-637 has been reported to regulate tumor progression and act as a prognosis biomarker of various cancers. Its functional role in NSCLC was investigated in this study. Methods The expression level of miR-637 in NSCLC tissues and adjacent normal tissues of 123 NSCLC patients was analyzed by qRT-PCR. The association between miR-637 and clinical pathological features in the prognosis of patients was analyzed. Cell transfection was performed to overexpress or knockdown miR-637 in H1299 and HCC827. The proliferation, migration, and invasion of H1299 and HCC827 were evaluated by CCK8 and Transwell assay. Results miR-637 expression was significantly decreased in NSCLC tissues and cell lines relative to normal tissues and cells. The survival rate of NSCLC patients with low miR-637 expression was lower than that of patients with high miR-637 expression. Additionally, miR-637 served as a tumor suppressor that inhibited cell proliferation, migration, and invasion of NSCLC. Conclusion Downregulation of miR-637 in NSCLC was associated with TNM stage and poor prognosis of patients and served as a tumor suppressor in NSCLC. These results provide a potential strategy to control NSCLC.

Aims: This study aimed to evaluate the roles and molecular targets of miRNA-141-3p in the cisplatin sensitivity of osteosarcoma. Background: Osteosarcoma is one of the most common-type bone tumors, occurring mainly in children and adolescents. Cancer cells display dysregulated cellular metabolism, such as the abnormally elevated glutamine metabolism. Objective: Non-coding RNA miRNA-141-3p has been reported to act as a tumor suppressor in osteosarcoma. Currently, the precise molecular mechanisms for the miR- 141-3p-mediated chemosensitivity through regulating glutamine metabolism remain unclear. Methods: We collected thirty paired OS tumors and their adjacent normal tissues. The osteosarcoma cell lines [Saos-2] and normal osteoblast cells, hFOB1.19, were used for in vitro experiments. RT-qPCR and Western blot were applied for gene expression detections. Targets of miR-141-3p were predicted from starBase. The MTT and flow cytometric assays were performed to determine cell growth and apoptosis rates. The cellular glutamine metabolism was monitored by glutamine uptake assay and the glutaminase [GLS] activity assay. Results: We reported that miR-141-3p were significantly downregulated in osteosarcoma tissues and cells. Overexpression of miR-141-3p suppressed OS cell growth and sensitized OS cells to cisplatin. In addition, glutamine metabolism was significantly increased in osteosarcoma. We characterized that GLS played oncogenic roles in osteosarcoma and validated GLS was a direct target of miR-141-3p in OS cells. Rescue experiments consistently demonstrated that miR-141-3p-promoted cisplatin sensitivity was achieved by targeting GLS directly. Conclusion: Overall, our findings revealed new molecular mechanisms of the miR-141- 3p-modulated cisplatin sensitization through targeting the GLS-glutamine metabolism pathway. This study will contribute to developing new therapeutic approaches for the treatments of chemoresistant osteosarcoma.

Polyploidy is defined as a cell with three or more whole genome sets and enables cell growth across the kingdoms of life. Studies in model organisms have revealed that polyploid cell growth can be required for optimal tissue repair and regeneration. In mammals, polyploid cell growth contributes to repair of many tissues, including the liver, heart, kidney, bladder, and eye, and similar strategies have been identified in Drosophila and zebrafish tissues. This review discusses the heterogeneity and versatility of polyploidy in tissue repair and regeneration. Polyploidy has been shown to restore tissue mass and maintain organ size as well as protect against oncogenic insults and genotoxic stress. Polyploid cells can also serve as a reservoir for new diploid cells in regeneration. The numerous mechanisms to generate polyploid cells provide an unlimited resource for tissues to exploit to undergo repair or regeneration.

Background: Colorectal cancer (CRC) is a significant public problem and the third cause of cancer-induced death all over the world. In addition, long noncoding RNA (lncRNA) has been reported as a vital mediator in human cancer. However, the precise role of lncRNA myocardial infarction associated transcript (MIAT) in CRC is unclear. Methods: The abundance of MIAT, miR-488-3p, and the type 1 insulin-like growth factor receptor (IGF1R) was measured by real-time quantitative polymerase chain reaction assay. The western blot assay was carried out to assess the protein level in CRC samples or control group. The cell activity, abilities of migration and invasion, and glycolysis were evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT), transwell, and testing glucose consumption and lactate product, correspondingly. The target association between miR-488-3p, MIAT, or IGF1R was predicted and established by bioinformatics tools, dual-luciferase reporter, and RNA pull-down assays, correspondingly. The effects of MIAT silencing in vivo were analyzed by animal experiments. Results: LncRNA MIAT was upregulated in CRC sample and that was positively correlated with IGF1R expression. Loss-of-functional assay suggested that knockdown of MIAT impeded cell activity, migration, invasion, and glycolysis of CRC cells in vivo, along with xenograft growth in vivo. Moreover, silencing of IGF1R inhibited the progression of CRC. Therefore, overexpression of IGF1R could abolish silencing of MIAT-induced effects on CRC cells. Mechanistically, MIAT was a sponge for miR-488-3p, thereby regulating IGF1R expression in CRC. Conclusion: The present study confirmed that the "MIAT/miR-488-3p/IGF1R" pathway was involved in the development of CRC, which may be the target for developing therapeutic approaches for CRC.

Colorectal cancer (CRC) is one of the most common cancers worldwide. In this study, we explored the role of RNA binding motif protein 15 (RBM15)-mediated MyD88 mRNA N6-methyladenosine (m6A) in CRC development. Cell proliferation, apoptosis, and invasion were detected by EdU, Annexin V-FITC/PI staining, and Transwell assays, respectively. RBM15 and MyD88 expression was detected by RT-qPCR and Western blot. RNA-seq, RIP-seq, and MeRIP-seq were used for RBM15 downstream target gene prediction and expression detection. In this research, we confirmed that RBM15 was highly expressed in CRC tissues and was negatively correlated with overall and disease-free survival rate. Silencing RBM15 significantly inhibited the proliferative and invasive abilities and promoted cell apoptosis in the CRC cell lines (SW480 and HCT116). Moreover, tumor growth and CRC liver metastasis were inhibited by silencing RBM15 in vivo. m6A methylation level was decreased in RBM15-silenced SW480 and HCT116 cells. MyD88 was the target mRNA of RBM15-mediated m6A methylation in CRC. MyD88 was lowly expressed in CRC and negatively correlated with RBM15 expression. Taken together, RBM15 silencing inhibited the CRC growth and metastasis in vitro and in vivo. RBM15 mediated m6A methylation modification of MyD88 mRNA in CRC cells.

Background: Colorectal cancer (CRC) is the third most common malignancy worldwide. Matrine can act as a potential antitumor drug, and its antitumor activities have been tested in various cancers, including CRC. However, the effect of matrine and the related mechanisms on CRC cells remains poorly defined. Materials and Methods: CRC cells were treated with different concentrations of matrine, and then MTT, flow cytometric, and transwell assays were used to assess cell proliferation, apoptosis, invasion, and migration. MiR-10b-5p and Phosphatase and tensin homolog (PTEN) expression levels were measured by quantitative real-time polymerase chain reaction and western blot assay. The binding interaction of miR-10b-5p and PTEN were predicted by TargetScan and verified by a dual-luciferase reporter and RIP assay. The effect of matrine, miR-10b-5p, and PTEN on CRC cell proliferation, apoptosis, migration, and invasion was detected by MTT, flow cytometric, and transwell assays severally. Results: Matrine notably restrained proliferation, invasion, and migration and boosted apoptosis of CRC cells, as well as downregulated miR-10b-5p expression and upregulated PTEN protein level. PTEN was a direct target of miR-10b-5p in CRC cells. MiR-10b-5p knockdown and matrine treatment inhibited cell proliferation, migration, and invasion and induced apoptosis, and reintroduction of si-PTEN partly regained the inhibiting effect. Besides, MiR-10b-5p knockdown and matrine treatment repressed CRC growth in vivo. Conclusion: Matrine could suppress proliferation, migration, and invasion and induce apoptosis of CRC cells via the miR-10b/PTEN pathway, providing the potential molecular mechanism of matrine in blocking CRC progression.

Purpose: The assessment of HER2 expression has a significant impact on optimizing cancer treatment protocol in patients. The aim of this study was to evaluate the potential usefulness of 99mTc-HYNIC-(Ser)3-LTVPWY peptide for detecting HER2 alteration after paclitaxel therapy of ovarian tumor xenografts in nude mice. Methods: Mice bearing SKOV-3 tumors were treated with paclitaxel and saline. The antitumor efficacy of paclitaxel was compared with the control group in tumor size and histopathological examinations. In biodistribution and imaging studies, the tumor uptakes of radiolabeled peptide were evaluated in mice-bearing ovarian tumors in both groups. The HER2 expressions in transplanted tumors were analyzed by immunohistochemistry (IHC). Results: The tumor sizes gradually increased in all mice during the treatment, whereas tumors had considerably faster growth in the saline group compared to those in the paclitaxel-treated mice. Paclitaxel could suppress ovarian tumor growth and prevent vascular and cell proliferation in the tumoral mass. The biodistribution and imaging results demonstrated nonsignificant radionuclide accumulations in transplanted tumors in the paclitaxel- and saline-treated groups. IHC staining confirmed the HER2 status that was similar in both groups. Conclusions: The response of HER2 status to paclitaxel in mice bearing HER2-expression tumors was profitably monitored by HER2 targeted 99mTc-HYNIC-(Ser)3-LTVPWY peptide that was agreement with IHC. The utilization of this radiolabeled peptide may be a valuable probe in evaluating HER2 status after chemotherapy.

Background: Endometrial cancer (EC) is an intractable gynecological cancer with increasing incidence and mortality worldwide. Accumulating studies indicated that long noncoding RNA nuclear enriched...

In cancer, human cells lose the ability to properly control the series of events that occur constantly during cell growth and division, including protein expression, stability, and dynamics. Heat shock proteins (Hsps) are key molecules in these events, constitutively expressed at high levels and could furthermore be induced by the response to cancer-induced stress. In tumor cells, Hsps have been shown to be implicated in the regulation of apoptosis, immune responses, angiogenesis and metastasis; in some cases, they can be overexpressed and dysregulated, representing important cancer hallmarks. In the past few years, it has been demonstrated that Hsps can be released by tumor cells through several secreting pathways, including the extracellular vesicles (EVs), thus modulating the tumor microenvironment as well as long-distance intercellular communication and metastatization. In this review, we discuss the role of extracellular Hsps in cancer, with a particular interest in Hsps in EVs. We would also like to highlight the importance of fully understanding of the role of extracellular Hsps released by EVs and encourage further research in this field the use of Hsps as early cancer biomarkers and therapeutic targets.

Mesenchymal stem cells (MSCs) have been demonstrated as promising cell sources for tissue regeneration due to their capability of self-regeneration, differentiation and immunomodulation. MSCs also exert extensive paracrine effects through release of trophic factors and extracellular vesicles. However, despite extended exploration of MSCs in pre-clinical studies, the results are far from satisfactory due to the poor engraftment and low level of survival after implantation. Hypoxia preconditioning has been proposed as an engineering approach to improve the therapeutic potential of MSCs. During in vitro culture, hypoxic conditions can promote MSC proliferation, survival and migration through various cellular responses to the reduction of oxygen tension. The multilineage differentiation potential of MSCs is altered under hypoxia, with consistent reports of enhanced chondrogenesis. Hypoxia also stimulates the paracrine activities of MSCs and increases the production of secretome both in terms of soluble factors as well as extracellular vesicles. The secretome from hypoxia preconditioned MSCs play important roles in promoting cell proliferation and migration, enhancing angiogenesis while inhibiting apoptosis and inflammation. In this review, we summarise current knowledge of hypoxia-induced changes in MSCs and discuss the application of hypoxia preconditioned MSCs as well as hypoxic secretome in different kinds of disease models.

The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway involved in cell proliferation and survival. The three-layered MAPK signaling cascade is initiated upon RTK and RAS activation. Three RAF isoforms ARAF, BRAF and CRAF, and their downstream MEK1/2 and ERK1/2 kinases constitute a coherently orchestrated signaling module that directs a range of physiological functions. Genetic alterations in this pathway are among the most prevalent in human cancers, which consist of numerous hot-spot mutations such as BRAFV600E. Oncogenic mutations in this pathway often override otherwise tightly regulated checkpoints to open the door for uncontrolled cell growth and neoplasia. The crosstalk between the RAF-MEK-ERK axis and other signaling pathways further extends the proliferative potential of this pathway in human cancers. In this review, we summarize the molecular architecture and physiological functions of the RAF-MEK-ERK pathway with emphasis on its dysregulations in human cancers, as well as the efforts made to target the RAF-MEK-ERK module using small molecule inhibitors.

Background: Circular RNAs (circRNAs) have important roles in human malignancies, including breast cancer (BC). In this study, we intended to explore the function of circRNA ribonuclease P RNA component H1 (circ_RPPH1) in BC development and clarify the mechanistic pathway. Methods: Expression of circ_RPPH1, microRNA-542-3p (miR-542-3p), and Rho GTPase-activating protein 1 (ARHGAP1) in BC tissues and cells was determined by quantitative real-time polymerase chain reaction or Western blot assay. The stability of circ_RPPH1 was confirmed by RNase R and actinomycin D treatment. Cell viability and colony formation ability were measured by methyl thiazolyl tetrazolium (MTT) assay and colony formation assay, respectively. Western blot analysis was also used to detect proliferation biomarker (Ki67) and epithelial-mesenchymal transition (EMT) biomarkers (E-cadherin, N-cadherin, and vimentin). Flow cytometry and Transwell assays were performed to monitor cell apoptosis, migration, and invasion. The binding potency between miR-542-3p and circ_RPPH1 or ARHGAP1 was validated by dual-luciferase reporter assay. Functional role of circ_RPPH1 in vivo was investigated by xenograft tumor reporter assay. Results: Upregulation of circ_RPPH1 and ARHGAP1, and downregulation of miR-542-3p were detected in BC tissues and cells. circ_RPPH1 knockdown or miR-542-3p introduction inhibited BC cell proliferation and metastasis, while promoted apoptosis in vitro. circ_RPPH1 sponged miR-542-3p to upregulate ARHGAP1 expression, thereby affecting BC progression. Moreover, depletion of circ_RPPH1 suppressed tumor growth in vivo. Conclusions: circ_RPPH1 contributed to BC tumorigenesis by sponging miR-542-3p and upregulating ARHGAP1, affording a novel mechanistic pathway in BC development.

Background: Long non-coding RNA actin filament-associated protein1-antisense RNA 1 (AFAP1-AS1) was confirmed to be associated with tumorigenesis. However, the role of AFAP1-AS1 in breast cancer was...

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl−secretion. We have examined the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes and cyst formation usingin vitroandin vivomodels of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells at 1 μM and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells with an IC50of 5-10 μM. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of the chaperone Hsp90, and reduced the levels of the CFTR Cl−channel. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement.In vivo, H2-GMZ (20mg/kg) was effective in slowing postnatal cyst formation and kidney enlargement in thePkd1flox/flox:Pkhd1-Cremouse model. Thus, H2-GMZ treatment decreases Cl−secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.

BACKGROUND: The effectiveness and availability of conservative therapies for osteonecrosis of the femoral head (ONFH) are limited. Transplantation of bone marrow mesenchymal stem cells (BMSCs) combined with Bio-Oss, which is a good bone scaffold biomaterial for cell proliferation and differentiation, is a new potential therapy. Of note, the expression of miRNAs was significantly modified in cells cultured with Bio-Oss, and MiR-214 was correlated positively with osteonecrosis. Furthermore, miR-214 was upregulated in cells exposed to Bio-Oss. OBJECTIVE: To investigate whether targeting miR-214 further improves the transplantation effect. METHODS: We treated BMSCs with agomiR-214 (a miR-214 agonist), antagomiR-214 (a miR-214 inhibitor), or vehicle, followed by their transplantation into ONFH model rats. RESULTS: Histological and histomorphometric data showed that bone formation was significantly increased in the experimental groups (Bio-Oss and BMSCs treated with antagomiR-214) compared with other groups. CONCLUSIONS: miR-214 participates in the inhibition of osteoblastic bone formation, and the inhibition of miR-214 to bone formation during transplantation therapy with Bio-Oss combined with BMSCs for ONFH.

Background: Gastric cancer (GC), one of the common clinical malignant tumors of the digestive system, is the fourth most commonly diagnosed cancer and the second lethal cancer worldwide and has the characteristics of high metastasis, fatality, and recurrence rate. This research was conducted to investigate the role and mechanism of miR-4295 in gastric cancer. Methods: The expression capacity of miR-4295 was determined in gastric cancer tissues and its normal tissues by qRT-PCR. PTEN expression level was detected by western blot. SGC-7901 and MGC-803 cell lines were cultured and transfected with miR-4295 or its inhibitor. The effects of miR-4295 on cell proliferation, colony formation, migration, and invasion in vitro were investigated. The mutual effect between miR-4295 and PTEN in 293T cells was explored by luciferase reporter gene assays. Results: The results showed that miR-4295 expression was higher in gastric cancer tissues and cell lines, and the miR-4295 level was significantly negatively associated with the tumor size and distal metastasis of gastric cancer. Notably, up-regulated miR-4295 promoted cell proliferation, migration and invasion in vitro, whereas it led to contrary effects while down-regulating miR-4295 expression. Further mechanism studies displayed that miR-4295 could directly fasten the PTEN 3’UTR and dramatically decrease the level of PTEN in vitro. Conclusion: The findings revealed that miR-4295 could promote gastric cancer cell proliferation, migration and invasion, which might be attributed to targeting PTEN. Our study suggested that miR-4295 might be a potential therapeutic target for gastric cancer.

Background: Our study seeks to obtain data to assess the impact of circPUM1 on pancreatic cancer (PC) and its mechanism. Methods: The expression of circPUM1 and miR-200c-3p in PC and normal tissues and PC cell lines was collected and detected, and subsequently dual-luciferase assay-based verification of the binding site of the two was carried out. After interfering with circPUM1 expression in MIAPaCa-2 and PANC-1 cells, cell proliferation, viability, apoptosis rate, invasion ability, glucose consumption, and lactate production were measured by MTT, colony formation, flow cytometry, Transwell assays, and glucose and lactate assay kits. Additionally, western blot was utilized for assessing PI3K/AKT signaling pathway-related proteins. From the results, highly expressed circPUM1 and miR-200c-3p in PC tissues and cells were proved. Results: Down-regulation of circPUM1 expression significantly inhibited cell proliferation, cell viability, invasion and glycolysis, while increasing the apoptosis rate. Down-regulated circPUM1 led to the inhibition of the PI3K/AKT signaling pathway activity in PC cells; while up-regulated circPUM1 increased its activity. Further experiments revealed that down-regulation of miR-200c-3p expression reversed the inhibitory effect of lowly expressed circPUM1 on PC cells. Conclusion: In summary, circPUM1 activates PI3K/AKT signaling pathway by sponging miR-200c-3p and promotes PC progression.

Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes acute inflammation due to extensive replication of the virus in the epithelial cells of the upper and lower respiratory system. The mammalian target of rapamycin (mTOR) is a l signalling protein with critical functions in cell growth, metabolism, and proliferation. It is known for its regulatory functions in protein synthesis and angiogenesis cascades. The structure of mTOR consists of two distinct complexes (mTORC1 and mTORC2) with diverse functions at different levels of the signalling pathway. By activating mRNA translation, the mTORC1 plays a key role in regulating protein synthesis and cellular growth. On the other hand, the functions of mTORC2 are mainly associated with cell proliferation and survival. By using an appropriate inhibitor at the right time, mTOR modulation could provide immunosuppressive opportunities as antirejection regimens in organ transplantation as well as in the treatment of autoimmune diseases and solid tumours. The mTOR also has an important role in the inflammatory process. Inhibitors of mTOR might indeed be promising agents in the treatment of viral infections. They have further been successfully used in patients with severe influenza A/H1N1 pneumonia and acute respiratory failure. The officially accepted mTOR inhibitors that have undergone clinical testing are sirolimus, everolimus, temsirolimus, and tacrolimus. Thus, further studies on mTOR inhibitors for SARS-CoV-2 infection or COVID-19 therapy are well merited.

Background The abnormal expression of long non-coding RNA (lncRNA) Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) has been observed in many human cancers and the underlying mechanisms have been well studied. However, the function of OIP5-AS1 in acute kidney injury (AKI) remains unclear. Material and methods To explore the role of OIP5-AS1 in the progression of AKI, the cisplatin-induced AKI mouse and cell model were established. To confirm the potential protective effect of OIP5-AS1 during cisplatin-induced AKI, rescue experiments were performed. Targetscan was used to predict the potential targets of miR-144-5p. To further determine whether the effect of miR-144-5p during cisplatin-induced AKI was mediated by PMK2, the recuse experiments using PMK2 overexpressing vector was applied. Results OIP5-AS1 was significantly downregulated both in cisplatin-induced AKI mice and human renal tubular cell line HK-2 cells. Moreover, overexpression of OIP5-AS1 efficiently promoted cell growth and reduced cisplatin-induced apoptosis of HK-2 cells. Furthermore, OIP5-AS1 was identified as a sponge of miR-144-5p, and upregulation of miR-144-5p could significantly reverse overexpression of OIP5-AS1-induced protective effect on the damage of cisplatin to HK-2 cells. In addition, pyruvate kinase M2 (PKM2) was found to be a direct target of miR-144-5p, and overexpression of PKM2 efficiently reversed the effect of miR-144-5p mimics on the damage in cisplatin-stimulated HK-2 cells. Conclusions OIP5-AS1 reduced the apoptosis of cisplatin-stimulated renal epithelial cells by targeting the miR-144-5p/PKM2 axis, which extended the regulatory network of lncRNAs in cisplatin-induced AKI and also provided a novel therapeutic target for AKI treatment.

Abstract: Colorectal cancer (CRC) is one of the deadliest cancers in the world. Specific strains of intestinal Escherichia coli (E. coli) may influence the initiation and development of CRC by exploiting virulence factors and inflammatory pathways. Mucosa-associated E. coli strains are more prevalent in CRC biopsies in comparison to healthy controls. Moreover, these strains can survive and replicate within macrophages and induce a pro-inflammatory response. Chronic exposure to inflammatory mediators can lead to increased cell proliferation and cancer. Production of colobactin toxin by the majority of mucosa-associated E. coli isolated from CRC patients is another notable finding. Colibactin-producing E. coli strains, in particular, induce double-strand DNA breaks, stop the cell cycle, involve in chromosomal rearrangements of mammalian cells and are implicated in carcinogenic effects in animal models. Moreover, some enteropathogenic E. coli (EPEC) strains are able to survive and replicate in colon cells as chronic intracellular pathogens and may promote susceptibility to CRC by downregulation of DNA Mismatch Repair (MMR) proteins. In this review, we discuss current evidence and focus on the mechanisms by which E. coli can influence the development of CRC.

Leukemias and lymphomas acquire the capacity for unrestrained cell growth and proliferation in conjunction with loss of responsiveness to molecular programs that promote terminal differentiation. Malignant cells generate the building blocks required for rapid cell division through both increased acquisition of nutrients from the environment and reprogrammed intermediary metabolism to shunt these molecules into producing the protein, lipids, and nucleic acids that comprise cell biomass. These accelerated metabolic processes require energy in the form of ATP and reducing equivalents in the form of NADPH, which power biosynthetic reactions and buffer oxidative stress encountered by the metabolically active cancer cell. Cancer-associated metabolic alterations can also promote accumulation or depletion of specific metabolites that directly regulate cell fate and function, thereby coupling metabolic reprogramming to dedifferentiation and stemness. This review will focus on the mechanisms by which leukemia and lymphoma cells rewire cellular metabolism to support: (1) bioenergetics, (2) biomass accumulation, (3) redox balance, and (4) differentiation blockade. We will further highlight examples of how specific pathways of leukemia and lymphoma metabolism confer therapeutic vulnerabilities that can be targeted to inhibit growth or promote differentiation.

Background Prostate cancer (PCa) is a heavy health-threat for human worldwide. Recent studies revealed that microRNAs (miRNAs) are associated with the progression of human cancers, including PCa. However, no study has been performed to investigate the role of microNA-4286 (miR-4286) on PCa. Methods Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was conducted to analyze the expression level of miR-4286 in PCa cells. Connection of miR-4286 and spalt like transcription factor 1 (SALL1) was analyzed with bioinformatic analysis tool, dual-luciferase activity reporter assay, and western blot. Effects of miR-4286 and SALL1 on PCa cell behaviors were examined in vitro. Results We showed miR-4286 expression was significantly increased in PCa cells compared with normal cell line. Knockdown of miR-4286 could inhibit PCa cell proliferation but promote cell apoptosis via targeting SALL1. Conclusions Our study suggested that miR-4286 overexpression represents a tumor promoter role in PCa.

Background: Nucleolar and spindle associated protein 1 (NUSAP1) is an indispensable mitotic regulator, which has been reported to be involved in the development, progression, and metastasis of several types of cancer. Here, we investigated the expression and biological function of NUSAP1 in human glioblastoma multiforme (GBM). Methods: The expression of NUSAP1 on GBM tissues and cells were determined by database analysis, immunohistochemistry and Western blot. EdU assay, transwell assay and flow cytometric analysis were performed to evaluate the effect of NUSAP1 knockdown on GBM cell proliferation, cell invasion and cell apoptosis. RNA sequencing was used to screen for downstream molecules altered in GBM cells after NUSAP1 depletion. An intracranial mice model and bioluminescent imaging were used to assess the effect of NUSAP1 on tumor growth and survival time in vivo. Results: Analysis of the molecular data in CGGA, TCGA and Rembrandt datasets demonstrated that NUSAP1 was significantly up-regulated in GBM relative to low grade gliomas and non-neoplastic brain tissue samples. Kaplan-Meier analysis indicated that patients with tumors showing high NUSAP1 expression exhibited significantly poorer survival in both CGGA (P = 0.002) and Rembrandt cohorts (P = 0.017). Analysis of RNA sequencing data from P3-cells with stable knockdown of NUSAP1 revealed topoisomerase 2A (TOP2A) as a possible molecule down-regulated by the loss of NUSAP1. SiRNA knockdown of either NUSAP1 or TOP2A in U251, T98 and GBM derived patient P3 cells inhibited GBM cell proliferation and invasion, and induced cell apoptosis. Finally, stable knockdown of NUSAP1 with shRNA led to decreased tumor growth in an orthotopic xenograft model of GBM in mice. Conclusions: Taken together, NUSAP1 gene silencing induced apoptosis possibly through the down-regulation of the candidate downstream molecule TOP2A. Interference with the expression of NUSAP1 might therefore inhibit malignant progression in GBM, and NUSAP1 might thus serve as a promising molecular target for GBM treatment.

My technical work and my STS research are connected primarily through the idea of insulin costs and exploring the efforts made toward providing insulin at an affordable price. My technical work focuses on the design of insulin, prioritizing keeping costs as low as possible while creating a safe and effective drug. My research explores the obstacles that exist that prevent insulin prices from being affordable, specifically focusing on the Affordable Insulin Now Act and its failure to provide affordable insulin for the uninsured. While my technical work and my STS research approach insulin costs from different angles, the theme of obtainable affordable insulin is consistent across both projects. My technical work explores the design of an affordable insulin glargine product. Insulin glargine is a slow-releasing and long-acting insulin product that benefits those who have to take insulin every day by easing the application and use of the drug. Our capstone team designed an insulin manufacturing plant located in Singapore to service the developing and developed nations in the surrounding areas of Asia. The goal of our project was to design a plant that would minimize the costs of insulin while remaining profitable. Ultimately, we were able to produce insulin that sells to the consumer for $0.0075/unit. Thus, our product will cost someone who weighs 75kg $43.88/month, a much less expensive price for patients when compared to our competitors. While we were able to keep costs low for patients, our yearly revenue of about $4.8 billion with an internal return rate of 242% renders our plant economically viable. Producing 764 batches per year allows us to service 4% of the target market, or 9 million people. Through our research, we were able to prove that it is possible to create an affordable insulin product while remaining profitable. My STS research also explores insulin costs but from a different angle. My research focuses on the relationships between insulin prices, manufacturer control, and government policy. Specifically, my research paper focuses on the failures of The Affordable Insulin Now Act. The failure in the creation of this policy yields many consequences: enrollees of Medicare Part D will have a $2,000 out-of-pocket cost for prescription drugs beginning in 2025, uninsured diabetics see no change in insulin prices, and there is no limit to the price that insulin manufacturers can charge. I claim that The Affordable Insulin Now Act failed to be inclusive due to pressure from large manufacturers to retain their monopoly and the United States government’s negligence concerning rising insulin prices and high out-of-pocket costs for many diabetic Americans. My paper explores this claim and discusses how influential each of these factors is. My research aims to stimulate a conversation around insulin prices and convince readers that it is possible to obtain affordable insulin prices for all people. Working on these two projects simultaneously greatly added value to both. My technical work gave me a better understanding of the possibility of producing affordable insulin, which helped me provide context for my paper and offer insight into manufacturers’ influence over insulin prices. My research paper helped me understand that, while manufacturers have a large say in the cost of insulin, policymakers also can pass laws that make insulin prices more affordable. Working on both projects together has allowed me to explore insulin prices from multiple angles and each work contributed to improving the quality of the other. Additionally, researching insulin prices from multiple angles made me more passionate about the discrepancy in accessibility to life-saving products for those above and below the poverty line.

Thioredoxin reductase (TrxR) is an essential enzyme for regulating the redox balance in cells, promoting cell proliferation, and inhibiting cellular apoptosis. The biochemical pathway of TrxR metab...

PURPOSE As a characteristic of age-related macular degeneration (AMD), choroidal neovascularization (CNV) causes severe vision loss. The current treatment has limited efficacy. This study was to investigate effects of Salidroside against CNV and explore its underlying mechanisms. METHODS RF/6A cells were treated with 200 mM cobalt chloride (CoCl2) for 6 hr to mimic hypoxic condition. Cells were then treated with Salidroside at 10, 30 and 100 µM for 24 hr. Cells treated with DMSO were used as negative control. The cell proliferation was assessed using 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium-bromid assay. The tube formation was investigated on Matrigel. The cell migration was measured by a Transwell assay. RT-qPCR was used to detect the gene expression. Immuohistochemistry and western blot were used to detect the expression of proteins. RESULTS Salidroside significantly inhibited the cell migration and tube formation activity of RF/6A cells under hypoxia. Moreover, Salidroside reduced the expression levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1) in RF/6A cells. CONCLUSIONS Our data suggested that Salidroside could be a potential novel therapeutic agent against CNV.

The underlying mechanisms of E2F5 upregulation and its pro-tumor functions have not been elucidated in gastric cancer (GC). Here, the expression, prognostic value, mutation status, and promoter methylation of E2F5 were evaluated. The effects of E2F5 depletion on cell proliferation and invasion in GC, were also assessed through in vitro experiments. Additionally, gene set enrichment analysis (GSEA) was applied to analyze the potential downstream regulator of E2F5. The study also assessed the correlation and transcription regulation between E2F5 and UBE2T. Finally, the roles of UBE2T in E2F5-related pro-tumor functions were examined. The findings revealed that E2F5 was upregulated and showed remarkable association with pathological variables and prognosis. Hypomethylation of the E2F5 promoter predicted poor prognosis and partially caused E2F5 upregulation in GC. E2F5 knockdown significantly inhibited the proliferation and invasion of GC cells. E2F5 had a significant positive correlation with UBE2T in GC. Mechanistically, E2F5 promoted UBE2T transcription and UBE2T overexpression reversed the effects of E2F5 depletion on the proliferation and invasion of cells in GC. Taken together, this study originally confirmed the upregulation of E2F5 in GC, revealed that E2F5 can directly upregulate UBE2T transcription, and subsequently promote the malignant progression, which highlights that the E2F5/UBE2T axis can potentially be used in the diagnosis and treatment of GC.

Background: Glioblastoma (GBM) is the most common but lethal brain cancer with poor prognosis. The developing brain homeobox 2 (DBX2) has been reported to play important roles in tumor growth. However, the mechanisms of DBX2 in GBM are still unknown. Objective: This study aims to investigate the function and mechanisms of DBX2 in GBM. Methods: The expressions of DBX2 and REST in GBM were measured by analyzing data from databases, and the results were checked by qPCR and/or western blot of GBM cell lines. Cell proliferation was determined by CCK8 assay, immunohistochemistry and colony formation assay. ChIP-qPCR was used to determine the binding sites of DBX2 on REST. Results: In this study, we found that the expression of DBX2 was upregulated in the GBM cell lines. The cell proliferation was damaged after blocking DBX2 expression in U87 and U251 GBM cell lines. The expression level of DBX2 had a positive relationship with that of REST. Our ChIP-qPCR results showed that DBX2 is directly bound to the promoter region of REST. Additionally, the increased GBM cell proliferation caused by DBX2 overexpression can be rescued by REST loss of function. Conclusion: DBX2 could promote cell proliferation of GBM by binding to the promoter region of REST gene and increasing REST expression.

Background and Objective: Colorectal cancer (CRC) is the fourth leading cause of cancer- related death globally, with a high incidence rate in economically fast-growing countries. Sphingosine- 1-phosphate (S1P) is a bioactive lipid mediator that plays critical roles in cancer cell proliferation, migration, and angiogenesis converted by the isoforms of sphingosine kinase (SK1 and SK2). SK1 is highly expressed in colorectal cancer; its inhibitors suppress the formation of S1P and increase ceramide levels having a pro-apoptotic function. RB005 is a selective SK1 inhibitor and a structural analog of PP2A activator FTY720. The purpose of this study is to test whether RB005, an SK1 inhibitor, can be used as an anticancer agent by inhibiting the growth of colon cancer cells. Methods: We performed MTT and colony-forming assay using colon cancer cell lines HT29 and HCT116 cells to examine the cell toxicity effect of RB005. To determine whether apoptosis of RB005 in colon cancer cell line is due to SK1 inhibition or other mechanisms due to its structural similarity with FTY720, we conducted LC/MS, siRNA knockdown, and PP2A activity experiments. Results: RB005 notably inhibited CRC cell growth and proliferation compared to PF543 and ABC294640 by inducing the mitochondria-mediated intrinsic apoptotic pathway. Apoptotic cell death is caused by increased mitochondrial permeability Initiated by the activation of pro-apoptotic protein BAX, increased ceramides, and activation of PP2A. Also, RB005 treatment in HT29 cells did not change the expression level of SK1, but strikingly decreased SK1 activity and S1P levels. All these events of cell death and apoptosis were less effective when SK1 was knocked down by siRNA. Conclusion: This result indicates that RB005 shows the in-vitro anti-CRC effect by inhibiting SK1 activity and PP2A activation, increasing proapoptotic ceramide levels following the activation of the intrinsic apoptotic pathway.

The purpose of this study was to research the physiological roles of ubiquitin carboxyl-terminal esterase L1 (UCHL1) in head and neck squamous cell carcinoma (HNSCC).Ten HNSCC samples and matched normal oral mucosal tissues were collected. UCHL1 expression of these tissues was detected by the immunohistochemical staining and real-time quantitative polymerase chain reaction. The human HNSCC cell line HN6 UCHL1 knockout (UCHL1 KO) cell line was constructed using CRISPR/CAS9 gene editing and verified by western blotting. Wound healing assay, cell proliferation assay, cell invasion assay, and flow cytometric analysis of the cell cycle and apoptosis were applied to research the role of UCHL1 in HNSCC. Also, an RNAseq gene expression data set and HNSCC patient survival data from The Cancer Genome Atlas were analyzed.UCHL1 was highly expressed in HNSCC tissues compared with normal oral mucosal tissues (P = .032). A decreased proliferation (P.0001), migration (P.0001), and invasion (P = .0049) ability of HN6 cells was exhibited after knockout of UCHL1. However, HN6 UCHL1 KO cells showed no significant differences in the cell cycle or apoptosis. The progression, nodal metastasis status, and stage of HNSCC had a positive correlation with the expression of UCHL1.UCHL1 plays an important role in HNSCC, and we consider that targeting UCHL1 may be a feasible therapeutic strategy for HNSCC.

Clostridium acetobutylicum has been extensively exploited to produce biofuels and solvents and its biofilm could dramatically improve the productivities. However, genetic control of C. acetobutylicum biofilm has not been dissected so far. Here, to identify potential genes controlling C. acetobutylicum biofilm formation, over 40 gene candidates associated with extracellular matrix, cell surface, cell signaling or gene transcription, were tried to be disrupted to examine their individual impact. A total of 25 disruptants were finally obtained over years of attempts, for which biofilm and relevant phenotypes were characterized. Most of these disruptants formed robust biofilm still, or suffered both growth and biofilm defect. Only a strain with a disrupted histidine kinase gene (CA_C2730, designated bfcK in this study) abolished biofilm formation without impairing cell growth or solvent production. Further analysis revealed that bfcK could control flagellar biogenesis and cell motility at protein levels. The bfcK also appeared to repress the phosphorylation of a serine/threonine protein kinase (encoded by CA_C0404) that might negatively regulate biofilm formation. Based on these findings, possible bfcK-mediated mechanisms for biofilm formation were proposed. This is a big step toward understanding the biofilm formation in C. acetobutylicum and will help further engineering of its biofilm-based industrial processes.

Pomegranate is a fruit widely used in folk medicine. The positive effect of pomegranate peel on the skin wound healing process has been evaluated in various in vivo studies. The objective of the present study was to investigate the effect of pomegranate peel ethanolic-extract (PPE) on the proliferation and migration of human dermal fibroblast (HDF) cells, and also to evaluate levels of fibronectin1 (FN1) and cyclin B1 (CCNB1) genes expression and glycosaminoglycans (GAG) and collagen synthesis in these cells. The total phenolic content of PPE was determined using Folin-Ciocalteu method. Cultured HDF cells were exposed to different concentrations of PPE and the cell viability for HDF cells was assessed by MTT test, then the cell migration rate was determined using scratch-wounded test. Expression level of FN1 and CCNB1 genes and the amount of GAG and collagen were analyzed after 24 h, 48 h, and 72 h incubation with PPE. The value of total phenolic content of PPE was 80 ± 0.083 mg GAE/g. The MTT test and scratch assay showed that incubation with PPE at a concentration of 25 µg/ml for 24 h increased cell proliferation and migration (p˂0.05). FN1 gene expression was upregulated after 48 h exposure to PPE at 25 µg/ml (p˂0.05). GAG and collagen content increased after incubation with PPE at 25 µg/ml for 72 h (p˂0.05). These findings suggest that PPE promoted wound healing through increasing FN1 gene expression and extracellular matrix components including GAGs and collagen contents, and therefore can be considered as a therapeutic agent for wound healing.

Aim: To investigate the effects of SKA3 on cell proliferation and metastasis in non-small-cell lung cancer (NSCLC) and its underlying mechanism. Methods: Immunohistochemistry was employed to analyze the expression of SKA3 in NSCLC. CCK-8 assay, EdU assay, Transwell assay and flow cytometry analysis were employed to assess cell proliferation, metastatic potential and apoptosis in vitro, respectively. A lung metastasis model was used to evaluate metastasis of NSCLC cells in vivo. A luciferase reporter gene assay was conducted to verify the targeting relationship. Results: SKA3 exhibited high expression in NSCLC tissues and cells. Overexpression of SKA3 remarkably accelerated cell proliferation and metastasis and suppressed apoptosis of NSCLC cells and promoted lung metastasis in a mouse model. miR-128-3p repressed SKA3 expression by targeting it. Conclusion: miR-128-3p inhibited the progression of NSCLC through targeting SKA3.

Background: Dehydrocostus lactone (DEH), one of the sesquiterpene lactones, has shown extensive pharmaceutical activities, including anti-cancer activity. However, its effects on human esophageal squamous cell carcinoma (ESCC) cells are still unknown. Objective: To investigate the effect of DEH on ESCC cells and the underling molecular mechanisms. Method: The cell proliferation was tested using CCK-8 and colony formation assay. Apoptosis was analyzed by flow cytometry, hoechst staining and caspase-3 activity assay. Cell cycle was analyzed by flow cytometry. IL-6 (STAT3 activator) was used to activate JAK2/STAT3 pathway. Immunofluorescence assay was performed to detect intracellular location of STAT3. SiRNA transfection was performed to knock down the expression of PLK1. The protein expression was analyzed by western blotting assay. Result: DHE treatment significantly reduced the viability of ESCC cells through apoptosis induction and cell cycle arrest. Furthermore, DHE treatment significantly inhibited the phosphorylation of JAK2 and STAT3. IF assay showed that the distribution of STAT3 in the nucleus was decreased by DHE treatment. In addition, coculture with IL-6 significantly prevented the inhibition of phosphorylation of JAK2 and STAT3 by DHE treatment and partly reversed the effect of DHE on ESCC cells. Moreover, DHE treatment significantly down-regulated the expression of PLK1, which was partly reversed by IL-6 coculture. Finally, knock down of PLK1 using siRNA reduced the viability of ESCC cells and induced apoptosis and cell cycle arrest Conclusion: Our study demonstrated that DHE has a potent anti-cancer effect on ESCC cells through apoptosis induction and cell cycle arrest via JAK2/STAT3/PLK signaling pathway.

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. The Rac1-GTP inhibitor NSC23766 has been shown to suppress PCa growth. However, these therapies have low tumor-targeting efficacy in vivo. Therefore, it is essential to produce a drug delivery system that specifically targets the tumor site. Herein, novel L-phenylalanine-based poly(ester amide) (Phe-PEA) polymers were synthesized and loaded with NSC23766 (NSC23766@8P6 NPs), which had a small particle size (162.3±6.7 nm) and high NSC23766 loading (8.0±1.1%) with a more rapid release of NSC23766 at pH 5.0. In vitro cellular uptake and cytotoxicity assays demonstrated that NSC23766@8P6 NPs were rapidly taken up by PC3 cells and showed significant effects of PCa cell proliferation inhibition and G2/M phase arrest. Furthermore, in vivo studies using PC3-bearing mice demonstrated that NSC23766@8P6 NPs delivered by intravenous injection not only increased the drug concentration with prolonged retention (96 h) at the tumor site, but also inhibited tumor growth and induced apoptosis. In conclusion, we have discovered that NSC23766@8P6 NPs can serve as a delivery system that targets the tumor site and is therefore a promising therapeutic approach for PCa treatment.

Regenerative medicine uses undifferentiated adipose-derived mesenchymal stem cells (ADMSCs) to differentiate into multiple cell types. Photobiomodulation (PBM) is a rapidly growing treatment for pain and inflammation reduction, as well as tissue healing. PBM's efficacy is dependent on wavelength and energy dosage. Red (600–700 nm) and near-infrared (780–1100 nm) wavelengths have been shown to promote cell proliferation. Light wavelengths such as green (495 nm–570 nm) have been found to influence ADMSC differentiation. The initiation of ADMSC proliferation and differentiation requires physiologically relevant levels of reactive oxygen species (ROS), while increased levels inhibit self-renewal. Stem cell differentiation is guided by mitochondrial metabolism, where an increased mitochondrial membrane potential (MMP) is associated with higher in vitro differentiation capacity. ADMSCs must home to and accumulate at the sites of injury in regenerative medicine, so cell homing is critical. The aim of this in vitro study was to compare consecutive NIR (825 nm) and green (525 nm) applications on ADMSC morphology and physiology with the possibility that multiple wavelengths could lead to a combination of the two effects. The results showed that concurrent use of NIR-green irradiation significantly stimulated ADMSC proliferation, increasing population density and cellular ATP. Furthermore, NIR-green showed a time dependent increase in ROS production and was significantly higher at 7 days. Consecutive NIR-green irradiation significantly increased MMP and was most effective at facilitating ADMSC migration over time. Findings suggest that with consecutive NIR and green irradiation, the ADMSCs can rapidly proliferate, but can also be modulated for regenerative purposes.

Mushrooms, both edible and medicinal have received considerable attention against cancer due to their polysaccharides, polysaccharides-protein complexes and low molecular weight secondary metabolites content. Every year, millions of people die because of this disease. Existing cancer therapies are poised with questions of efficacy, toxicity and adverse effects, hence justifying the search for finding new, alternative and efficient means to fend off the disease. Mushrooms and their derived active molecules can prevent oncogenesis and tumour metastasis via directly inhibiting tumour cells growth or indirectly improving immunity functions and by acting as chemotherapy adjuvants. While the mechanisms of such effects are not fully known, the roles of the bioactive compounds on cell signaling pathways involved in the promotion and progression of the disease appear to be key, particularly in view of their role(s) in multiple cellular processes, including cell survival, proliferation, and differentiation. This review discusses the aberrant cell signaling pathways involved in inhibition of tumour cell growth as target for mushrooms and their bioactive compounds as well as the associated challenges for the molecules therein to be successfully considered as preventive/therapeutic agents against cancer.

Background: Fomitopsis officinalis (Vill. ex Fr. Bond. et Sing) is a medicinal mushroom, commonly called ‘Agarikon’; it has traditionally been used to treat cough and asthma in the Mongolian population. Objective: The objective of the study was to examine the significance of biological activity of F. officinalis and evaluation of the antioxidant activity and anticancer activity of six fractions of F. officinalis residues (Fo1-powder form dissolved in ethanol, Fo2-petroleum ether residue, Fo3-chloroformic, Fo4-ethylacetate, Fo5-buthanolic, and Fo6-waterethanolic) against hepatocellular carcinoma cells. Methods: We performed in vitro studies of cell proliferation and viability assay, annexin V-FITC/Propidium Iodide assay, and NF-kB signaling pathway by immunoblot analysis. Results: Our findings revealed that all six fractions/extracts have antioxidant activity, and somehow, they exert anticancerous effects against cancer cells. In cancerous cell lines (HepG2 and LO2), Fo3 chloroformic extract promoted the cancer cell apoptosis and cell viability, activated G2/M-phase cell cycle, and selectively induced NF-kB proteins, revealing as a novel antitumor extract. Conclusion: This study reports that Fo3-chloroformic extract is rich in antitumor activity, which was previously not investigated in cancer. To develop the impact of F. officinalis among natural products to treat/prevent oxidative stress disorders or cancers, further examinations of F. officinalis are needed to develop new natural drugs to treat cancer. However, this study assessed only one extract, Fo3-chloroformic, which has a significant impact against cancer cell lines.

Background: Colon cancer is one of the most common types of cancer worldwide. Multiple studies have unveiled the key role of microRNAs (miRNAs) in the development of various types of cancer. However, the mechanism of action of miR-125b in the development and progression of colon cancer remains unknown. Objective: In this study, we explored the association of miR-125b and signal transducer and activator of transcription 3 (STAT3) and its role in the proliferation and apoptosis of SW480 colon cancer cells. Methods: The miR-125b expression in NCM460, SW480, HT29, and HCT8 cells was detected using quantitative real-time polymerase chain reaction (qRT-PCR). SW480 cells were transfected with lentiviruses of GFP-miR-125b and GFP-NC to establish a stable miR-125b overexpression colon cancer cell model and a control model. The targeting relationship between miR-125b and STAT3 was analyzed using bioinformatics and verified by the dual-luciferase reporter gene assay. Cell proliferation and apoptosis were assessed using the Cell Counting Kit-8 assay and TUNEL staining. The expression levels of STAT3, Bcl-2, and Bax were analyzed using Western blot analysis. Results: It was found that the relative mRNA expression of miR-125b was decreased in SW480, HT29, and HCT8 cells compared with that in NCM460 cells (P Conclusion: The miR-125b regulates the expression of Bax and Bcl-2 by downregulating the expression of STAT3, thereby inhibiting proliferation and inducing apoptosis of SW480 colon cancer cells.

Background Long non-coding RNA small nucleolar RNA host gene 8 (SNHG8) has been found correlated with cancer progression. This work was aimed to investigate the functions of SNHG8 in ovarian cancer (OC). Methods Expression level of SNHG8 in OC tissues and cells was analyzed using real time-quantitative polymerase chain reaction (RT-qPCR) method. The biological roles of SNHG8 in OC were analyzed through proliferation assay, wound healing assay, and transwell invasion assay. Furthermore, interactions of SNHG8 or S100 calcium binding protein A11 (S100A11) and microRNA-1270 (miR-1270) were explored. Moreover, the effects of SNHG8, miR-1270, and S100A11 on the overall survival of OC patients were investigated. Results SNHG8 has increased expression in OC tissues and cells compared with normal counterparts, and correlated with poorer overall survival of OC patients. OC cell proliferation, migration, and invasion abilities were enhanced by SNHG8 overexpression but inhibited by its knockdown. In addition, we showed that SNHG8 regulates OC progression through targeting the miR-1270 and S100A11. Conclusions Our work indicated that SNHG8 regulates OC progression through miR-1270/S100A11 axis, which may provide novel therapeutic targets for OC.

Background: Despite emerging research on new treatment strategies, chemotherapy remains one of the most important therapeutic modalities for cancers. Imidazopyridines are important targets in organic chemistry and, given their numerous applications, they are worthy of attention. Objective: The objective of this study was to design and synthesize a novel series of imidazo[1,2-a]pyridine-derived compounds and investigate their antitumor effects and the underlying mechanisms. Methods: Imidazo[1,2-a]pyridine-derived compounds were synthesized with new strategies and conventional methods. The antitumor activities of the new compounds were evaluated by MTT assay. Flow cytometry and immunofluorescence were performed to examine the effects of the most effective antiproliferative compound on cell apoptosis. Western blot analysis was used to assess the expression of apoptotic proteins. Results: Fifty-two new imidazo[1,2-a]pyridine compounds were designed and successfully synthesized. The compound, 1-(imidazo[1,2-a]pyridin-3-yl)-2-(naphthalen-2-yl)ethane-1,2-dione, named La23, showed high potential for suppressing the viability of HeLa cells (IC50 15.32 μM). La23 inhibited cell proliferation by inducing cell apoptosis, and it reduced the mitochondrial membrane potential of HeLa cells. Moreover, treatment with La23 appeared to increase the expression of apoptotic-related protein P53, Bax, cleaved caspase-3, and cytochrome c at a low concentration range. Conclusion: The novel imidazo[1,2-a]pyridine compound, La23, was synthesized and it suppressed cell growth by inducing cell apoptosis via the p53/Bax mitochondrial apoptotic pathway.

BRM-associated factor (BAF) 60c promotes muscle glycolysis and improves glucose homeostasis. This study explored the mechanism of BAF60c in heart failure (HF). Fetal/adult rat models of HF were established, and the levels of cardiac contractile proteins and energy metabolism-, oxidative metabolism- and glycolysis-related factors were detected. Overexpression/siRNA BAF60c plasmids were injected into adult HF rats to estimate myocardial glucose uptake, high-energy phosphate contents, mitochondrial function, and cell proliferation and apoptosis. The overexpression/siRNA BAF60c plasmids were transfected into cardiac hypertrophic H9C2 cells to explore the in vitro effects. The interaction of BAF60c and PGC1α was detected. The results suggested that adult HF rats presented increased levels of fetal proteins (ssTnI and fTnT), BAF60c and glycolysis-related factors, and reduced levels of cardiac contractile proteins, PGC1α, PPARα, and oxidative metabolism-related factors. BAF60c knockdown improved glucose uptake, maintained the oxidative metabolism/glycolysis balance, promoted H9C2 cell proliferation, and inhibited apoptosis. PGC1α interacted with BAF60c. Knocking down BAF60c also activated the PGC1α/PPARα/mTOR pathway. Overexpression of PGC1α decreased the damage to H9C2 cells caused by BAF60c. Altogether, BAF60c downregulation activated the PGC1α/PPARα/mTOR pathway, maintained the oxidative metabolism/glycolysis balance and improved mitochondrial function in rat models of HF. This study may offer novel insights into HF treatment.

Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by BCR-ABL oncoprotein. Tyrosine kinase inhibitors have been developed to inhibit the activity of BCR-ABL; however, drug resistance and side effect occur in clinic application. Therefore, it is urgent to find novel drugs for CML treatment. Under the guidance of cytotoxic activity, crude extracts of 55 fungal strains from the medicinal mangrove Acanthus ilicifolius were evaluated, and one potent cytotoxic natural compound, brefeldin A (BFA), was discovered from Penicillium sp. (HS-N-29). Objective: This study was aimed to determine the cytotoxic activity of BFA and the effect on the activation and expression of BCR-ABL in K562 cells. Method: We evaluated cytotoxic activity by MTT assay and soft agar clone assay; apoptosis and cell cycle distribution by Muse cell analyzer. The protein level of BCR-ABL and signaling molecules was detected by western blotting, and the mRNA level of BCR-ABL was determined by RT-PCR. Results: BFA inhibited cell proliferation, induced G2/M cell cycle arrest, and stimulated cell apoptosis in K562 cells. Importantly, for the first time, we revealed that BFA inhibited the activation of BCR-ABL and consequently inhibited the activation of its downstream signaling molecules in K562 cells. Moreover, we found BFA degraded BCR-ABL without affecting its transcription in K562 cells, and BFA-induced BCR-ABL degradation was related to caspase activation, while not to autophagy or ubiquitinated proteasome degradation pathway. Conclusion: Our present results indicate that BFA acts as a dual functional inhibitor and degrader of BCR-ABL, and BFA is a potential compound for chemotherapeutics to overcome CML.

Objective Recently, fibulin-1 (FBLN1) has been shown to be downregulated in various cancers via promoter hypermethylation. Our study aimed to determine the expression and methylation status of FBLN1 in tongue squamous cell carcinoma (TSCC) tissues and cells. Methods Methylation-specific PCR was implemented to detect the methylation status of the FBLN1 gene in TSCC tissues and Western blot analysis was used to detect the expression of FBLN1 protein. The human TSCC cell lines, CAL27 and SCC9, were cultured in vitro and treated with 5-aza-deoxycytidine (5-Aza-dC). CCK-8, colony formation, and Transwell assays were performed to test TSCC cell proliferation, migration, and invasion following 5-Aza-dC treatment or overexpression of FBLN1, which was further verified in in vivo experiments. Results FBLN1 was hypermethylated and the protein expression was reduced in TSCC tissues. After human TSCC cell lines (CAL27 and SCC9) were treated with 5-Aza-dC or overexpressed FBLN1, FBLN1 expression was upregulated and the TSCC cell proliferation, migration, and invasion abilities were suppressed. In vivo experiments further showed that demethylation or overexpression of FBLN1 slowed tumor growth in nude mice. Conclusion This study demonstrated that 5-Aza-dC treatment or overexpression of FBLN1 inhibited the growth of human TSCC.

Background Systematic and local factors give various effects to teeth during odontogenesis or after eruption. Discoloration of teeth is also caused by systematic and local factors and sometimes leads to esthetic and biological problems. Bilirubin is the product of heme metabolism and causes greenish discoloration and hypodontia with its high concentration in blood. Objective This review aimed to indicate effects of bilirubin on odontogenesis with in vitro model established by stem cells of human exfoliated deciduous teeth (SHED). Results Recent studies showed that bilirubin suppressed cell proliferation and promoted cell death in SHED with alteration of their involved-signaling pathways. In addition, it was indicated that pamidronate recovered bilirubin-altered signaling pathways and bilirubin-impaired dentinogenic function of SHED. Conclusion SHED could be tool to established human in vitro model to elucidate human pathogenesis and for screening to pick up the candidates of medicines.

Background:Survival and progression of cancer cells are highly dependent on aerobic glycolysis. Strobilanthes crispus has been shown to have promising anticancer effects on breast cancer cells. The involvement of the glycolysis pathway in producing these effects is unconfirmed, thus further investigation is required to elucidate this phenomenon.Objective:This study aims to determine the effect of S. crispus active fraction (F3) and its bioactive components on glycolysis in triple-negative breast cancer cells (MDA-MB-231).Methods:This study utilizes F3, lutein, β-sitosterol, and stigmasterol to be administered in MDA-MB-231 cells for measurement of antiglycolytic activities through cell poliferation, glucose uptake, and lactate concentration assays. Cell proliferation was assessed by MTT assay of MDA-MB-231 cells after treatment with F3 and its bioactive components lutein, β-sitosterol, and stigmasterol. The IC50 value in each compound was determined by MTT assay to be used in subsequent assays. The determination of glucose uptake activity and lactate concentration were quantified using fluorescence spectrophotometry.Results:Antiproliferative activities were observed for F3 and its bioactive components, with IC50 values of 100 μg/mL (F3), 20 μM (lutein), 25 μM (β-sitosterol), and 90 μM (stigmasterol) in MDA-MB-231 cells at 48 h. The percentage of glucose uptake and lactate concentration in MDA-MB-231 cells treated with F3, lutein, or β sitosterol were significantly lower than those observed in the untreated cells in a time-dependent manner. However, treatment with stigmasterol decreased the concentration of lactate without affecting the glucose uptake in MDA-MB-231 cells.Conclusion:The antiglycolytic activities of F3 on MDA-MB-231 cells are attributed to its bioactive components.

Background: Triple Negative Breast Cancer (TNBC) is considered as the most deadly subtype of breast cancer, because of heterogeneity, less treatment options and resistance to chemotherapy. Objective: To find out an efficient chemotherapeutic options, in this study we have investigated the combined therapy of 5-Fluorouracil (5-FU) and thymoquinone (TQ) against TNBC cell lines BT-549 and MDA-MB-231. Methods: We have tested 5-FU and TQ alone and in combination (5-FU + TQ) to observe the cellular growth, cell cycle and apoptosis status of BT-549 and MDA-MB-231 cells. Also we have measured the mRNA level expression of genes related to cell cycle and apoptosis. Results: Experimental results suggest that both of 5-FU and TQ are effective in controlling cell growth, cell cycle and inducing apoptosis, but their combination is much more effective. 5-FU was found to be more effective in controlling cell growth, while TQ was found to be more effective in inducing apoptosis, but in both cases, their combination was most effective. TQ was found more effective in increasing and BAX/BCL-2 ratio, while 5-FU was more effective in inhibiting thymidylate synthase. They showed significant increasing effects on caspases and P53 and decreasing effect on CDK-2, where their combination was found most effective. Conclusions: Thus, TQ and 5-FU probably showed synergistic effect on both of cell cycle and apoptosis of tested TNBC cell lines. Our study reveals that TQ can synergise 5-FU action, and increase its anticancer efficiency against TNBC cells, which might be good choice in drug development for TNBC treatment.

Background: Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancer (BC) cases and is a severe type of BC. Since medicinal herbs containing biocompatible substances that are accepted by patient more than chemical therapeutics, they can be considered a safe option for treating BC. Objective: This study evaluated the effect of Sambucus Ebulus (S. ebulus) extract on a model of TNBC. Methods: S. ebulus extract was prepared using petroleum ether, ethyl acetate, and methanol. The petroleum ether extract was fractionated and analyzed using vacuum liquid chromatography and GC-MS, respectively. MDAMB- 231 and MCF-10A were used as TNBC and normal breast cells, respectively. Flowcytometry and MTT assays were performed to evaluate cell cycle, apoptosis, and viability of the cells. Gene expression analysis was performed using RT-qPCR. Nude mouse allograft tumor models were used, and pathological sections were evaluated. Results: The findings indicated that S. ebulus extract remarkably decreased cell proliferation and viability. The extract had no toxicity to the normal breast cells but efficiently killed the cancer cells. Cell cycle- and apoptosisrelated gene expression showed that fraction 4 of S. ebulus extract significantly increased the expression of Bax, Bak, P53, and c-MYC. Conclusion: This study showed satisfactory results of the effect of S. ebulus extract on clearing BC cells both in vitro and in vivo. Thus, S. ebulus extract may be a safe herbal compound for eliminating BC cells without toxicity to host cells.