The emerging roles of long non-coding RNA (lncRNA) H19 in gynecologic cancers.

Long non-coding RNA (lncRNA) H19 has gained significant recognition as a pivotal contributor to the initiation and advancement of gynecologic cancers, encompassing ovarian, endometrial, cervical, and breast cancers. H19 exhibits a complex array of mechanisms, demonstrating dualistic effects on tumorigenesis as it can function as both an oncogene and a tumor suppressor, contingent upon the specific context and type of cancer being investigated. In ovarian cancer, H19 promotes tumor growth, metastasis, and chemoresistance through modulation of key signaling pathways and interaction with microRNAs. Conversely, in endometrial cancer, H19 acts as a tumor suppressor by inhibiting proliferation, inducing apoptosis, and regulating epithelial-mesenchymal transition. Additionally, H19 has been implicated in cervical and breast cancers, where it influences cell proliferation, invasion, and immune evasion. Moreover, H19 has potential as a diagnostic and prognostic biomarker for gynecologic cancers, with its expression levels correlating with clinical parameters and patient outcomes. Understanding the functional roles of H19 in gynecologic cancers is crucial for the development of targeted therapeutic strategies and personalized treatment approaches. Further investigation into the intricate molecular mechanisms underlying H19's involvement in gynecologic malignancies is warranted to fully unravel its therapeutic potential and clinical implications. This review aims to elucidate the functional roles of H19 in various gynecologic malignancies.

Different expression of DACT1, DACT2, and CYCLIN D1 genes in human colorectal cancer tissues and its association with clinicopathological characteristics.

Aberrant activation of Wnt pathway is linked to dysregulation of several genes. DACT1 and DACT2 are members of the DACT family that participate in antagonizing of the Wnt signaling cascade. Thus in this study, we assessed the mRNA levels of DACT1, DACT2, and CYCLIN D1 in 70 pairs of CRC tissues compared to the adjacent tissues. Determination of the mRNA levels of DACT1, DACT2, and CYCLIN D1 was done by Quantitative Real-Time PCR (qRT-PCR). The correlation between DACT1, DACT2, and CYCLIN D1 genes was also examined. Receiver operating characteristic (ROC) curves was plotted to assess the diagnostic power. The association between histopathological parameters and the DACT1, DACT2, and CYCLIN D1 genes was investigated. The expression levels of DACT1 and CYCLIN D1 were remarkably higher in CRC tissues compared to the adjacent tissues (p < 0.0001). However, the expression of DACT2 was decreased (p < 0.001). Our results showed a significant correlation between the expression of DACT1 and CYCLIN D1 (p < 0.0001). DACT1 (AUC = 0.74, p < 0.0001), DACT2 (AUC = 0.69, p < 0.0003), and CYCLIN D1 (AUC = 0.75, p < 0.0001) had good effectiveness in separation between CRC samples and adjacent tissues. We found a significant association between DACT1 expression with tumor site (p < 0.01). Also, a significant association was detected between DACT2 and CYCLIN D1 with tumor stage (p < 0.005 and p < 0.038, respectively). The findings suggested that DACT1 could function as an oncogene, whereas DACT2 was downregulated and can be considered as a tumor suppressor in CRC.

Emerging roles of long non-coding RNA FTX in human disorders

Long non-coding RNAs (lncRNAs) are involved the progression of cancerous and non-cancerous disorders via different mechanism. FTX (five prime to xist) is an evolutionarily conserved lncRNA that is located upstream of XIST and regulates its expression. FTX participates in progression of various malignancy including gastric cancer, glioma, ovarian cancer, pancreatic cancer, and retinoblastoma. Also, FTX can be involved in the pathogenesis of non-cancerous disorders such as endometriosis and stroke. FTX acts as competitive endogenous RNA (ceRNA) and via sponging various miRNAs, including miR-186, miR-200a-3p, miR-215-3p, and miR-153-3p to regulate the expression of their downstream target. FTX by targeting various signaling pathways including Wnt/β-catenin, PI3K/Akt, SOX4, PDK1/PKB/GSK-3β, TGF-β1, FOXA2, and PPARγ regulate molecular mechanism involved in various disorders. Dysregulation of FTX is associated with an increased risk of various disorders. Therefore, FTX and its downstream targets may be suitable biomarkers for the diagnosis and treatment of human malignancies. In this review, we summarized the emerging roles of FTX in human cancerous and non-cancerous cells (AU)

Small extracellular vesicles - A host for advanced bioengineering and "Trojan Horse" of non-coding RNAs.

Small extracellular vesicles (sEVs) are a type of membranous vesicles that can be released by cells into the extracellular space. The relationship between sEVs and non-coding RNAs (ncRNAs) is highly intricate and interdependent. This symbiotic relationship plays a pivotal role in facilitating intercellular communication and holds profound implications for a myriad of biological processes. The concept of sEVs and their ncRNA cargo as a "Trojan Horse" highlights their remarkable capacity to traverse biological barriers and surreptitiously deliver their cargo to target cells, evading detection by the host-immune system. Accumulating evidence suggests that sEVs may be harnessed as carriers to ferry therapeutic ncRNAs capable of selectively silencing disease-driving genes, particularly in conditions such as cancer. This approach presents several advantages over conventional drug delivery methods, opening up new possibilities for targeted therapy and improved treatment outcomes. However, the utilization of sEVs and ncRNAs as therapeutic agents raises valid concerns regarding the possibility of unforeseen consequences and unintended impacts that may emerge from their application. It is important to consider the fundamental attributes of sEVs and ncRNAs, including by an in-depth analysis of the practical and clinical potentials of exosomes, serving as a representative model for sEVs encapsulating ncRNAs.

The oncogenic role of SAMMSON lncRNA in tumorigenesis: A comprehensive review with especial focus on melanoma.

LncRNA Survival Associated Mitochondrial Melanoma Specific Oncogenic Non-coding RNA (SAMMSON) is located on human chromosome 3p13, and its expression is upregulated in several tumours, including melanoma, breast cancer, glioblastoma and liver cancer and has an oncogenic role in malignancy disorders. It has been reported that SAMMSON impacts metabolic regulation, cell proliferation, apoptosis, EMT, drug resistance, invasion and migration. Also, SAMMSON is involved in regulating several pathways such as Wnt, MAPK, PI3K, Akt, ERK and p53. SAMMSON is considered a potential diagnostic and prognostic biomarker in several types of cancer and a suitable therapeutic target. In addition, the highly expressed SAMMSON is closely associated with clinicopathological features of various cancers. SAMMSON has a significant role in regulating epigenetic processes by regulating histone protein or the status of DNA methylation. Herein for the first time, we comprehensively summarized the currently available SAMMSON, molecular regulatory pathways, and clinical significance. We believe that clarifying all the molecular aspects of this lncRNA can be a good guide for cancer studies in the future.

A review on the biological roles of LncRNA PTCSC3 in cancerous and non-cancerous disorders.

Long non-coding RNA papillary thyroid carcinoma susceptibility candidate 3 (LncRNA PTCSC3) is located on human chromosome 14q13.3. PTCSC3 functions as a tumor suppressor lncRNA to regulate essential cellular processes such as apoptosis, cell proliferation, migration, invasion, angiogenesis, and epithelial-to-mesenchymal transition. PTCSC3 is also involved in the regulation of the Wnt/ß-catenin signaling pathway, aerobic glycolysis, and p53 pathways. Downregulation of PTCSC3 has been associated with an increased risk of many tumors such as thyroid, gastric, laryngeal, breast, cervical, oral, lung, and glioma cancers. In addition, dysregulation of PTCSC3 has been reported in non-cancerous disorders notably osteoporosis and periodontitis. However, a number of single nucleotide polymorphisms at PTCSC3 have been linked to a higher risk of human diseases. This literature review summarizes the diagnostic, prognostic, and the clinical value of abnormal expression of PTCSC3 in cancerous and non-cancerous disorders and comprehensively analyzes potential molecular regulatory mechanism related to PTCSC3, which is expected to provide clear guidance for future PTCSC3 research.

Emerging roles of long non-coding RNA FTX in human disorders.

Long non-coding RNAs (lncRNAs) are involved the progression of cancerous and non-cancerous disorders via different mechanism. FTX (five prime to xist) is an evolutionarily conserved lncRNA that is located upstream of XIST and regulates its expression. FTX participates in progression of various malignancy including gastric cancer, glioma, ovarian cancer, pancreatic cancer, and retinoblastoma. Also, FTX can be involved in the pathogenesis of non-cancerous disorders such as endometriosis and stroke. FTX acts as competitive endogenous RNA (ceRNA) and via sponging various miRNAs, including miR-186, miR-200a-3p, miR-215-3p, and miR-153-3p to regulate the expression of their downstream target. FTX by targeting various signaling pathways including Wnt/ß-catenin, PI3K/Akt, SOX4, PDK1/PKB/GSK-3ß, TGF-ß1, FOXA2, and PPARγ regulate molecular mechanism involved in various disorders. Dysregulation of FTX is associated with an increased risk of various disorders. Therefore, FTX and its downstream targets may be suitable biomarkers for the diagnosis and treatment of human malignancies. In this review, we summarized the emerging roles of FTX in human cancerous and non-cancerous cells.

Conversion of antibacterial quinolone drug levofloxacin to potent cytotoxic agents.

Levofloxacin, the optical S-(-) isomer of ofloxacin, is a broad-spectrum antibacterial agent widely used to control various infections caused by Gram-positive and Gram-negative bacteria. While the COOH group is necessary for antibacterial activity, its modification can offer anticancer activity to the fluoroquinolone framework. Therefore, several levofloxacin carboxamides 11a-j and 12 containing 5-substituted-1,3,4-thiadiazole residue were synthesized and screened in vitro for their anticancer activity. The in vitro MTT viability assay revealed that the most compounds had significant activity against cancer cells MCF-7, A549, and SKOV3. In particular, the 3-chloro- and 4-fluoro- benzyl derivatives (11b and 11h), with IC50 values of 1.69-4.76 µM were as potent as or better than doxorubicin. It should be noted that the mother quinolone levofloxacin showed no activity on the tested cancer cell lines. The SAR analysis demonstrated that the 3-chloro or 4-fluoro substituent on the S-benzyl moiety had positive effect on the activity. Further in vitro evaluations of the most promising compounds 11b and 11h by flow cytometric analysis and comet test revealed the ability of compounds in the induction of apoptosis and blockage of the cell proliferation at the G1-phase by nuclear fragmentation and DNA degradation in cancer cells. The obtained results demonstrated that the alteration of 6-COOH functional group in the levofloxacin structure and conjugation with a proper heterocyclic pharmacophore is a good strategy to obtain new anticancer agents.

Functional roles of lncRNA-TUG1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) or hepatoma is malignant cancer that starts from the main liver cells. Although various classical methods have been used for patients with HCC, various molecular mechanisms involved in HCC progression should be invested. Previous studies demonstrated that abnormal expression of long non-coding RNAs (lncRNAs) presented important roles in the pathogenesis of HCC cells. LncRNA TUG1 was found to mediate HCC cell growth, EMT, and metastasis. Therefore, targeting TUG1 and its downstream genes may be a suitable approach for patients with HCC. In this review, we summarized the potential roles of TUG1 in HCC.

Downregulation of NRARP exerts anti-tumor activities in the breast tumor cells depending on Wnt/ß-catenin-mediated signals: The role of miR-130a-3p.

The Notch-regulated ankyrin repeat protein (NRARP) functions as a molecular link between Notch and Wnt signaling pathways. Although it has recently been identified to be overexpressed in breast cancer (BC), the molecular mechanisms that regulate NRARP remain unknown. Since microRNAs (miRNAs) regulate gene expression post-transcriptionally, miRNA dysregulation could explain the abnormal gene expression. Here, we identified miR-130a-3p as an NRARP regulator and evaluated its effects on the behavior of BC cells. Quantitative real-time PCR was performed to assess the transcriptional levels of miR-130a-3p and NRARP in BC cells. Next, miR-130a-3p was transiently transfected into BC cells to assess its influence on NRARP expression. Owing to the positive regulatory effects of NRARP on the Wnt/ß-catenin signaling pathway, we also analyzed the expression levels of five Wnt/ß-catenin pathway genes and one downstream target gene in BC cells. We then assessed anti-tumor activities of miR-130a-3p in BC cells using the MTT proliferation assay, the soft agar colony formation assay for anchorage-independent growth (AIG), as well as scratch and transwell assays for cell migration. The results showed that miR-130a-3p was downregulated in BC cells, whereas NRARP was upregulated. Overexpression of miR-130a-3p inhibited the expression of NRARP and some Wnt/ß-catenin signaling pathway genes, as well as exerted anti-tumor effects as evidenced by decreased cell proliferation, AIG, and migration of BC cells. In conclusion, the tumor-suppressive function of miR-130a-3p in BC may be mediated by inhibiting NRARP and Wnt/ß-catenin signaling pathway. As a result, miR-130a-3p could be introduced as a therapeutic target for miRNA therapy in BC.

Long non-coding RNA MIR4435-2HG: a key molecule in progression of cancer and non-cancerous disorders.

MIR4435-2HG (LINC00978) is a long non-coding RNA (lncRNA) that acts as an oncogene in almost all cancers. This lncRNA participates in the molecular cascades involved in other disorders such as coronary artery diseases, osteonecrosis, osteoarthritis, osteoporosis, and periodontitis. MIR4435-2HG exerts its functions via the spectrum of different mechanisms, including inhibition of apoptosis, sponging microRNAs (miRNAs), promoting cell proliferation, increasing cell invasion and migration, and enhancing epithelial to mesenchymal transition (EMT). MIR4435-2HG can regulate several signaling pathways, including Wnt, TGF-ß/SMAD, Nrf2/HO-1, PI3K/AKT, MAPK/ERK, and FAK/AKT/ß­catenin signaling pathways; therefore, it can lead to tumor progression. In the present review, we aimed to discuss the potential roles of lncRNA MIR4435-2HG in developing cancerous and non-cancerous conditions. Due to its pivotal role in different disorders, this lncRNA can serve as a potential biomarker in future investigations. Moreover, it may serve as a potential therapeutic target for the treatment of various diseases.

Long noncoding RNA LINC00978 acts as a potential diagnostic biomarker in patients with colorectal cancer.

Colorectal cancer (CRC) as a lethal malignancy has been associated with dysregulation of several genes and pathways. Long noncoding RNAs (lncRNAs) play an important role in gene expression regulation. In the current research, we aim to evaluate the expression of LINC00978 in CRC samples and adjacent tissues. Using Quantitative Real-Time PCR (qRT-PCR) method, we assessed the expression levels of LINC00978 and ß-catenin in 70 pairs of CRC and adjacent tissues. Moreover, the association between clinicopathological features and the LINC00978 expression levels was investigated. To assess the diagnostic power of LINC00978 expression in CRC, receiver operating characteristic (ROC) curve was plotted. The relationship between LINC00978 and ß-catenin expression levels was evaluated using correlation analysis. A markedly increased level of LINC00978 and ß-catenin expression levels was observed in CRC samples compared with adjacent tissues (P < 0.0001). No significant association was detected between LINC00978 expression level and the patient's clinicopathological features. The results of Pearson's correlation coefficient highlighted a positive correlation between LINC00978 and ß-catenin expression (r2 = 0.4695, P < 0.0001). According to the area under curve (AUC) value, LINC00978 expression differentiates CRC samples from the adjacent tissues (AUC = 0.81, P < 0.0001). The present results suggest that LINC00978 may play a critical role in CRC progression via Wnt pathway. The potential role of LINC00978 as a diagnostic biomarker needs to be further investigated in future studies.

Synthesis, in silico, in vitro and in vivo evaluations of isatin aroylhydrazones as highly potent anticonvulsant agents.

In this study, a series of new isatin aroylhydrazones (5a-e and 6a-e) was synthesized and evaluated for their anticonvulsant activities. The (Z)-configuration of compounds was confirmed by 1H NMR. In vivo studies using maximal electroshock (MES) and pentylenetetrazole (PTZ) models of epilepsy in mice revealed that while most of compounds had no effect on chemically-induced seizures at the higher dose of 100 mg/kg but showed significant protection against electrically-induced seizures at the lower dose of 5 mg/kg. Certainly, N-methyl analogs 6a and 6e were found to be the most effective compounds, displaying 100% protection at the dose of 5 mg/kg. Protein binding and lipophilicity(logP) of the selected compounds (6a and 6e) were also determined experimentally. In silico evaluations of title compounds showed acceptable ADME parameters, and drug-likeness properties. Distance mapping and docking of the selected compounds with different targets proposed the possible action of them on VGSCs and GABAA receptors. The cytotoxicity evaluation of 6a and 6e against SH-SY5Y and Hep-G2 cell lines indicated safety profile of compounds on the neuronal and hepatic cells.

Contribution of long noncoding RNA HOTAIR variants to preeclampsia susceptibility in Iranian women.

Objective: To investigate the possible association of lncRNA HOTAIR rs920778 and rs874945 polymorphisms with preeclampsia risk in a sample from the Iranian population. Method: The study subjects included 250 preeclamptic women and 250 healthy women. The genotyping for rs920778 and rs874945 polymorphisms were performed using the TP-ARMS-PCR method. Results: HOTAIR rs920778 increased the risk of preeclampsia under the dominant and recessive inheritance patterns (OR = 4.84, 95% CI: 3.30-7.10, P < 0.0001; OR = 6.86, 95% CI: 3.51-13.42, P < 0.0001; respectively). Conclusion: This study confirmed the association of HOTAIR rs920778 polymorphism with preeclampsia in Iranian women. Further studies should be performed to confirm our findings.

Synthesis and biological assessment of ciprofloxacin-derived 1,3,4-thiadiazoles as anticancer agents.

The quinolone-3-carboxylic acid scaffold is essential structure for antibacterial activity of fluoroquinolones such as ciprofloxacin. Modification of 3-carboxylic functionality in this structure can be used for switching its activity from antibacterial to anticancer. Accordingly, a series of C-3 modified ciprofloxacin derivatives containing N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-carboxamide moiety was synthesized as novel anticancer agents. Most of compounds showed significant activity against MCF-7, A549 and SKOV-3 cancer cells in the MTT assay. In particular, compounds 13a-e and 13g were found to be as potent as standard drug doxorubicin against MCF-7 cell line (IC50s = 3.26-3.90 µM). Furthermore, the 4-fluorobenzyl derivatives 13h and 14b with IC50 values of 3.58 and 2.79 µM exhibited the highest activity against SKOV-3 and A549 cells, being as potent as doxorubicin. Two promising compounds 13e and 13g were further tested for their apoptosis inducing activity and cell cycle arrest. Both compounds could significantly induce apoptosis in MCF-7 cells, while compound 13e was more potent apoptosis inducer resulting in an 18-fold increase in the proportion of apoptotic cells at the IC50 concentration in MCF-7 cells. The cell cycle analysis revealed that compounds 13e and 13g could increase cell portions in the sub-G1 phase, inducing oligonucleosomal DNA fragmentation and apoptosis confirmed by comet assay.

New thiazole-2(3H)-thiones containing 4-(3,4,5-trimethoxyphenyl) moiety as anticancer agents.

A new series of thiazole-2(3H)-thiones containing 4-(3,4,5-trimethoxyphenyl) moiety were synthesized as diaryl-heterocylic analogs of combretastatin A-4 with anticancer activity. The cytotoxicity evaluation of synthesized compounds against cancer cell lines (A549, MCF-7 and SKOV3) revealed that most of them had potent cytotoxic activity toward all tested cell lines (IC50s < 10 µg/mL). Among them, 3-(chlorobenzyl) derivatives 5c and 5d showed the best inhibitory effect on MCF-7 cells (IC50 values of 1.14 and 2.41 µg/mL, respectively). Furthermore, the ability of tubulin polymerization inhibition and apoptosis induction were evaluated for the promising compounds 5c and 5d. Results suggested that these compounds remarkably inhibit tubulin polymerization and induce apoptosis resulting in cell death. In vitro studies revealed that these compounds had no significant cytotoxicity against normal cells at the concentrations required for growth inhibition of cancer cells. In vitro biding assay and in silico docking study also confirmed the binding of prototype compound to the colchicine binding site of tubulin.

Spiroquinazolinone-induced cytotoxicity and apoptosis in K562 human leukemia cells: alteration in expression levels of Bcl-2 and Bax.

Spiroquinazolinone compounds have been considered as a new series of potent apoptosis-inducing agents. In this study, anti-proliferative and apoptotic effects of the derivatives from the spiroquinazolinone family were investigated in the human chronic myeloid leukemia K562 cells. The K562 cells were treated with various concentrations of the spiroquinazolinone (10-300 µM) for 3 days and cell viability was determined by MTT growth inhibition assay. 4t-QTC was more active among these compounds with IC50 of 50 ± 3.6 µM and was selected for further studies. Apoptosis, as the mechanism of cell death was investigated morphologically by acridine orange/ethidium bromide (AO/EtBr) double staining, cell surface expression assay of phosphatidyl serine by Annexin V/PI technique, as well as the formation of DNA ladder. The K562 cells underwent apoptosis upon a single dose (at IC50 value) of the 4t-QTC compound, and over-expressed caspase-3 expression by more than 1.7-fold, following a 72 hr treatment. Furthermore, RT-PCR and Western blot analysis revealed that treatment of the K562 cells with 4t-QTC down-regulates and up-regulates the expression of Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic), respectively. Based on the present data, it seems that these compounds from the spiroquinazolinone family are good candidates for further evaluation as an effective chemotherapeutic family acting through induction of apoptosis in chronic myeloid leukemia.