MicroRNAs in Stress Signaling and Human Disease

The crosstalk between miRNAs and signaling pathways in human cancers: Potential therapeutic implications.

microRNAs (miRNAs) are short, single-stranded RNA molecules that function together with the partner proteins and cause degradation of target mRNAs or inhibit their translation. A particular miRNA can have hundreds of targets; therefore, miRNAs cumulatively influence the expression of a large proportion of genes. The functions of miRNAs in human diseases have been studied since their discovery in mammalian cells approximately 12years ago. However, the role of miRNAs in allergic disease has only very recently begun to be uncovered. The purpose of this review is to provide an overview of the functions of miRNAs involved in the development of allergic diseases. We describe here the functions of miRNAs that regulate Th2 polarization and influence general inflammatory and tissue responses. In addition, we will highlight findings about the functions of extracellular miRNAs as possible noninvasive biomarkers of diseases with heterogeneous phenotypes and complex mechanisms and briefly discuss advances in the development of miRNA-based therapeutics.

Background: Sepsis very well define as life-threatening medical condition and may be characterize as dangerous condition described by dysregulated inflammation. The objective of this study is investigating the effects of pre-treatment with didox in attenuation of acute lung injury caused by sepsis through down regulation of IL-33 pathway. Method and materials: A total of 30 Adult male of Swiss Albino mice were used for the study, with weights ranged between 30 g - 35 g. The experimental animal subjected to cecal ligation and puncture (CLP) and pretreated with 200mg /Kg i.p. of didox 1 hour before sepsis induced. The lung tissue for histopathology examination and proinflammatory markers level (IL-1β, IL-33 and MCP-1) beside serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA). ApHOX analyzer (Nova Biomedical, Waltham, USA) used for the determination of blood gases as indication to lung function in mice groups. Results: When compared the data of different mice sets with the sham collection, levels of serum and lung tissues IL-1β and MCP-1 are showed significant (p<0.001) increased within control and vehicle groups. Sepsis induction set also shows significant (p<0.001) increase in serum IL-33 which cause impairment of lung functions expressed as a significant reduction in partial pressure values for oxygen (pO2) and as well as a significant elevation in partial pressure values for carbon dioxide (pCO2). These changes are consistent with histopathologic examination which shows severe pulmonary damage as compared to sham set. All these changes were counteracted by administration of didox. Conclusions: Our results revealed didox have been shown to decrease sepsis-induced acute lung injury through interfering with inflammatory mediators (IL-1β, IL-33 and MCP-1) and down regulation of IL-33 signaling pathway. How to Cite this Article Pubmed Style NASSER GHALY YOUSIF, ALI NAJAH AL-KHAYYAT, ZAINAB ABD OLKADHIM, NAJAH R. HADI, SARA N. ALTIMIMI, AHMAD ALTIMIMI. ameliorates sepsis induced acute lung injury via down regulation of IL-33 signaling pathway in SRP. 2020; 11(1): 96-107. doi:10.5530/srp.2020.1.15 Web Style NASSER GHALY YOUSIF, ALI NAJAH AL-KHAYYAT, ZAINAB ABD OLKADHIM, NAJAH R. HADI, SARA N. ALTIMIMI, AHMAD ALTIMIMI. ameliorates sepsis induced acute lung injury via down regulation of IL-33 signaling pathway in http://www.sysrevpharm.org/?mno=82743 [Access: March 29, 2021]. doi:10.5530/srp.2020.1.15 AMA (American Medical Association) Style NASSER GHALY YOUSIF, ALI NAJAH AL-KHAYYAT, ZAINAB ABD OLKADHIM, NAJAH R. HADI, SARA N. ALTIMIMI, AHMAD ALTIMIMI. ameliorates sepsis induced acute lung injury via down regulation of IL-33 signaling pathway in SRP. 2020; 11(1): 96-107. doi:10.5530/srp.2020.1.15 Vancouver/ICMJE Style NASSER GHALY YOUSIF, ALI NAJAH AL-KHAYYAT, ZAINAB ABD OLKADHIM, NAJAH R. HADI, SARA N. ALTIMIMI, AHMAD ALTIMIMI. ameliorates sepsis induced acute lung injury via down regulation of IL-33 signaling pathway in SRP. (2020), [cited March 29, 2021]; 11(1): 96-107. doi:10.5530/srp.2020.1.15 Harvard Style NASSER GHALY YOUSIF, ALI NAJAH AL-KHAYYAT, ZAINAB ABD OLKADHIM, NAJAH R. HADI, SARA N. ALTIMIMI, AHMAD ALTIMIMI (2020) ameliorates sepsis induced acute lung injury via down regulation of IL-33 signaling pathway in SRP, 11 (1), 96-107. doi:10.5530/srp.2020.1.15 Turabian Style NASSER GHALY YOUSIF, ALI NAJAH AL-KHAYYAT, ZAINAB ABD OLKADHIM, NAJAH R. HADI, SARA N. ALTIMIMI, AHMAD ALTIMIMI. 2020. ameliorates sepsis induced acute lung injury via down regulation of IL-33 signaling pathway in Systematic Reviews in Pharmacy, 11 (1), 96-107. doi:10.5530/srp.2020.1.15 Chicago Style NASSER GHALY YOUSIF, ALI NAJAH AL-KHAYYAT, ZAINAB ABD OLKADHIM, NAJAH R. HADI, SARA N. ALTIMIMI, AHMAD ALTIMIMI. Didox ameliorates sepsis induced acute lung injury via down regulation of IL-33 signaling pathway in mice. Systematic Reviews in Pharmacy 11 (2020), 96-107. doi:10.5530/srp.2020.1.15 MLA (The Modern Language Association) Style NASSER GHALY YOUSIF, ALI NAJAH AL-KHAYYAT, ZAINAB ABD OLKADHIM, NAJAH R. HADI, SARA N. ALTIMIMI, AHMAD ALTIMIMI. Didox ameliorates sepsis induced acute lung injury via down regulation of IL-33 signaling pathway in mice. Systematic Reviews in Pharmacy 11.1 (2020), 96-107. Print. doi:10.5530/srp.2020.1.15 APA (American Psychological Association) Style NASSER GHALY YOUSIF, ALI NAJAH AL-KHAYYAT, ZAINAB ABD OLKADHIM, NAJAH R. HADI, SARA N. ALTIMIMI, AHMAD ALTIMIMI (2020) ameliorates sepsis induced acute lung injury via down regulation of IL-33 signaling pathway in Systematic Reviews in Pharmacy, 11 (1), 96-107. doi:10.5530/srp.2020.1.15

Inflammation can positively and negatively affect tumorigenesis based on the duration, scope, and sequence of related events through the regulation of signaling pathways. A transcriptomic analysis of five pulmonary arterial hypertension, twelve Crohn's disease, and twelve ulcerative colitis high throughput sequencing datasets using R language specialized libraries and gene enrichment analyses identified a regulatory network in each inflammatory disease. IRF9 and LINC01089 in pulmonary arterial hypertension are related to the regulation of signaling pathways like MAPK, NOTCH, human papillomavirus, and hepatitis c infection. ZNF91 and TP53TG1 in Crohn's disease are related to the regulation of PPAR, MAPK, and metabolic signaling pathways. ZNF91, VDR, DLEU1, SATB2-AS1, and TP53TG1 in ulcerative colitis are related to the regulation of PPAR, AMPK, and metabolic signaling pathways. The activation of the transcriptomic network and signaling pathways might be related to the interaction of the characteristic microbiota of the inflammatory disease, with the lung and gut cell receptors present in membrane rafts and complexes. The transcriptomic analysis highlights the impact of several coding and non-coding RNAs, suggesting their relationship with the unlocking of cell phenotypic plasticity for the acquisition of the hallmarks of cancer during lung and gut cell adaptation to inflammatory phenotypes.

Simple SummaryHuman uveal melanoma (UM) is the most common primary intraocular tumor with high metastatic risk in adults. Currently, no effective treatment is available for metastatic UM; therefore, new therapeutic approaches are needed to improve overall survival. Given the increased understanding of microRNAs (miRNAs) and their roles in UM tumorigenesis and metastasis, miRNA-based therapy may offer the hope of improving therapeutic outcomes. This review summarizes the actions of select miRNAs examined in preclinical studies using miRNAs as therapeutic targets in UM. The focus of this review is the application of established nanotechnology-assisted delivery systems to overcome the limitations of therapeutic miRNAs. A blend of therapeutic miRNAs and nanodelivery systems may facilitate the translation of miRNA therapies to clinical settings.Uveal melanoma (UM) is the most common adult intraocular cancer, and metastatic UM remains deadly and incurable. UM is a complex disease associated with the deregulation of numerous genes and redundant intracellular signaling pathways. As understanding of epigenetic dysregulation in the oncogenesis of UM has increased, the abnormal expression of microRNAs (miRNAs) has been found to be an epigenetic mechanism underlying UM tumorigenesis. A growing number of miRNAs are being found to be associated with aberrant signaling pathways in UM, and some have been investigated and functionally characterized in preclinical settings. This review summarizes the miRNAs with promising therapeutic potential for UM treatment, paying special attention to the therapeutic miRNAs (miRNA mimics or inhibitors) used to restore dysregulated miRNAs to their normal levels. However, several physical and physiological limitations associated with therapeutic miRNAs have prevented their translation to cancer therapeutics. With the advent of nanotechnology delivery systems, the development of effective targeted therapies for patients with UM has received great attention. Therefore, this review provides an overview of the use of nanotechnology drug delivery systems, particularly nanocarriers that can be loaded with therapeutic miRNAs for effective delivery into target cells. The development of miRNA-based therapeutics with nanotechnology-based delivery systems may overcome the barriers of therapeutic miRNAs, thereby enabling their translation to therapeutics, enabling more effective targeting of UM cells and consequently improving therapeutic outcomes.

Dengue virus (DENV) is the etiological agent of dengue fever. Severe dengue could be fatal and there is currently no effective antiviral agent or vaccine. The only licensed vaccine, Dengvaxia, has low efficacy against serotypes 1 and 2. Cellular miRNAs are post-transcriptional regulators that could play a role in direct regulation of viral genes. Host miRNA expressions could either promote or repress viral replications. Induction of some cellular miRNAs could help the virus to evade the host immune response by suppressing the IFN-α/β signaling pathway while others could upregulate IFN-α/β production and inhibit the viral infection. Understanding miRNA expressions and functions during dengue infections would provide insights into the development of miRNA-based therapeutics which could be strategized to act either as miRNA antagonists or miRNA mimics. The known mechanisms of how miRNAs impact DENV replication are diverse. They could suppress DENV multiplication by directly binding to the viral genome, resulting in translational repression. Other miRNA actions include modulation of host factors. In addition, miRNAs that could modulate immunopathogenesis are discussed. Major hurdles lie in the development of chemical modifications and delivery systems for in vivo delivery. Nevertheless, advancement in miRNA formulations and delivery systems hold great promise for the therapeutic potential of miRNA-based therapy, as supported by Miravirsen for treatment of Hepatitis C infection which has successfully completed phase II clinical trial.

Especially in chemoresistant cancers, such as lung and pancreatic cancer, there is a clear need to understand molecular mechanisms behind drug resistance and develop effective therapies. Resistance can be caused by a range of mechanisms, including modulation by microRNAs (miRNAs). miRNAs are involved in many biological processes and have been implicated in cancer initiation and progression. However, they can also alter cellular response to anticancer agents by modulating survival pathways, apoptosis and DNA repair systems. One of the major features of miRNAs is their ability to target multiple genes and therefore interfere in multiple pathways. This explains their role in multiple pathways involved in resistance and makes them attractive as novel class of therapeutic targets. Here, we describe the molecular basis of miRNAs in anticancer drug resistance, including alterations in cell survival and apoptosis, as well as drug targets. The possibility to modulate miRNA expression to enhance drug sensitivity and the development of miRNA-based therapeutics as novel drugs is discussed. The implications are illustrated with a clinical focus on the application of miRNAs in pancreatic cancer and lung cancer, for which resistance to current therapies remains a major problem.

Simple SummaryThe overall survival of brain cancer patients remains grim, with conventional therapies such as chemotherapy and radiotherapy only providing marginal benefits to patient survival. Cancers are complex, with multiple pathways being dysregulated simultaneously. Non-coding RNAs such as microRNA (miRNAs) are gaining importance due to their potential in regulating a variety of targets implicated in the pathology of cancers. This could be leveraged for the development of targeted and personalized therapies for cancers. Since miRNAs can upregulate and/or downregulate proteins, this review aims to understand the role of these miRNAs in primary and metastatic brain cancers. Here, we discuss the regulatory mechanisms of ten miRNAs that are highly dysregulated in glioblastoma and metastatic brain tumors. This will enable researchers to develop miRNA-based targeted cancer therapies and identify potential prognostic biomarkers. Brain cancer is one among the rare cancers with high mortality rate that affects both children and adults. The most aggressive form of primary brain tumor is glioblastoma. Secondary brain tumors most commonly metastasize from primary cancers of lung, breast, or melanoma. The five-year survival of primary and secondary brain tumors is 34% and 2.4%, respectively. Owing to poor prognosis, tumor heterogeneity, increased tumor relapse, and resistance to therapies, brain cancers have high mortality and poor survival rates compared to other cancers. Early diagnosis, effective targeted treatments, and improved prognosis have the potential to increase the survival rate of patients with primary and secondary brain malignancies. MicroRNAs (miRNAs) are short noncoding RNAs of approximately 18–22 nucleotides that play a significant role in the regulation of multiple genes. With growing interest in the development of miRNA-based therapeutics, it is crucial to understand the differential role of these miRNAs in the given cancer scenario. This review focuses on the differential expression of ten miRNAs (miR-145, miR-31, miR-451, miR-19a, miR-143, miR-125b, miR-328, miR-210, miR-146a, and miR-126) in glioblastoma and brain metastasis. These miRNAs are highly dysregulated in both primary and metastatic brain tumors, which necessitates a better understanding of their role in these cancers. In the context of the tumor microenvironment and the expression of different genes, these miRNAs possess both oncogenic and/or tumor-suppressive roles within the same cancer.

Uveal melanoma (UM) is the most common intraocular malignant tumor in adults with an extremely high mortality rate. Genetic and epigenetic dysregulation contribute to the development of UM. Recent discoveries have revealed dysregulation of the expression levels of microRNAs (miRNAs) as one of the epigenetic mechanisms underlying UM tumorigenesis. Based on their roles, miRNAs are characterized as either oncogenic or tumor suppressive. This review focuses on the roles of miRNAs in UM tumorigenesis, diagnosis, and prognosis, as well as their therapeutic potentials. Particularly, the actions of collective miRNAs are summarized with respect to their involvement in major, aberrant signaling pathways that are implicated in the development and progression of UM. Elucidation of the underlying functional mechanisms and biological aspects of miRNA dysregulation in UM is invaluable in the development of miRNA-based therapeutics, which may be used in combination with conventional treatments to improve therapeutic outcomes. In addition, the expression levels of some miRNAs are correlated with UM initiation and progression and, therefore, may be used as biomarkers for diagnosis and prognosis.

Targeted delivery of microRNA (miRNA) mimics into specific cells/tissues and real-time monitoring on the biological function of delivered miRNA mimics at molecular level represent two major challenges in the development of miRNA-based therapeutics. Here we report a highly efficient method to address these two challenges simultaneously by using the self-assembled nanocomplex formed by miRNA mimics with a multi-functional peptide conjugate. Using the nanocomplex formed by tumor-suppressive miR-34a and the multi-functional peptide conjugate FA-R9-FPcas3 , we demonstrated the highly efficient and target-selective delivery of miR-34a into HeLa cells and tumors. With the activatable fluorescence probe integrated in the peptide conjugate FA-R9-FPcas3 , the intracellular function of miR-34a delivered by the nanocomplex to upregulate active Caspase-3 was imaged in real-time. The nanocomplex also showed significant therapeutic effects to induce apoptosis in HeLa cells and to suppress tumor growth upon tail vein injection into living mice bearing subcutaneous HeLa tumors.

Breast cancer is a heterogeneous type of disease in which genetic and environmental factors play a crucial role. There are several types of treatment for breast cancer (BC) patients. However, the biggest problem in the treatment of breast cancer is the resistance that occurs during the treatment with chemotherapeutic agents. Usnic acid, a secondary metabolite of lichen, has been identified as a drug candidate molecule in cancer treatment. The determination of miRNA target proteins is essential for the understanding of molecular mechanisms of miRNA-related tumorigenesis. We determined that mir-185-5p has therapeutic potential at the miRNA level by applying usnic acid to BT-474 breast cancer cells in a previous study. Herein, we aimed to investigate the molecular mechanisms of miR-185-5p on BT-474 breast cancer cells using a proteomics approach. We explored the changes in the protein expression level of BT-474 breast cancer cells in response to the up-regulation of miR-185-5p after applying usnic acid as a novel candidate anti-- cancer drug molecule. We performed quantitative proteome analysis based on an LC-MS/MS assay, which was validated by western blotting. The differentially expressed proteins were analyzed using the latest data available in bioinformatics tools. The up-regulated expression of YWHAE, Cathepsin D, and the down-regulated levels of PAK-1 were demonstrated by western blot assay. According to the results, 86 proteins showing >2-fold change were identified as differentially expressed between breast cancer and normal breast epithelial cells. The apoptosis pathway was the main clade containing most of the proteins regulated by miR-185-5p. The results indicate that miR-185-5p modulates apoptosis signaling pathways in BT-474 breast cancer cells. Breast cancer inhibition due to increased expression of YWHAE, Cathepsin D, and decreased expression of PAK-1 is likely to be mediated by inducing miR-185-5p mediated apoptosis. In this study, the identification of miR-185-5p protein targets demonstrated the potential for the development of targeted therapy and the development of miRNA-based therapeutics and presented it as a biomarker for breast cancer diagnosis, prognosis, and treatment response. In this regard, proteome analyses provided an understanding of the molecular mechanism underlying the effect of miR-185-5p on breast cancer.

Several microRNAs have been implicated in neurogenesis, neuronal differentiation, neurodevelopment, and memory. Development of miRNA-based therapeutics, however, needs tools for effective miRNA modulation, tissue-specific delivery, and in vivo evidence of functional effects following the knockdown of miRNA. Expression of miR-29a is reduced in patients and animal models of several neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, and spinocerebellar ataxias. The temporal expression pattern of miR-29b during development also correlates with its protective role in neuronal survival. Here, we report the cellular and behavioral effect of in vivo, brain-specific knockdown of miR-29. We delivered specific anti-miRNAs to the mouse brain using a neurotropic peptide, thus overcoming the blood-brain-barrier and restricting the effect of knockdown to the neuronal cells. Large regions of the hippocampus and cerebellum showed massive cell death, reiterating the role of miR-29 in neuronal survival. The mice showed characteristic features of ataxia, including reduced step length. However, the apoptotic targets of miR-29, such as Puma, Bim, Bak, or Bace1, failed to show expected levels of up-regulation in mice, following knockdown of miR-29. In contrast, another miR-29 target, voltage-dependent anion channel1 (VDAC1), was found to be induced several fold in the hippocampus, cerebellum, and cortex of mice following miRNA knockdown. Partial restoration of apoptosis was achieved by down-regulation of VDAC1 in miR-29 knockdown cells. Our study suggests that regulation of VDAC1 expression by miR-29 is an important determinant of neuronal cell survival in the brain. Loss of miR-29 results in dysregulation of VDAC1, neuronal cell death, and an ataxic phenotype.

Combination of microRNA therapeutics with small-molecule anticancer drugs: Mechanism of action and co-delivery nanocarriers

MiRNA in cervical cancer: Diagnosis to therapy: Systematic review

Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.