We recently showed that suramin treatment prevents the onset of renal fibrosis in a model of obstructive nephropathy induced by unilateral ureteral obstruction (UUO). In this study, we further ...assessed the effect of delayed administration of suramin on the progression of tubulointerstitial fibrosis. Mice were given a single dose of suramin at 20 mg/kg starting at day 3 of obstruction, and kidneys were harvested after an additional 7 or 14 days of obstruction. Suramin completely blocked further increase in expression of type I collagen and fibronectin and largely suppressed expression of α-smooth muscle actin (α-SMA) in both treatment groups. UUO injury induced phosphorylation of Smad-3, a key mediator of transforming growth factor-β (TGF-β) signaling, epidermal growth factor receptor, and platelet-derived growth factor receptor after 3 days and further increased at 10 days after UUO injury. When suramin was administered at 3 days after obstruction, phosphorylation of these molecules was not further increased in the obstructed kidney. Suramin treatment also inhibited activation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1 and 2, two signaling pathways associated with renal fibrogenesis. Furthermore, delayed application of suramin suppressed TGF-β1-induced expression of α-SMA and fibronectin in cultured renal interstitial fibroblasts. These results indicate that administration of suramin is effective in attenuating the progression of renal fibrosis after injury and suggest the potential clinical application of suramin as an antifibrotic treatment in patients with chronic kidney disease.
Cadmium (Cd) is an ubiquitous environmental and occupational toxic metal concerned with a variety of adverse effects. The present study was undertaken to evaluate the role of diallyl tetrasulfide ...(DTS), an organosulfur compound in alleviating the Cd induced biochemical changes in male Wistar rats. During the experiment, rats were injected with Cd (3
mg/(kg
day)) subcutaneously alone or with oral administration of DTS at different doses (10, 20 and 40
mg/(kg
day)) for 3 weeks. In Cd treated rats, the activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma glutamyl transferase (GGT) were significantly increased in serum with elevated levels of bilirubin, urea and creatinine. The hemoglobin level and creatinine clearance were also significantly decreased in Cd treated rats. In addition, the levels of plasma lipid peroxidation markers: thiobarbituric acid reactive substances and lipid hydroperoxides were significantly increased while the levels of plasma reduced glutathione (GSH), Vitamins C and E were significantly decreased in Cd administered rats. Administration of DTS along with Cd significantly decreased the serum
, liver and kidney markers towards near normal level in a dose dependent manner. DTS at a dose of 40
mg/(kg
day) was highly effective when compared to other doses (10 and 20
mg/(kg
day)). DTS also significantly reduced the accumulation of Cd in blood and tissues as well as decreased the level of lipid peroxidation markers with elevation of antioxidants in plasma. All these changes were accompanied by histological observations in liver. The obtained results demonstrated the beneficial effect of DTS in reducing the harmful effects of Cd.
Our recent studies showed that transglutaminase-1 (TGase-1) is uniquely expressed in mouse renal proximal tubular cells (RPTC) and mediates cell proliferation. In this study, we investigated the role ...of TGase-1 in cell survival and the survival signaling pathways regulated by TGase-1 in RPTC following oxidant injury. Exposure of RPTC to hydrogen peroxide (H2O2) resulted in apoptosis and an increase in TGase activity. Inhibition of TGase activity with monodansylcadervine (MDC), a TGase inhibitor, or knockdown of TGase-1 with small interference (si)RNA enhanced apoptosis and decreased cell survival in H2O2-treated RPTC. Conversely, overexpression of TGase-1 rendered RPTC more resistant to H2O2 toxicity and MDC treatment blocked this response. Concurrent with RPTC apoptosis, phosphorylation of AKT, signal transducer and activator of transcription-3 (STAT3), and glucogen synthase kinase-3beta (GSK-3beta) were observed. Pretreatment of cells with MDC or TGase-1 siRNA inhibited phosphorylation of all these molecules. Inhibition of either the AKT or STAT3 pathway potentiated H2O2-induced cell death and increased GSK-3beta activity by dephosphorylation at serine 9. Furthermore, treatment with GSK-3beta inhibitors reduced H2O2-induced apoptosis and abolished the death-promoting effect of AKT and STAT3 inhibition. Therefore, we have identified TGase-1 as a novel survival factor in renal epithelial cells and it contributes to cell survival through activation of the AKT and STAT3 signaling pathways following oxidant injury.
Cardiomyocyte proliferation and regeneration are key to the functional recovery of myocardial tissue from injury. In the recent years, studies on cardiomyocyte proliferation overturned the ...traditional belief that adult cardiomyocytes permanently withdraw from the cell cycle activity. Hence, targeting cardiomyocyte proliferation is one of the potential therapeutic strategies for myocardial regeneration and repair. To achieve this, a deep understanding of the fundamental mechanisms involved in cardiomyocyte cell cycle as well as differences between neonatal and adult cardiomyocytes’ cell cycle activity is required. This review focuses on the recent progress in understanding of cardiomyocyte cell cycle activity at different life stages viz., gestation, birth, and adulthood. The temporal expression/activities of major cell cycle activators (cyclins and CDKs), inhibitors (p21, p27, p57, p16, and p18), and cell-cycle-associated proteins (Rb, p107, and p130) in cardiomyocytes during gestation and postnatal life are described in this review. The influence of different transcription factors and microRNAs on the expression of cell cycle proteins is demonstrated. This review also deals major pathways (PI3K/AKT, Wnt/β-catenin, and Hippo-YAP) associated with cardiomyocyte cell cycle progression. Furthermore, the postnatal alterations in structure and cellular events responsible for the loss of cell cycle activity are also illustrated.
Circular RNAs (circRNAs), a novel type of non-coding RNAs (ncRNAs), are ubiquitously expressed in eukaryotic cells during post-transcriptional processes. Unlike linear RNAs, circRNAs form ...covalent-closed continuous loops without 5' to 3' polarities and poly (A) tails. With advances in high-throughput sequencing technology, numerous circRNAs have been identified in plants, animals and humans. Notably, circRNAs display cell-type, tissue-type and developmental-stage specific expression patterns in eukaryotic transcriptome, which reveals their significant regulatory functions in gene expression. More importantly, circRNAs serve as microRNA (miRNA) sponges and crucial regulators of gene expression. Additionally, circRNAs modulate pre-mRNA alternative splicing and possess protein-coding capacity. CircRNAs exhibit altered expression under pathological conditions and are strongly associated with the development of various human diseases. Interestingly, circRNAs can also induce antiviral immune responses. A recent study found that the delivery of circRNAs generated
activates RIG-I-mediated innate immune responses and provides protection against viral infection. The antiviral dsRNA-binding proteins, NF90/NF110, act as key regulators in circRNA biogenesis. NF90/NF110 are also functional in inhibiting viral replication through binding to viral mRNAs. In this review, we provide a comprehensive overview on the classification, biogenesis and functions of circRNAs. We also discuss the critical role of circRNAs in eliciting antiviral immunity, providing evidence for the potential implications of circRNAs in antiviral therapies.
MEF2 signaling and human diseases Chen, Xiao; Gao, Bing; Ponnusamy, Murugavel ...
Oncotarget,
12/2017, Volume:
8, Issue:
67
Journal Article
Open access
The members of myocyte Enhancer Factor 2 (MEF2) protein family was previously believed to function in the development of heart and muscle. Recent reports indicate that they are also closely ...associated with development and progression of many human diseases. Although their role in cancer biology is well established, the molecular mechanisms underlying their action is yet largely unknown. MEF2 family is closely associated with various signaling pathways, including Ca
signaling, MAP kinase signaling, Wnt signaling, PI3K/Akt signaling, etc. microRNAs also contribute to regulate the activities of MEF2. In this review, we summarize the known molecular mechanism by which MEF2 family contribute to human diseases.
PIWI‑interacting RNA is a class of non‑coding small RNA that is ~30 nt long and is primarily found in mammalian germ cells from mice and humans. In cooperation with the members of PIWI protein ...family, this macromolecule participates in germ cell development, inhibits DNA self‑-replication and maintains genomic stability. Increasing evidence has demonstrated that PIWI‑interacting RNA (piRNAs) are abnormally expressed in various human cancers, such as liver cancer, stomach cancer, colorectal cancer, osteosarcoma, breast cancer, lung cancer, prostate cancer, etc. piRNAs abnormal expression is also associated with the occurrence and development of human cancers, such as liver cancer, stomach cancer, colorectal cancer, etc. Despite their unclear molecular mechanisms, piRNAs may act as oncogenes or tumor suppressors by interacting with multiple cancer‑related signal pathways including STAT3/Bcl‑xl or coding genes, such as heat shock transcription factor‑1. Hence, piRNAs may be potential markers and targets and provide new opportunities for cancer diagnosis, treatment or prognosis monitoring. The current review mainly aims to highlight the latest research progress made in the biological functions and regulation of piRNAs in mammals, their involvement in various cancer forms and their potential clinical applications.
Circular RNAs (circRNAs) have important roles in several cellular processes. No study has established the pathophysiological role for circRNAs in the heart. Here, we show that a circRNA ...(mitochondrial fission and apoptosis-related circRNA (MFACR)) regulates mitochondrial fission and apoptosis in the heart by directly targeting and downregulating miR-652-3p; this in turn blocks mitochondrial fission and cardiomyocyte cell death by suppressing MTP18 translation. MTP18 deficiency reduces mitochondrial fission and suppresses cardiomyocyte apoptosis and MI. miR-652-3p directly downregulates MTP18 and attenuates mitochondrial fission, cardiomyocyte apoptosis, and MI in vitro and in vivo. MFACR directly sequesters miR-652-3p in the cytoplasm and inhibits its activity. MFACR knockdown in cardiomyocytes and mice attenuates mitochondrial fission and MI. Our results reveal a crucial role for circRNA in regulating mitochondrial dynamics and apoptosis in the heart; as such, circRNAs may serve as a potential therapeutic avenue for cardiovascular diseases.
Increased Src activity has been associated with the pathogenesis of renal tumors and some glomerular diseases, but its role in renal interstitial fibrosis remains elusive. To evaluate this, cultured ...renal interstitial fibroblasts (NRK-49F) were treated with PP1, a selective inhibitor of Src. This resulted in decreased expression of α-smooth muscle actin, fibronectin, and collagen I in response to serum, angiotension II, or transforming growth factor-β1 (TGF-β1). Silencing Src with siRNA also inhibited expression of those proteins. Furthermore, inhibition of Src activity blocked renal fibroblast proliferation. In a murine model of renal interstitial fibrosis induced by unilateral ureteral obstruction, the active form of Src (phopsho-Src Tyr416) was upregulated in both renal interstitial fibroblasts and renal tubular cells of the fibrotic kidney. Its inactivation reduced renal fibroblast activation and attenuated extracellular matrix protein deposition. Src inhibition also suppressed activation of TGF-β1 signaling, activation of the epidermal growth factor receptor and STAT3, and reduced the number of renal epithelial cells arrested at the G2/M phase of the cell cycle after ureteral obstruction. Thus, Src is an important mediator of renal interstitial fibroblast activation and renal fibrosis, and we suggest that Src is a potential therapeutic target for treatment of chronic renal fibrosis.
Growing evidence suggests that alterations of gene expression including expression and activities of transcription factors are closely associated with carcinogenesis. Forkhead Box Class K (FOXK) ...proteins, FOXK1 and FOXK2, are a family of evolutionarily conserved transcriptional factors, which have recently been recognized as key transcriptional regulators involved in many types of cancer. Members of the FOXK family mediate a wide spectrum of biological processes, including cell proliferation, differentiation, apoptosis, autophagy, cell cycle progression, DNA damage and tumorigenesis. Therefore, the deregulation of FOXKs can affect the cell fate and they promote tumorigenesis as well as cancer progression. The mechanisms of FOXKs regulation including post-translational modifications (PTMs), microRNAs (miRNAs) and protein–protein interactions are well demonstrated. However, the detailed mechanisms of FOXKs activation and deregulation in cancer progression are still inconclusive. In this review, we summarize the regulatory mechanisms of FOXKs expression and activity, and their role in the development and progression of cancer. We have discussed whether FOXKs act as tumor suppressors/oncoproteins in tumor cells and their therapeutic applications in malignant diseases are also discussed. This review may assist in designing experimental studies involving FOXKs and it would strength the therapeutic potential of FOXKs as targets for cancers.
•FOXKs mediate multiple physiological and pathological processes by inducing transcription of target genes.•FOXKs possess double-edged effect on cancer.•Deregulation of FOXKs is associated with a series of malignancies.•FOXKs are potential targets of chemotherapeutic drugs.
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