Long noncoding RNAs (lncRNAs) are RNAs whose transcripts are longer than 200nt in length and lack the ability to encode proteins due to lack of specific open reading frames. lncRNAs were once thought ...to represent transcriptome noise or garbage sequences and a byproduct of RNA polymerase II (Pol II), and thereby ignored by researchers. In fact, lncRNA was involved in a wide variety of physiological and pathological processes in organisms. Comprehensive study of lncRNA does not only provide explanations to the physiological and pathological processes of living organisms, but also gives us new perspectives to the diagnosis, prevention and treatment of some clinical diseases. Therefore, the study of lncRNA is a very broad field of great research value and significance.
This article reviews the function of lncRNAs and their role in major human diseases.
Numerous studies show that lncRNA might serve as a biomarker for diagnosis and prognosis of various diseases. Compared to conventional biomarkers, lncRNA seems to have a higher diagnostic and prognostic values, not only because of their tissue and disease specific expression patterns, but also due to their highly stable physical and chemical properties.
Purpose
Nonalcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in developing countries. The pathogenesis is complex, and there is currently no effective ...treatment. Betaine is an essential intermediate in choline catabolism and an important component of the methionine cycle. Betaine deficiency is associated with NAFLD severity, and its mechanism needs to be further elaborated.
Methods
In this study, an NAFLD mouse model was established by feeding ApoE
−/−
mice a high-fat diet. The effects of betaine on NAFLD were investigated, including its mechanism.
Results
In this study, after treatment with betaine, blood lipid levels and liver damage were significantly decreased in the NAFLD mouse model. The fat infiltration of the liver tissues of high-fat diet (HFD)-fed mice after betaine administration was significantly improved. Betaine treatment significantly upregulated AMP-activated protein kinase (AMPK), fibroblast growth factor 10 (FGF10), and adipose triglyceride lipase (ATGL) protein levels both in vivo and in vitro and suppressed lipid metabolism-related genes. Furthermore, the overexpression of FGF10 increased the protein level of AMPK and decreased lipid accumulation in HepG2 cells.
Conclusion
Taken together, the data strongly suggest that betaine significantly prevents high-fat diet-induced NAFLD through the FGF10/AMPK signaling pathway in ApoE
−/−
mice.
Atherosclerosis, an immunoinflammatory disease of medium and large arteries, is associated with life-threatening clinical events, such as acute coronary syndromes and stroke. Chronic inflammation and ...impaired lipoprotein metabolism are considered to be among the leading causes of atherosclerosis, while numerous risk factors, including arterial hypertension, diabetes mellitus, obesity, and aging, can contribute to the development of the disease. In recent years, emerging evidence has underlined the key role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Mitochondrial dysfunction is believed to result in an increase in reactive oxygen species, leading to oxidative stress, chronic inflammation, and intracellular lipid deposition, all of which can contribute to the pathogenesis of atherosclerosis. Critical cells, including endothelial cells, vascular smooth muscle cells, and macrophages, play an important role in atherosclerosis. Mitochondrial function is also involved in maintaining the normal function of these cells. To better understand the relationship between mitochondrial dysfunction and atherosclerosis, this review summarizes the findings of recent studies and discusses the role of mitochondrial dysfunction in the risk factors and critical cells of atherosclerosis.
•Two processes are believed to play a decisive role in the development of atherosclerosis: chronic inflammation and impaired lipoprotein metabolism•Mitochondrial dysfunction is the major unifying mechanism of several risk factors associated with atherosclerosis
•Therapies targeting mitochondrial dysfunction are promising strategies to treat atherosclerosis.
•How does excessive reactive oxygen species production affect the pathogenesis of atherosclerosis?•How do lipid metabolism disorders affect mitochondrial function?
During the entire processes of thymus organogenesis, maturation, and involution, gene regulation occurs post-transcriptionally via recently discovered microRNA (miRNA) transcripts. Numerous reports ...indicate that miRNAs may be involved in the construction of a normal thymic microenvironment, which constitutes a critical component to support T lymphocyte development. MiRNAs are also expressed in thymic stromal cells including thymic epithelial cells (TECs) during maturation and senescence. This review focuses on the function of miRNAs in thymic development and involution. A better understanding of these processes will provide new insights into the regulatory network of TECs and further comprehension of how genes control TECs to maintain the thymic microenvironment during thymus development and aging, thus supporting a normal cellular immune system.
Pancreatic cancer (PC) is among the most aggressive malignancies associated with a 5-year survival rate of <9%, and the treatment options remain limited. Antibody-drug conjugates (ADCs) are a new ...class of anticancer agents with superior efficacy and safety profiles. We studied the antitumor activity of Oba01 ADC and the mechanism underlying the targeting of death receptor 5 (DR5) in preclinical PC models. Our data revealed that DR5 was highly expressed on the plasma membrane of PC cells and Oba01 showed potent in vitro antitumor activity in a panel of human DR5-positive PC cell lines. DR5 was readily cleaved by lysosomal proteases after receptor-mediated internalization. Monomethyl auristatin E (MMAE) was then released into the cytosol to induce G2/M-phase growth arrest, cell death via apoptosis induction, and the bystander effect. Furthermore, Oba01 mediated cell death via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. For improved potency, we investigated the synergetic effect of Oba01 in combination with approved drugs. Oba01 combined with gemcitabine showed better antiproliferative activity than either standalone treatment. In cell- and patient-derived xenografts, Oba01 showed excellent tumoricidal activity in mono- or combinational therapy. Thus, Oba01 may provide a novel biotherapeutic approach and a scientific basis for clinical trials in DR5-expressing patients with PC.
Age-related thymic involution is primarily induced by defects in nonhematopoietic thymic epithelial cells (TECs). It is characterized by dysfunction of multiple transcription factors (TFs), such as ...p63 and FoxN1, and also involves other TEC-associated regulators, such as Aire. These TFs and regulators are controlled by complicated regulatory networks, in which microRNAs (miRNAs) act as a key player. miRNAs can either directly target the 3′-UTRs (untranslated regions) of the TFs to suppress TF expression or target TF inhibitors to reduce or increase TF inhibitor expression and thereby indirectly enhance or inhibit TF expression. Here, we review the current understanding and recent studies about how miRNAs are involved in age-related thymic involution via regulation of TEC-autonomous TFs. We also discuss potential strategies for targeting miRNAs to rejuvenate age-related declined thymic function.
Abstract
Objectives
We previously reported that ex vivo TGF-β and IL-2–induced CD8+CD103+ regulatory T cells (CD8+CD103+ iTregs) displayed similar immunosuppressive effect and therapeutic function on ...lupus mice nephritis to that of CD4+Foxp3+ Tregs. In view of the important role of glomerular endothelial cell (GEC) injury in inflammatory processes in SLE, this study aimed to investigate the nature and mechanism of CD8+CD103+ iTregs–mediated amelioration of LN by attenuating GEC injury.
Methods
Treg cells from patients with SLE and from healthy controls were characterized by flow cytometry analysis. The expression of pro-inflammatory mediators and VEGF were analysed in healthy controls, patients with SLE and MRL/lpr mice by ELISA, western blot, and real-time quantitative RT-PCR (qRT-PCR). Typical lesions of diffuse proliferative LN were observed in MRL/lpr mice through the use of haematoxylin and eosin, Masson, periodic acid–Schiff, periodic acid–Schiff methenamine, transmission electron microscopy and IF microscopy. Angiogenesis was analysed in GECs by cell investigating proliferation, migration, and tube formation.
Results
The results revealed that the frequency of Treg cells was inversely correlated with the expression of VCAM-1 and ICAM-1 in patients with SLE. Furthermore, adoptive transfer of CD8+CD103+ iTregs to MRL/lpr mice was associated with decreased levels of autoantibodies and proteinuria, reduced renal pathological lesions, and lowered renal deposition of IgG/C3. We further found that CD8+CD103+ iTregs not only suppressed the expression of pro-inflammatory mediators but also attenuated GEC injury by promoting angiogenesis.
Conclusion
Our study has identified the role of CD8+CD103+ iTregs on attenuating GEC injury and provided a possible application of this new iTregs subset in lupus nephritis and other autoimmune diseases.
Background and aim
Interferon‐γ (IFN‐γ) is a versatile cytokine which broadly involves in the inflammatory diseases, mediating both immune activation and tolerance. Here, we aimed to investigate the ...role of IFN‐γ in the initiation of adjuvant‐induced arthritis (AIA).
Methods and Results
In an AIA mice model, increasing IFN‐γ mRNA was observed at day 3 and peaked on day 7. At day 3, the majority of IFN‐γ‐producing cells were located around vessels observed by immunofluorescent staining. Recombinant IFN‐γ or anti‐IFN‐γ antibody was injected into the AIA paw on day 2 to study the outcome of AIA. The recipients of IFN‐γ showed increased synovial inflammation, whereas anti‐IFN‐γ antibody injection repressed the expansion of inflammatory cells. As the percentages of blood monocytes were approximately equivalent, we hypothesized that IFN‐γ might impact the access of innate leucocytes from blood to expand local inflammation at this stage. Analysis of tissue CD31 and vascular cell adhesion molecule‐1 (VCAM‐1) expressions suggested a positive effect of these factors in the development of inflammation, and IFN‐γ affected the VCAM‐1 expression. To further verify this idea, mice regionally injected with IFN‐γ were systematically administrated with anti‐VCAM‐1 antibody during AIA induction. The IFN‐γ expression was inhibited, and the development of AIA was partly abolished in these mice regardless of regional IFN‐γ injection.
Conclusion
These data suggested that IFN‐γ might be critical for the expansion of AIA at early stage through helping inflammatory cell access.
Cysteinyl leukotrienes (CysLTs) play a key role in inflammatory diseases such as asthma and their receptors' antagonists are currently used as anti-asthmatic drugs. CysLTs have also been found to ...participate in other inflammatory reactions. Here, we reported that in rheumatoid arthritis (RA) animals model, collagen-induced arthritis, (CIA), CysLT1, a receptor for CysLTs, was up-regulated in hind paw and lymph node, while CysLTs levels in the blood were also higher than normal mice. Montelukast, a drug targeting CysLT1, has been shown to effectively reduce the CIA incidence, peak severity, and cumulative disease scores. Further study indicated that CysLT1 signaling did not affect the differentiation of pathogenic T helper cells. We conclude that montelukast may play important roles in the pathogenesis of CIA, mainly by inducing infiltration of pathogenic T cells, increasing IL-17A secretion and expression of IL-17A, while these effects can be blocked by CysLT1 antagonists. Our findings indicate that antagonist of CysLT1 receptor may be used to treat rheumatoid arthritis.
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