STAT1/STAT3 transcription factors are important regulators for development of normal, infected or inflammed cells. They are also critically involved in the progression of various malignant tumours, including epithelial-derived carcinomas. Here, we focus on colorectal cancer (CRC) insights for STAT1/3, where controversial functions for STAT3 were reported. For a long time STAT3 has been regarded as a driver of tumour malignancy and its activation was associated with negative clinical outcome. In contrast, STAT1 was generally viewed as an independent tumour suppressor and positive prognostic marker. Here we discuss the experimental evidence for the tight association and regulation of oncogenic STAT3 transcription kept at bay by nuclear STAT1. We summarise current research and describe cellular models of different STAT1/STAT3 expression ratios. STAT1/3 expression levels are influenced by the mutational status of carcinoma cells associated with nuclear unphosphorylated STAT1. Animal tumour models and results from in vitro experiments allow for the conclusion that both proteins interact as antagonistic transcription factors in CRC cells. These STATs steer also important processes during infection and inflammation that influence development and progression of CRC. The STAT1/3 interplay is important to understand gene regulation and we describe it here similar like the YIN/YANG dualism. Thus, we propose to evaluate both STAT1 and STAT3 expression patterns in cancers in a dual manner instead of regarding them as independent transcription factors. This conceptual dualistic view could advance diagnostic predictions in the future.
Pancreatic β-cell functions are regulated by a variety of endogenous and exogenous factors. Calcium is one of the most potent triggers of β-cell growth, insulin production and exocytosis. Recently, others and we showed that TRPV channels are expressed in insulin producing cell lines and/or primary β-cells. These channels modulate calcium ions, insulin secretion and cell proliferation. Besides the classical roles of TRPV channels in the sensory system, there are also novel functions described in non-excitable cells such as in insulin-producing β-cells. This review summarises the current knowledge about the expression and the role of TRPV channels in controlling β-cell functions based upon studies performed in isolated primary β-cells as well as permanent β-cell models.
During pre-mRNA splicing events, introns are removed from the pre-mRNA, and the remaining exons are connected together to form a single continuous molecule. Alternative splicing is a common mechanism for the regulation of gene expression in eukaryotes. More than 90% of human genes are known to undergo alternative splicing. The most common type of alternative splicing is exon skipping, which is also known as cassette exon. Other known alternative splicing events include alternative 5′ splice sites, alternative 3′ splice sites, intron retention, and mutually exclusive exons. Alternative splicing events are controlled by regulatory proteins responsible for both positive and negative regulation. In this review, we focus on neuronal splicing regulators and discuss several notable regulators in depth. In addition, we have also included an example of splicing regulation mediated by the RBFox protein family. Lastly, as previous studies have shown that a number of splicing factors are associated with neuronal diseases such as Alzheime's disease (AD) and Autism spectrum disorder (ASD), here we consider their importance in neuronal diseases wherein the underlying mechanisms have yet to be elucidated.
Together H-, N- and KRAS mutations are major contributors to ~30% of all human cancers. Thus, Ras inhibition remains an important anti-cancer strategy. The molecular mechanisms of isotypic Ras oncogenesis are still not completely understood. Monopharmacological therapeutics have not been successful in the clinic. These disappointing outcomes have led to attempts to target elements downstream of Ras, mainly targeting either the Phosphatidylinositol 3-Kinase (PI3K) or Mitogen-Activated Protein Kinase (MAPK) pathways. While several such approaches are moderately effective, recent efforts have focused on preclinical evaluation of combination therapies to improve efficacies. This review will detail current understanding of the contributions of plasma membrane microdomain targeting of Ras to mitogenic and tumorigenic signaling and tumor progression. Moreover, this review will outline novel approaches to target Ras in cancers, including targeting schemes for new drug development, as well as putative re-purposing of drugs in current use to take advantage of blunting Ras signaling by interfering with Ras plasma membrane microdomain targeting and retention.
Hepatitis C, caused by the hepatitis C virus (HCV) that attacks the liver and leads to inflammation, is a severe threat to human health. Pegylated interferon α (INF-α) and ribavirin based therapy was once the standard therapy for HCV infection. However, it is suboptimal in efficacy and poorly tolerated in some patients. In the last five years, four classes of direct antiviral drugs (NAAs) that target non-structural proteins (NS) of the virus including NS3/NS4A, NS5A, and NS5B have been developed and opened a new era in HCV treatment as they are more effective and tolerable than the INF-α and ribavirin combination regimen. Importantly, the newly introduced multiple NAAs combination therapy makes it possible to eradicate all genotypes of HCV. We review recent progress on the research and development of DAAs in the present article.
Human DDX3 paralogs are housed on the X chromosome (DDX3X) as well as in the non- recombining region Yq11 of the Y-chromosome (DDX3Y or DBY). A gene encoding RNA helicase DDX3Y is located in the AZoospermia Factor a (AZFa) region of the Y-chromosome and expressed only in male germ cells. Deletions encompassing the DDX3Y gene lead to azoospermia and cause Sertoli Cell-Only Syndrome (SCOS) in humans. SCOS is characterized by a complete germ cell lack with preservation of somatic Sertoli cells. This review summarizes current advances in the study of DDX3Y functions in maintenance and development of early male germ cells. Data obtained from a mouse xenotransplantation model reveals that DDX3Y expression is enough to drive germ cell differentiation of AZFa-deleted human induced pluripotent stem cells (iPSCs) and for activation of the specific set of germline developmental genes. Results achieved using the testes of Drosophila demonstrate that DDX3Y homolog Belle is required cell-autonomously for mitotic progression and survival of germline stem cells and spermatogonia as the upstream regulator of mitotic cyclin expression.
The end-of-life (EOL) care bonus introduced by the Japanese government works as a financial incentive and framework of quality preservation, including advance care planning, for EOL care among nursing home residents. This study aims to clarify the effects of the EOL care bonus in promoting EOL care in nursing homes. A longitudinal observational study using a questionnaire was conducted. We invited 378 nursing homes in Kanagawa prefecture in Japan, a region with a rapidly aging population, to participate in the study. The outcome was the number of residents dying in nursing homes from 2004 to 2014. In a linear mixed model, fixed-effect factors included year established, unit care, regional elderly population rate and hospital beds, adjacent affiliated hospital, full-time physician on site, physician's support during off-time, basic EOL care policy, usage of the EOL care bonus, EOL care conference, and staff experience of EOL care. A total of 237 nursing home facilities responded (62.7%). The linear mixed model showed that the availability of the EOL care bonus (coefficient 3.1, 95 % CI 0.67-5.51, p = 0.012) and years of usage of the EOL care bonus (p < 0.001) were significantly associated with increased numbers of residents dying in nursing homes. Our analysis revealed that the EOL care bonus has the potential to increase the number of residents receiving EOL care in nursing homes over several years. EOL care conferences, physician support for emergency care during off-time, and the presence of an adjacent affiliated hospital may also increase the number of residents receiving EOL care in nursing homes. These results suggest that a government financial incentive may contribute to effective EOL care among nursing home residents in other developed countries with rapidly aging populations.
Globally, the overall mortality rate among HIV-infected patients has significantly declined during the HAART era. Deaths among HIV-infected inpatients need to be characterized in order to formulate intervention strategies to further improve medical care for this population and their prognosis. In the current study, deaths among HIV-infected inpatients from 2006 to 2015 at a medical center for HIV infection and AIDS patient care in Shanghai, China were retrospectively analyzed. Trends in mortality rates and the proportion of deaths caused by AIDS or non-AIDS-related illnesses were evaluated. A bivariate analysis was performed to identify the demographic and clinical factors associated with AIDS or non-AIDS-related deaths among HIV-infected inpatients. Among 6,473 HIV-infected patients who were discharged from 2006 to 2015, 326 deaths (5.04%) were identified. The yearly mortality rate declined significantly over time (χ2 = 34.41, p < 0.001). Results revealed that most deaths were attributed to AIDS-related illnesses (76.9 %, 233/303), and the proportion of causes of death did not change significantly over time (χ2 = 13.847, p = 0.127). Bivariate analysis identified characteristic factors associated with AIDS-related mortality. Compared to patients who died of non-AIDS illnesses, patients who died of AIDS-related illnesses had a CD4+ T cell count lower than 50 cells/μL (OR 4.587, 2.377-8.850) and fewer liver (OR 0.391, 0.177-0.866) or renal comorbidities (OR 0.188, 0.067-0.523) on admission. Results indicated that the overall in-hospital mortality rate among HIV-infected patients has declined over the past decade. However, AIDS-related illnesses were still the major causes of deaths among HIV-infected inpatients, suggesting that further efforts are needed to improve AIDS care in China.
Ankylosing spondylitis (AS) is a spinal arthritic disease that is often associated with human leukocyte antigen (HLA)-B27, while only part of HLA-B27 carriers become AS patients. T cells have been reported to play an important role in the pathology of AS. T-cell immunoglobulin and mucin-domain-containing molecule 3 (Tim-3) and programmed death-1 (PD-1) have been known to negatively regulate the immune response. In this study, we used flow cytometry to analyze the immunological differences of peripheral bloodfrom 21 patients with AS, 22 cases who didn't have AS but were found to be HLA-B27 positive (HLA-B27+ group), and 16 normal healthy individuals (Healthy group). The level of CD4+, CD8+ T cells,and Treg of each group was observed. The expression of Tim-3 and PD-1 and the production of IFN-γ, IL-6, TNF-α, IL-4, and IL-10 were examined as well. We found that the percentage of Treg in AS group was lower than that of healthy group. The expression of PD-1 on CD8+ T cells and Tim-3 on CD4+ T cells was lower in the AS group. AS group had lower IL-10 production by CD4+ T cells and higher IL-6 production by CD8+ T cells. The results of HLA-B27+ group were similar to that of the healthy group. These data suggested that patients with AS had an impairment in the ability to negatively regulate the immune response, which might be related to the etiology of AS. To further investigate the roles of Tim-3 and PD-1 on is a dysfunction of T cells in AS that is associated with PD-1 and Tim-3.
Epithelial to mesenchymal transition (EMT) is a physiological phenomenon in mammalian embryogenesis by which epithelial cells become mesenchymal stem cells. Studies have indicated that an inappropriate EMT plays a key role in a variety of pathogenic processes such as embryonic development and tumor metastasis. Moreover, recent studies have indicated EMT also plays an important role in renal fibrosis. In the current study, glucose and angiotensin II promoted EMT in podocytes as well as changes in the cellular morphology of podocytes. A high concentration of glucose and angiotensin II also promoted podocyte movement and migration. Moreover, a high concentration of glucose and angiotensin II promoted TCF8 expression. Inhibiting TCF8 expression with siRNA reversed EMT in podocytes in the presence of a high concentration of glucose and angiotensin. Inhibiting TCF8 expression also reversed changes in cellular morphology and podocyte movement and migration. Therefore, glucose and angiotensin II may promote EMT in podocytes via TCF8.
Aster yomena (Kitam.) Honda has been widely used as a traditional herbal medicine for centuries to treat cough, asthma, insect bites, etc. Recent reports indicate that A. yomena possesses a wide spectrum of pharmacological activities; however, few experiments have described its anti-inflammatory properties. The present study examined the anti-inflammatory effects of an ethanol extract of A. yomena leaves (EEAY) on lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages. Treatment with EEAY significantly reduced the secretion of pro-inflammatory molecules, such as nitric oxide and interleukin-1β, in LPS-stimulated RAW 264.7 cells, without incurring any significant cytotoxicity. These protective effects were accompanied by a marked reduction in the expression of regulatory genes at the transcription level. Treatment with EEAY also inhibited the DNA-binding activity of nuclear factor-κB (NF-κB) by suppression of nuclear translocation of NF-κB and by degradation of the inhibitor of NF-κB; these effects were associated with suppression of the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase signaling pathways. The EEAY treatment also potently suppressed LPS-induced toll like receptor (TLR) 4 expression and attenuated the binding of LPS to the macrophage cell surface. In addition, EEAY treatment markedly inhibited LPS-induced accumulation of intracellular reactive oxygen species in RAW 264.7 macrophages. Therefore, the inhibitory effects of EEAY on LPS-stimulated inflammatory responses in RAW 264.7 macrophages were apparently associated with suppression of the TLR-mediated NF-κB signaling pathway. More work is needed to fully understand the critical role and clinical usefulness of EEAY treatment, but the findings of the present study provide some insights into the potential of EEAY as a therapeutic agent for treatment of inflammatory disorders.
As is similar to glial cell line-derived neurotrophic factor (GDNF), the Yangjing Capsule (YC) extract could also lead to proliferation of spermatogonial stem cells (SSCs) by stimulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway; however, the regulatory effect of YC extract on the expression of POU3F1 still remains unknown. The objective of this study is to determine whether the transcription factor POU3F1 is up-regulated by YC extract through the PI3K/AKT signaling pathway to regulate SSCs survival and proliferation. Cultured GC-1 spermatogonial (spg) cells were treated with 0.01, 0.1, and 1 mg/mL YC extract for 48 h. Cell viability was analyzed using MTT assay, while POU3F1 expression was quantitatively detected using real time-polymerase chain reaction and Western blot analysis. POU3F1, GDNF family receptor alpha1 (GFRα1) short interfering ribonucleic acid (siRNA), and LY294002 (PI3K inhibitor) were applied as blockers to explore the underlying pathway. After 48 h treatment with YC extract, GC-1 spg cells proliferated and POU3F1 expression was significantly increased in a dose-dependent manner. POU3F1 siRNA partially blocked those effects of YC extract. Both GFRα1 siRNA and LY294002, as upstream blockers, reduced POU3F1 expression induced by YC extract. The conclusion is that YC extract promotes proliferation of GC-1 spg cells via up-regulation of POU3F1. The potential mechanism is that YC extract triggers the activation of the PI3K/AKT pathway and then up-regulates POU3F1 expression.
Malignant mesothelioma (MM) is an insidious, lethal asbestos-related cancer that is poorly responsive to current treatments. Specific and sensitive biomarkers providing early MM diagnosis in exposed subjects, who are at high-risk of developing it, are sorely needed. MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs with a well-established diagnostic role in cancer and pollution exposure. In a recent systematic review and qualitative meta-analysis followed by a functional investigation, we examined all the available data on the miRNA biomarkers involved in asbestos exposure and MM pathways. This invited commentary aims to provide an insightful critique into the state of the art of the research into clinically relevant miRNA biomarkers, highlighting the strengths and weaknesses of current research efforts in this field. It also reviews the suggestions advanced to improve biomarker development productivity and the translation of research results into clinical practice, stressing that multicenter multidisciplinary studies adopting standardized methods and protocol sharing are the key to move from the workbench to the clinic.
Acute Myeloid Leukemia (AML) is the commonest form of leukemia in the adults, with an incidence of 3-4 cases per 100,000 people/year. After the first description of the effective cytarabine + antracycline (3+7) induction regimen, in the last 3 decades, no effective targeted drug has been included in the standard treatment of AML. Many efforts of modifying 3+7 adding a third drug or increasing the dose of anthracycline, cytarabine or both did not lead to substantial improvements, mainly due to increased toxicity. Many in vitro and in vivo evidences suggested that fludarabine may increase efficacy of cytarabine through a synergistic effect. Considering the continuous improvements in supportive care and management of infectious complications the feasibility of more intensive induction strategies have increased and a renewed interest in fludarabine-containing induction strategies arose. The recent MRC AML 15 trial has shown that a fludarabine-containing induction, FLAG-Ida, resulted superior to conventional 3+7 in terms of complete remission rates, relapse incidence and survival, although only a minority of patients could complete the whole planned consolidation program due to an excessive hematological toxicity. Our group recently published a 10-year experience with a fludarabine-containing induction that slightly differed from the MRC one and resulted in good efficacy and higher feasibility. In this commentary we review the major evidences supporting the employ of a fludarabine-containing induction in AML, and discuss the future perspectives.
Epsin N-terminal homology (ENTH) domains are present at the N-terminus of either the epsin or epsin-related (epsinR) proteins. These proteins have been involved in clathrin-mediated trafficking and are critical for membrane deformation at the site of vesicle budding. While more than one type of these proteins have been described in many eukaryotic cells, the protozoa parasite Giardia lamblia contains only one member of this ENTH-protein family. In the last two years, four works have been published showing that this giardial protein might play diverse functions. This commentary gives a brief overview on the current status of the particular characteristics and functions of this unique protein
Since the first outbreak of human infection with avian influenza A (H7N9) virus was identified in 2013, five seasonal outbreaks have occurred in China. The fifth outbreak started earlier than usual. A sudden increase in cases of human infection with avian influenza A (H7N9) virus has been reported in China since September 2016, and the number of cases reported in this season is exceeding that reported in previous seasons. This increase in the number of new cases of H7N9 infection has caused domestic and international concern. This paper summarizes the current prevalence of H7N9 in China and it also discusses measures that China has taken to control this outbreak. This paper also describes steps China must take in the future. This paper can serve as a reference for prevention and control of H7N9 outbreaks around the world.
The fifth outbreak of human infection with avian influenza A (H7N9) virus has struck far and wide in China. The number of cases of infection with the avian influenza A (H7N9) suddenly increased in 2013-2014, but the number of cases reported this winter has exceeded the number reported in all previous seasons. Given this situation, the National Health and Family Planning Commission issued updated Chinese guidelines (2017 version) on diagnosis and treatment of infection with the avian influenza A (H7N9) virus on January 24, 2017. In addition, the Chinese Government closed many live poultry markets in urban and rural areas in a number of provinces and the Government has taken proactive measures to surveil, respond to, and prevent potential pandemics involving the avian influenza A (H7N9) virus.