Current Molecular Medicine - Volume 16, Issue 5, 2016

Lysosomes are membrane-bound organelles that are responsible for degrading and recycling macromolecules. Lysosomal dysfunction occurs in enzymatic and non-enzymatic deficiencies, which result in abnormal accumulation of materials. Although lysosomal storage disorders affect different organs, the central nervous system is the most vulnerable. Evidence shows the role of lysosomal dysfunction in different neurodegenerative diseases, such as Niemann–Pick Type C disease, juvenile neuronal ceroid lipofuscinosis, Alzheimer’s disease and Parkinson’s disease. Lysosomal enzymes such as lysosomal acid phosphatase 2 (Acp2) play a critical role in mannose-6-phosphate removal and Acp2 controls molecular and cellular functions in the brain during development and adulthood. Acp2 is essential in cerebellar development, and mutations in this gene cause severe cerebellar neurodevelopmental and neurodegenerative disorders. In this mini-review, we highlight lysosomal dysfunctions in the pathogenesis of neurodevelopmental and/or neurodegenerative diseases with special attention to Acp2 dysfunction.

Central nervous system (CNS) malignances include tumors of the brain and spinal cord. Taking into account the cell type where they originate from, there are almost 120 different types of CNS tumors. Benign tumors are not aggressive and normally do not invade other organs; however, they require surgical removal before they alter the surrounding brain functions. Primary malignant brain tumors commonly include astrocytomas, oligodendrogliomas, and ependimomas, where astrocytomas represent around 76%. The World Health Organization (WHO) has defined four histological grades of astrocytomas that range from the less aggressive tumors (grade I) to highly malignant tumors (grade IV). These grade IV tumors, also called glioblastoma (GBM), are the most aggressive of the primary malignant brain tumors. Patients with GBM have a median survival of 12 to 15 months. Current treatment for GBM includes surgery, radiotherapy and chemotherapy. Although there have been some advances in diagnosis and treatment, there is still no optimal treatment available for GBMs. In this review, we will discuss the approaches for GBM diagnosis and treatment, with a special emphasis on post-treatment imaging, and whether novel targeted therapies have impacted the survival of GBM patients. In addition, we will discuss clinical trials and the future of GBM diagnosis and treatment.

Impairments in cognitive function represent a consistent, non-specific, and clinically significant feature in metabolic, mood, and dementing disorders. The foregoing observation is instantiated by evidence demonstrating that these disorders share pathophysiological mechanisms including, but not limited to, aberrant insulin signaling, inflammation, and glucocorticoid activity. Moreover, these mechanisms have been consistently reported to increase vulnerability to and/or exacerbate impairments in cognitive function. Notwithstanding evidence suggesting a bidirectional relationship between disturbances in the metabolic milieu, mood, and increased risk for dementia, efficacious treatments that target cognitive impairments in these populations do not presently exist. Taken together, it is proposed that anti-diabetic agents may aid the management of mood disorders and future risk for dementia through disease modification by targeting underlying pathophysiological mechanisms (e.g., aberrant metabolic function) rather than focusing solely on symptom mitigation. The current aim is to provide a brief narrative review of extant studies that report on the potential neurotherapeutic effects of anti-diabetic agents on disturbances in mood and impairments in cognitive function.

Dysregulation in the expression of miRNAs has been observed in various human cancers, including lung cancer. Recent studies have identified the role of a number of miRNAs in regulating key cellular processes and signaling pathways involved in lung tumourigenesis, including cell proliferation, differentiation, angiogenesis, apoptosis, invasion and metastasis. Due to their variable behavior and regulatory role in various nodal junctions in cellular pathways, miRNAs have also been used as potential therapeutic targets and clinical biomarkers in lung cancer. In this non-systematic review, we briefly focus on biogenesis and function of cytoplasmic miRNA and the role of methylation in the regulation of miRNA biogenesis in non-small cell lung cancer (NSCLC). Further, we elaborate the role of differentially expressed miRNAs and their regulatory role on various signaling pathways, cell cycle, and apoptosis in NSCLC.

Background: The accumulation of damaged or misfolded proteins in retinal pigment epithelial (RPE) cells was considered a contributing factor for RPE dysfunction in age-related macular degeneration (AMD). The ubiquitinproteasome pathway (UPP) and the autophagy-lysosome pathway (ALP) are the two major proteolytic systems for clearance of misfolded or damaged proteins. Objective: The aim is to investigate how these two systems communicate and coordinate with each other in RPE cells for eliminating intracellular misfolded and damaged proteins. Methods: Cultured ARPE-19 cells were treated with proteasome inhibitor MG132 and lysosomotropic agent chloroquine (CQ), respectively. The levels and cellular distributions of ubiquitinated proteins, LC3-I, LC3-II, LAMP1 and p62 were analyzed by Western blotting and immunofluorescence. Proteasome activity was determined using Suc-LLVY-AMC as a substrate. Results: The level of ubiquitinated protein aggregations was significantly increased after the treatment of MG132 in RPE cells. The levels of LC3-I, LC3-II and LAMP1 increased in MG132 treated cells. The levels of γ-tubulin and p62 also increased in MG132 treated cells, suggesting that inhibition of the UPP up-regulates autophagy-lysosome pathway. Inhibition of lysosomal activity with CQ also increased the levels of high mass ubiquitin conjugates, LC3-II and p62. In addition, proteasome activity was compromised upon prolonged lysosomal inhibition. Conclusions: These data indicate that the UPP and the ALP are interrelated and that dysfunction of the ALP would also result in dysfunction of the UPP and severely compromise the capacity of eliminating misfolded and other forms of damaged proteins.

TGF-β signaling is shown to be involved in cardiac remodeling, but the detailed function and underlying mechanism are still incompletely understood. In this study, we generated cardiomyocyte-specific TGF-β type 2 receptor (TβR2) knockout mice to study the function of TGF-β signaling in cardiac hypertrophy. Although the mutant mice displayed no obvious physiological abnormality, they developed severer cardiac hypertrophy in response to isoproterenol (ISO) stimulation than control mice did. The expression of p-Smad2 was markedly reduced, while the concentration of p-ERK was increased in the hearts of mutant mice. In addition, we also found that cardiomyocyte-specific Smad2 knockout mice did not demonstrate cardiac phenotype as observed on TβR2 knockout mice, while inhibition of MEK-1-mediated activation of MAPK using PD98059 partially rescued the phenotype of TβR2-deleted cardiomyocytes, indicating that activation of TGF-β noncanonical signaling might contribute to cardiac phenotype observed in TβR2 knockout mice. Thus, our data provided the first in vivo genetic evidence to show that TβR2 may function as an anti-hypertrophic factor of cardiac hypertrophy subjected to adrenergic stimulation, suggesting the complex role of TβR2 in cardiac hypertrophy under stimulation of different stresses.

The molecular mechanism underlying the pathogenesis of keloid is largely unknown. MicroRNA (miRNA) is a class of small regulatory RNA that has emerged as a group of posttranscriptional gene repressors, participating in diverse pathophysiological processes of skin diseases. We investigated the expression profiles of miRNAs in the sera of patients to decipher the complicated factors involved in the development of keloid disease. MiRNA expression profiling in the sera from 9 keloid patients and 7 normal controls were characterized using a miRNA microarray containing established human mature and precursor miRNA sequences. Quantitative real-time PCR was performed to confirm the expression of miRNAs. The putative targets of differentially expressed miRNAs were functionally annotated by bioinformatics. MiRNA microarray analysis identified 37 differentially expressed miRNAs (17 upregulated and 20 downregulated) in keloid patients, compared to the healthy controls. Functional annotations revealed that the targets of those differentially expressed miRNAs were enriched in signaling pathways essential for scar formation and wound healing. The expression profiling of miRNAs is altered in the keloid, providing a clue for the molecular mechanisms underlying its initiation and progression. MiRNAs may partly contribute to the etiology of keloids by affecting the critical signaling pathways relevant to keloid pathogenesis.

The human Hole gene (hHole) encodes a six-transmembrane protein with 319- amino acids. Our previous study showed that hHole was strongly expressed in adult heart and may act as a suppressor of extracellular signal-regulated kinases (ERKs), overactivation of which contributed to pathological cardiac hypertrophy. In this study, it was observed that Hole expression was up-regulated in murine hypertrophic hearts. In a cardiac specific transgenic mouse model, it was observed that overexpression of hHole specifically in heart attenuated cardiac hypertrophy and fibrosis induced by isoproterenol (ISO), with blunted transcriptions of ERK1/2, total ERK1/2 proteins and phosphorylated ERK1/2 (p-ERK1/2) levels. Furthermore, overexpression of hHole in mice by hydrodynamic tail-vein injection with hHole plamids also inhibited cardiac hypertrophy induced by ISO. Our work identified hHole as a novel repressor of cardiac hypertrophy, and provided new insights into the possible target for the prevention or treatment of cardiac diseases.