ResearchPad - cell-and-developmental-biology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Phosphorylation-Dependent Pin1 Isomerization of ATR: Its Role in Regulating ATR’s Anti-apoptotic Function at Mitochondria, and the Implications in Cancer]]> https://www.researchpad.co/article/elastic_article_7642 Peptidyl-prolyl isomerization is an important post-translational modification of protein because proline is the only amino acid that can stably exist as cis and trans, while other amino acids are in the trans conformation in protein backbones. This makes prolyl isomerization a unique mechanism for cells to control many cellular processes. Isomerization is a rate-limiting process that requires a peptidyl-prolyl cis/trans isomerase (PPIase) to overcome the energy barrier between cis and trans isomeric forms. Pin1, a key PPIase in the cell, recognizes a phosphorylated Ser/Thr-Pro motif to catalyze peptidyl-prolyl isomerization in proteins. The significance of the phosphorylation-dependent Pin1 activity was recently highlighted for isomerization of ATR (ataxia telangiectasia- and Rad3-related). ATR, a PIKK protein kinase, plays a crucial role in DNA damage responses (DDR) by phosphorylating hundreds of proteins. ATR can form cis or trans isomers in the cytoplasm depending on Pin1 which isomerizes cis-ATR to trans-ATR. Trans-ATR functions primarily in the nucleus. The cis-ATR, containing an exposed BH3 domain, is anti-apoptotic at mitochondria by binding to tBid, preventing activation of pro-apoptotic Bax. Given the roles of apoptosis in many human diseases, particularly cancer, we propose that cytoplasmic cis-ATR enables cells to evade apoptosis, thus addicting cancer cells to cis-ATR formation for survival. But in normal DDR, a predominance of trans-ATR in the nucleus coordinates with a minimal level of cytoplasmic cis-ATR to promote DNA repair while preventing cell death; however, cells can die when DNA repair fails. Therefore, a delicate balance/equilibrium of the levels of cis- and trans-ATR is required to ensure the cellular homeostasis. In this review, we make a case that this anti-apoptotic role of cis-ATR supports oncogenesis, while Pin1 that drives the formation of trans-ATR suppresses tumor growth. We offer a potential, novel target that can be specifically targeted in cancer cells, without killing normal cells, to significantly reduce the adverse effects usually seen in cancer treatment. We also raise important issues regarding the roles of phosphorylation-dependent Pin1 isomerization of ATR in diseases and propose areas of future studies that would shed more understanding on this important cellular mechanism.

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<![CDATA[Membrane Compartmentalization and Scaffold Proteins in Leukocyte Migration]]> https://www.researchpad.co/article/elastic_article_7548 Leukocyte migration across vessels into and within peripheral and lymphoid tissues is essential for host defense against invading pathogens. Leukocytes are specialized in sensing a variety of guidance cues and to integrate environmental stimuli to navigate in a timely and spatially controlled manner. These extracellular signals must be transmitted across the leukocyte’s plasma membrane in a way that intracellular signaling cascades enable directional cell movement. Therefore, the composition of the membrane in concert with proteins that influence the compartmentalization of the plasma membrane or contribute to delineate intracellular signaling molecules are key in controlling leukocyte navigation. This becomes evident by the fact that mislocalization of membrane proteins is known to deleteriously affect cellular functions that may cause diseases. In this review we summarize recent advances made in the understanding of how membrane cholesterol levels modulate chemokine receptor signaling and hence leukocyte trafficking. Moreover, we provide an overview on the role of membrane scaffold proteins, particularly tetraspanins, flotillins/reggies, and caveolins in controlling leukocyte migration both in vitro and in vivo.

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<![CDATA[Unraveling Adipocytes and Cancer Links: Is There a Role for Senescence?]]> https://www.researchpad.co/article/elastic_article_7541 Senescence is characterized by a permanent cell cycle arrest that is elicited in response to different stresses. In addition, senescent cells undergo multiple other phenotypic alterations, such as autophagy modulation, metabolic reprogramming, and the senescence-associated secretory phenotype (SASP). These senescence-related and inflammatory effects prevail within tumors and are strongly controlled by cancer properties, and inflammatory mediators further maintain and propagate the senescence process to adjacent cells. It is important to consider these detrimental effects that may drive tumorigenesis or cancer relapse. Importantly, cancer-associated adipocytes (CAAs) are one of the primary stromal cells in various tumor microenvironments and favor tumor progression by releasing various factors that can mediate local and systemic effects. However, it remains unclear whether CAAs possess senescent features. In this review, we discuss the complex relationship between senescence and CAAs and highlight important considerations for therapeutics.

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<![CDATA[Phospholipids of the Plasma Membrane – Regulators or Consequence of Cell Polarity?]]> https://www.researchpad.co/article/elastic_article_7540 Cell polarity is a key feature of many eukaryotic cells, including neurons, epithelia, endothelia and asymmetrically dividing stem cells. Apart from the specific localization of proteins to distinct domains of the plasma membrane, most of these cells exhibit an asymmetric distribution of phospholipids within the plasma membrane too. Notably, research over the last years has revealed that many known conserved regulators of apical-basal polarity in epithelial cells are capable of binding to phospholipids, which in turn regulate the localization and to some extent the function of these proteins. Conversely, phospholipid-modifying enzymes are recruited and controlled by polarity regulators, demonstrating an elaborated balance between asymmetrically localized proteins and phospholipids, which are enriched in certain (micro)domains of the plasma membrane. In this review, we will focus on our current understanding of apical-basal polarity and the implication of phospholipids within the plasma membrane during the cell polarization of epithelia and migrating cells.

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<![CDATA[Interleaflet Coupling of Lipid Nanodomains – Insights From <i>in vitro</i> Systems]]> https://www.researchpad.co/article/elastic_article_7530 The plasma membrane is a complex system, consisting of two layers of lipids and proteins compartmentalized into small structures called nanodomains. Despite the asymmetric composition of both leaflets, coupling between the layers is surprisingly strong. This can be evidenced, for example, by recent experimental studies performed on phospholipid giant unilamellar vesicles showing that nanodomains formed in the outer layer are perfectly registered with those in the inner leaflet. Similarly, microscopic phase separation in one leaflet can induce phase separation in the opposing leaflet that would otherwise be homogeneous. In this review, we summarize the current theoretical and experimental knowledge that led to the current view that domains are – irrespective of their size – commonly registered across the bilayer. Mechanisms inducing registration of nanodomains suggested by theory and calculations are discussed. Furthermore, domain coupling is evidenced by experimental studies based on the sparse number of methods that can resolve registered from independent nanodomains. Finally, implications that those findings using model membrane studies might have for cellular membranes are discussed.

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<![CDATA[Inhibitory Effects of Fosmidomycin Against <i>Babesia microti in vitro</i>]]> https://www.researchpad.co/article/elastic_article_7521 Babesia microti, the main pathogen causing human babesiosis, has been reported to exhibit resistance to the traditional treatment of azithromycin + atovaquone and clindamycin + quinine, suggesting the necessity of developing new drugs. The methylerythritol 4-phosphate (MEP) pathway, a unique pathway in apicomplexan parasites, was shown to play a crucial function in the growth of Plasmodium falciparum. In the MEP pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a rate-limiting enzyme and fosmidomycin (FSM) is a reported inhibitor for this enzyme. DXR has been shown as an antimalarial drug target, but no report is available on B. microti DXR (BmDXR). Here BmDXR was cloned, sequenced, analyzed by bioinformatics, and evaluated as a potential drug target for inhibiting the growth of B. micorti in vitro. Drug assay was performed by adding different concentrations of FSM in B. microti in vitro culture. Rescue experiment was done by supplementing 200 μM isopentenyl pyrophosphate (IPP) or 5 μM geranylgeraniol (GG-ol) in the culture medium together with 5 μM FSM or 10 μM diminazene aceturate. The results indicated that FSM can inhibit the growth of B. microti in in vitro culture with an IC50 of 4.63 ± 0.12 μM, and growth can be restored by both IPP and GG-ol. Additionally, FSM is shown to inhibit the growth of parasites by suppressing the DXR activity, which agreed with the reported results of other apicomplexan parasites. Our results suggest the potential of DXR as a drug target for controlling B. microti and that FSM can inhibit the growth of B. microti in vitro.

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<![CDATA[Organoid-Transplant Model Systems to Study the Effects of Obesity on the Pancreatic Carcinogenesis <i>in vivo</i>]]> https://www.researchpad.co/article/elastic_article_7519 Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality among adults in developed countries. The discovery of the most common genetic alterations as well as the development of organoid models of pancreatic cancer have provided insight into the fundamental pathways driving tumor progression from a normal cell to non-invasive precursor lesion and finally to widely metastatic disease, offering new opportunities for identifying the key driver of cancer evolution. Obesity is one of the most serious public health challenges of the 21st century. Several epidemiological studies have shown the positive association between obesity and cancer-related morbidity/mortality, as well as poorer prognosis and treatment outcome. Despite strong evidence indicates a link between obesity and cancer incidence, the molecular basis of the initiating events remains largely elusive. This is mainly due to the lack of an accurate and reliable model of pancreatic carcinogenesis that mimics human obesity-associated PDAC, making data interpretation difficult and often confusing. Here we propose a feasible and manageable organoid-based preclinical tool to study the effects of obesity on pancreatic carcinogenesis. Therefore, we tracked the effects of obesity on the natural evolution of PDAC in a genetically defined transplantable model of the syngeneic murine pancreatic preneoplastic lesion (mP) and tumor (mT) derived-organoids that recapitulates the progression of human disease from early preinvasive lesions to metastatic disease. Our results suggest that organoid-derived transplant in obese mice represents a suitable system to study early steps of pancreatic carcinogenesis and supports the hypothesis that inflammation induced by obesity stimulates tumor progression and metastatization during pancreatic carcinogenesis.

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<![CDATA[Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism]]> https://www.researchpad.co/article/elastic_article_7513 NAD+, a co-enzyme involved in a great deal of biochemical reactions, has been found to be a network node of diverse biological processes. In mammalian cells, NAD+ is synthetized, predominantly through NMN, to replenish the consumption by NADase participating in physiologic processes including DNA repair, metabolism, and cell death. Correspondingly, aberrant NAD+ metabolism is observed in many diseases. In this review, we discuss how the homeostasis of NAD+ is maintained in healthy condition and provide several age-related pathological examples related with NAD+ unbalance. The sirtuins family, whose functions are NAD-dependent, is also reviewed. Administration of NMN surprisingly demonstrated amelioration of the pathological conditions in some age-related disease mouse models. Further clinical trials have been launched to investigate the safety and benefits of NMN. The NAD+ production and consumption pathways including NMN are essential for more precise understanding and therapy of age-related pathological processes such as diabetes, ischemia–reperfusion injury, heart failure, Alzheimer’s disease, and retinal degeneration.

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<![CDATA[CD40L Reverse Signaling Influences Dendrite Spine Morphology and Expression of PSD-95 and Rho Small GTPases]]> https://www.researchpad.co/article/elastic_article_7509 CD40-activated CD40L reverse signaling is a major physiological regulator of neural process growth from many kinds of developing neurons. Here we have investigated whether CD40L-reverse signaling also influences dendrite spine number and morphology in striatal medium spiny neurons (MSNs). Golgi preparations revealed no differences in the spine density, but because the dendrite arbors of MSNs were larger and branched in Cd40–/– mice, the total number of spines was greater in Cd40–/– mice. We also detected more mature spines compared with wild-type littermates. Western blot revealed that MSN cultures from Cd40–/– mice had significantly less PSD-95 and there were changes in RhoA/B/C and Cdc42. Immunocytochemistry revealed that PSD-95 was clustered in spines in Cd40–/– neurons compared with more diffuse labeling in Cd40+/+ neurons. Activation of CD40L-reverse signaling with CD40-Fc prevented the changes observed in Cd40–/– cultures. Our findings suggest that CD40L-reverse signaling influences dendrite spine morphology and related protein expression and distribution.

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<![CDATA[MicroRNA-381-3p Functions as a Dual Suppressor of Apoptosis and Necroptosis and Promotes Proliferation of Renal Cancer Cells]]> https://www.researchpad.co/article/elastic_article_7506 Renal cell carcinoma (RCC) is the most common type of kidney cancer. It has a poor prognosis, with approximately 20–30% of patients developing recurrent and/or metastatic diseases that is relatively high resistant to conventional therapy. Resisting cell death is a hallmark of cancer cells. Apoptosis is a form of programmed cell death mediated by the activation of caspases. Necroptosis is a form of regulated necrosis that relies on the activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL), the substrate of RIPK3. Cancer cells often display apoptosis resistance via upregulation of anti-apoptotic genes and defective necroptosis due to the epigenetic silence of Ripk3. MicroRNAs (miRNAs) are non-coding small RNAs that are involved in numerous biological processes including cell proliferation, differentiation and death. In this study, we screened a set of ∼120 miRNAs for apoptosis-regulating miRNAs and identified miR-381-3p as a suppressor of TNF-induced apoptosis in various cancer cells. Ectopic expression of miR-381-3p inhibits the activation of caspase-8 and caspase-3. The expression level of miR-381-3p inversely correlates with the sensitivity of cancer cells to TNF-induced apoptosis. Moreover, we found that overexpression of miR-381-3p blocks TNF-induced necroptosis by inhibiting the activation of RIPK3 and MLKL. Of note, Kaplan-Meier Plotter analysis demonstrates that papillary RCC patients with high miR-381-3p expression have a lower overall survival than those with low expression level of miR-381-3p. Importantly, miR-381-3p overexpression promotes colony formation in human renal cancer cells. Thus, miR-381-3p acts as an oncogenic miRNA that counteracts both apoptotic and necroptotic signaling pathways. Our findings highlight miR-381-3p as a biomarker for predicting sensitivity to apoptosis and necroptosis, and as a possible therapeutic target for RCC.

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<![CDATA[Recent Advances in Computer-Assisted Algorithms for Cell Subtype Identification of Cytometry Data]]> https://www.researchpad.co/article/elastic_article_7478 The progress in the field of high-dimensional cytometry has greatly increased the number of markers that can be simultaneously analyzed producing datasets with large numbers of parameters. Traditional biaxial manual gating might not be optimal for such datasets. To overcome this, a large number of automated tools have been developed to aid with cellular clustering of multi-dimensional datasets. Here were review two large categories of such tools; unsupervised and supervised clustering tools. After a thorough review of the popularity and use of each of the available unsupervised clustering tools, we focus on the top six tools to discuss their advantages and limitations. Furthermore, we employ a publicly available dataset to directly compare the usability, speed, and relative effectiveness of the available unsupervised and supervised tools. Finally, we discuss the current challenges for existing methods and future direction for the new generation of cell type identification approaches.

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<![CDATA[Non-esterified Fatty Acid Induce Dairy Cow Hepatocytes Apoptosis via the Mitochondria-Mediated ROS-JNK/ERK Signaling Pathway]]> https://www.researchpad.co/article/elastic_article_7461 Elevated plasma non-esterified fatty acid (NEFA) levels and hepatocytes damage are characteristics of ketosis in dairy cows. Oxidative stress is associated with the pathogenesis of NEFA-induced liver damage. However, the exact mechanism by which oxidative stress mediates NEFA-induced hepatocytes apoptosis and liver injury remains poorly understood. The results of the present study demonstrated that NEFA contribute to reactive oxygen species (ROS) generation, resulting in an imbalance between oxidative and antioxidant species, transcriptional activation of p53, transcriptional inhibition of nuclear factor E2-related factor 2 (Nrf2), loss of mitochondria membrane potential (MMP) and release of apoptosis-inducing factor (AIF) and cytochrome c (cyt c) into the cytosol, leading to hepatocytes apoptosis. Besides, NEFA triggered apoptosis in dairy cow hepatocytes via the regulation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), Bcl-2-associated X protein (Bax), B-cell lymphoma gene 2 (Bcl-2), caspase 9 and poly (ADP-ribose) polymerase (PARP). Pretreatment with the inhibitor SP600125 or PD98059 or the antioxidant N-acetylcysteine (NAC) revealed that NEFA-ROS-JNK/ERK-mediated mitochondrial signaling pathway plays a crucial role in NEFA-induced hepatocytes apoptosis. Moreover, the results suggested that the transcription factors p53 and Nrf2 function downstream of this NEFA-ROS-JNK/ERK pathway and are involved in NEFA-induced hepatocytes apoptosis. In conclusion, these findings indicate that the NEFA-ROS-JNK/ERK-mediated mitochondrial pathway plays an important role in NEFA-induced dairy cow hepatocytes apoptosis and strongly suggests that the inhibitors SP600125 and PD98059 and the antioxidant NAC may be developed as therapeutics to prevent hyperlipidemia-induced apoptotic damage in ketotic dairy cows.

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<![CDATA[Molecular Insights Into Therapeutic Potential of Autophagy Modulation by Natural Products for Cancer Stem Cells]]> https://www.researchpad.co/article/N83c4b782-6563-4621-8951-29391cea7a17 Autophagy, a cellular self-digestion process that is activated in response to stress, has a functional role in tumor formation and progression. Cancer stem cells (CSCs) accounting for a minor proportion of total cancer cells-have distinct self-renewal and differentiation abilities and promote metastasis. Researchers have shown that a numeral number of natural products using traditional experimental methods have been revealed to target CSCs. However, the specific role of autophagy with respect to CSCs and tumorigenesis using natural products are still unknown. Currently, CSCs are considered to be one of the causative reasons underlying the failure of anticancer treatment as a result of tumor recurrence, metastasis, and chemo- or radio-resistance. Autophagy may play a dual role in CSC-related resistance to anticancer treatment; it is responsible for cell fate determination and the targeted degradation of transcription factors via growth arrest. It has been established that autophagy promotes drug resistance, dormancy, and stemness and maintenance of CSCs. Surprisingly, numerous studies have also suggested that autophagy can facilitate the loss of stemness in CSCs. Here, we review current progress in research related to the multifaceted connections between autophagy modulation and CSCs control using natural products. Overall, we emphasize the importance of understanding the role of autophagy in the maintenance of different CSCs and implications of this connection for the development of new strategies for cancer treatment targeting natural products.

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<![CDATA[Deconstructing Neurogenesis, Transplantation and Genome-Editing as Neural Repair Strategies in Brain Disease]]> https://www.researchpad.co/article/N8fc2e832-0493-42ae-9681-98694b2c1781

Neural repair in injury and disease presents a pressing unmet need in regenerative medicine. Due to the intrinsically reduced ability of the brain to replace lost and damaged neurons, reversing long-term cognitive and functional impairments poses a unique problem. Over the years, advancements in cellular and molecular understanding of neurogenesis mechanisms coupled with sophistication of biotechnology tools have transformed neural repair into a cross-disciplinary field that integrates discoveries from developmental neurobiology, transplantation and tissue engineering to design disease- and patient-specific remedies aimed at boosting either native rehabilitation or delivering exogenous hypoimmunogenic interventions. Advances in deciphering the blueprint of neural ontogenesis and annotation of the human genome has led to the development of targeted therapeutic opportunities that have the potential of treating the most vulnerable patient populations and whose findings from benchside suggest looming clinical translation. This review discusses how findings from studies of adult neurogenesis have informed development of interventions that target endogenous neural regenerative machineries and how advances in biotechnology, including the use of new gene-editing tools, have made possible the development of promising, complex neural transplant-based strategies. Adopting a multi-pronged strategy that is tailored to underlying neural pathology and that encompasses facilitation of endogenous regeneration, correction of patient’s genomic mutations and delivery of transformed neural precursors and mature disease-relevant neuronal populations to replace injured or lost neural tissue remains no longer a fantasy.

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<![CDATA[Human Umbilical Mesenchymal Stem Cells Display Therapeutic Potential in Rheumatoid Arthritis by Regulating Interactions Between Immunity and Gut Microbiota via the Aryl Hydrocarbon Receptor]]> https://www.researchpad.co/article/N47c116e7-c646-41f6-8a64-8a1bdec05c41

Background

Rheumatoid arthritis (RA) is an autoimmune disease that may be associated with gut microbiota via the aryl hydrocarbon receptor (AhR). Human umbilical mesenchymal stem cells (HUMSCs) have therapeutic potential against RA, but the underlying mechanism has not been fully elucidated. The purpose of this study was to explore the mechanism of action of HUMSCs in rats with collagen-induced arthritis (CIA).

Method

HUMSCs (1 × 106) were transplanted into each rat with CIA. The tissue localization of HUMSCs and the therapeutic effects in the ankles were assessed. The immune status and expression of immune-related genes and proteins in related lymphoid tissues were subsequently tested. Furthermore, the levels of immune-related factors in serum and the changes in gut microbiota in the ileum were detected, and the levels of indole and their derivatives in plasma and the levels of AhR in the ileum were evaluated.

Results

HUMSCs homed to the popliteal lymph node (PLN), mesenteric lymph node (MLN), ankle cartilage, and ileum mucosa in rats with CIA. The transplantation of HUMSCs reduced the pathology scores and the degree of bone damage in the ankles. The immune status of T regulatory cells (Tregs) and T helper (Th)17 cells and the gene expression levels of interleukin (IL)-10, transforming growth factor (TGF)-β1, and IL-17A were altered in the PLN, which is the lymph tissue closest to the nidus, and the MLN, which is one of the gut-associated lymphoid tissues (GALTs). The proportion and function of B cells, Tregs, and Th17 cells were regulated in other GALTs, namely, Peyer’s patches and the lamina propria. The gene expression of TGF-β1 and IL-17A and protein expression of IL-10, TGF-β1, IL-17A, IL-22, and immunoglobulin A (IgA) were modulated in the ileum, and the serum levels of IL-10, TGF-β1, IL-17A, IL-1β, and tumor necrosis factor (TNF)-α were regulated in the rats with CIA. The relative abundances of the genera Bacteroides and Bacillus were increased in the HUMSCs-treated rat with CIA; in addition, the levels of indole, indoleacetic acid, and indole-3-lactic acid were consistently upregulated, and this upregulation was accompanied by increases in AhR gene and protein expression.

Conclusion

Our study demonstrates that HUMSCs play a therapeutic role in rats with CIA by regulating the interactions between host immunity and gut microbiota via the AhR.

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<![CDATA[A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration]]> https://www.researchpad.co/article/N9eac7440-41ad-476d-baad-6465f189c47e

Alzheimer's disease (AD, OMIM: 104300) is an age-related disorder that affects millions of people. One of the underlying causes of AD is generation of hydrophobic amyloid-beta 42 (Aβ42) peptides that accumulate to form amyloid plaques. These plaques induce oxidative stress and aberrant signaling, which result in the death of neurons and other pathologies linked to neurodegeneration. We have developed a Drosophila eye model of AD by targeted misexpression of human Aβ42 in the differentiating retinal neurons, where an accumulation of Aβ42 triggers a characteristic neurodegenerative phenotype. In a forward deficiency screen to look for genetic modifiers, we identified a molecularly defined deficiency, which suppresses Aβ42-mediated neurodegeneration. This deficiency uncovers hippo (hpo) gene, a member of evolutionarily conserved Hippo signaling pathway that regulates growth. Activation of Hippo signaling causes cell death, whereas downregulation of Hippo signaling triggers cell proliferation. We found that Hippo signaling is activated in Aβ42-mediated neurodegeneration. Downregulation of Hippo signaling rescues the Aβ42-mediated neurodegeneration, whereas upregulation of Hippo signaling enhances the Aβ42-mediated neurodegeneration phenotypes. It is known that c-Jun-amino-terminal kinase (JNK) signaling pathway is upregulated in AD. We found that activation of JNK signaling enhances the Aβ42-mediated neurodegeneration, whereas downregulation of JNK signaling rescues the Aβ42-mediated neurodegeneration. We tested the nature of interactions between Hippo signaling and JNK signaling in Aβ42-mediated neurodegeneration using genetic epistasis approach. Our data suggest that Hippo signaling and JNK signaling, two independent signaling pathways, act synergistically upon accumulation of Aβ42 plaques to trigger cell death. Our studies demonstrate a novel role of Hippo signaling pathway in Aβ42-mediated neurodegeneration.

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<![CDATA[Upregulation of RND3 Affects Trophoblast Proliferation, Apoptosis, and Migration at the Maternal-Fetal Interface]]> https://www.researchpad.co/article/N7f7ae30a-29a5-43a5-8821-9da1b87d6e2a

Trophoblasts as the particular cells of the placenta play an important role in implantation and formation of the maternal-fetal interface. RND3 (also known as RhoE) is a unique member of the Rnd subfamily of small GTP-binding proteins. However, its function in cytotrophoblasts (CTBs) at the maternal-fetal interface is poorly understood. In the present study, we found that RND3 expression was significantly increased in trophoblasts from the villous tissues of patients with recurrent miscarriage (RM). RND3 inhibited proliferation and migration and promoted apoptosis in HTR-8/SVneo cells. Using dual-luciferase reporter and chromatin immunoprecipitation assays, we found that forkhead box D3 (FOXD3) is a key transcription factor that binds to the RND3 core promoter region and regulates RND3 expression. Here, the level of FOXD3 was upregulated in the first-trimester CTBs of patients with RM, which in turn mediated RND3 function, including inhibition of cell proliferation and migration and promotion of apoptosis. Further, we found that RND3 regulates trophoblast migration and proliferation via the RhoA-ROCK1 signaling pathway and inhibits apoptosis via ERK1/2 signaling. Taken together, our findings suggest that RND3 and FOXD3 may be involved in pathogenesis of RM and may serve as potential therapeutic targets.

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<![CDATA[Mesenchymal Stem Cell-Derived Extracellular Vesicles: Challenges in Clinical Applications]]> https://www.researchpad.co/article/Nb2c682d9-77a5-4361-9565-e475b1b1a32d

Stem cell therapy has garnered much attention and application in the past decades for the treatment of diseases and injuries. Mesenchymal stem cells (MSCs) are studied most extensively for their therapeutic roles, which appear to be derived from their paracrine activity. Recent studies suggest a critical therapeutic role for extracellular vesicles (EV) secreted by MSCs. EV are nano-sized membrane-bound vesicles that shuttle important biomolecules between cells to maintain physiological homeostasis. Studies show that EV from MSCs (MSC-EV) have regenerative and anti-inflammatory properties. The use of MSC-EV, as an alternative to MSCs, confers several advantages, such as higher safety profile, lower immunogenicity, and the ability to cross biological barriers, and avoids complications that arise from stem cell-induced ectopic tumor formation, entrapment in lung microvasculature, and immune rejection. These advantages and the growing body of evidence suggesting that MSC-EV display therapeutic roles contribute to the strong rationale for developing EV as an alternative therapeutic option. Despite the success in preclinical studies, use of MSC-EV in clinical settings will require careful consideration; specifically, several critical issues such as (i) production methods, (ii) quantification and characterization, (iii) pharmacokinetics, targeting and transfer to the target sites, and (iv) safety profile assessments need to be resolved. Keeping these issues in mind, the aim of this mini-review is to shed light on the challenges faced in MSC-EV research in translating successful preclinical studies to clinical platforms.

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<![CDATA[Mechanical Regulation of Nuclear Translocation in Migratory Neurons]]> https://www.researchpad.co/article/N8b9fb5d3-12c2-44ed-9523-727b79f772f2

Neuronal migration is a critical step during the formation of functional neural circuits in the brain. Newborn neurons need to move across long distances from the germinal zone to their individual sites of function; during their migration, they must often squeeze their large, stiff nuclei, against strong mechanical stresses, through narrow spaces in developing brain tissue. Recent studies have clarified how actomyosin and microtubule motors generate mechanical forces in specific subcellular compartments and synergistically drive nuclear translocation in neurons. On the other hand, the mechanical properties of the surrounding tissues also contribute to their function as an adhesive support for cytoskeletal force transmission, while they also serve as a physical barrier to nuclear translocation. In this review, we discuss recent studies on nuclear migration in developing neurons, from both cell and mechanobiological viewpoints.

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<![CDATA[MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers]]> https://www.researchpad.co/article/N4ce9eb9c-1715-4aa2-bbaa-1a8a79fb881c

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are components of many signaling pathways associated with tumor aggressiveness and cancer metastasis. Some lncRNAs are classified as competitive endogenous RNAs (ceRNAs) that bind to specific miRNAs to prevent interaction with target mRNAs. Studies have shown that the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-Met) pathway is involved in physiological and pathological processes such as cell growth, angiogenesis, and embryogenesis. Overexpression of c-Met can lead to sustained activation of downstream signals, resulting in carcinogenesis, metastasis, and resistance to targeted therapies. In this review, we evaluated the effects of anti-oncogenic and oncogenic non-coding RNAs (ncRNAs) on c-Met, and the interactions among lncRNAs, miRNAs, and c-Met in cancer using clinical and tissue chromatin immunoprecipition (ChIP) analysis data. We summarized current knowledge of the mechanisms and effects of the lncRNAs/miR-34a/c-Met axis in various tumor types, and evaluated the potential therapeutic value of lncRNAs and/or miRNAs targeted to c-Met on drug-resistance. Furthermore, we discussed the functions of lncRNAs and miRNAs in c-Met-related carcinogenesis and potential therapeutic strategies.

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