scholarly journals Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

2021 ◽  
Vol 9 ◽  
Author(s):  
Marijn F. Stokman ◽  
Sophie Saunier ◽  
Alexandre Benmerah
Keyword(s):  
Animal Models ◽  
Signaling Pathways ◽  
Kidney Development ◽  
Critical Role ◽  
Model Systems ◽  
Therapeutic Approaches ◽  
Infantile Form ◽  
Juvenile Form

Nephronophthisis (NPH) is an autosomal recessive ciliopathy and a major cause of end-stage renal disease in children. The main forms, juvenile and adult NPH, are characterized by tubulointerstitial fibrosis whereas the infantile form is more severe and characterized by cysts. NPH is caused by mutations in over 20 different genes, most of which encode components of the primary cilium, an organelle in which important cellular signaling pathways converge. Ciliary signal transduction plays a critical role in kidney development and tissue homeostasis, and disruption of ciliary signaling has been associated with cyst formation, epithelial cell dedifferentiation and kidney function decline. Drugs have been identified that target specific signaling pathways (for example cAMP/PKA, Hedgehog, and mTOR pathways) and rescue NPH phenotypes in in vitro and/or in vivo models. Despite identification of numerous candidate drugs in rodent models, there has been a lack of clinical trials and there is currently no therapy that halts disease progression in NPH patients. This review covers the most important findings of therapeutic approaches in NPH model systems to date, including hypothesis-driven therapies and untargeted drug screens, approached from the pathophysiology of NPH. Importantly, most animal models used in these studies represent the cystic infantile form of NPH, which is less prevalent than the juvenile form. It appears therefore important to develop new models relevant for juvenile/adult NPH. Alternative non-orthologous animal models and developments in patient-based in vitro model systems are discussed, as well as future directions in personalized therapy for NPH.

Combining galiximab with the chemotherapeutic agents fludarabine or doxorubicin improves efficacy in animal models of lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3040-3040 ◽  
Author(s):  
H. K. Hariharan ◽  
T. Murphy ◽  
D. Clanton ◽  
L. Berquist ◽  
P. Chu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Clinical Benefit ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Chemotherapeutic Agents ◽  
Model Systems ◽  
Anti Cd20

3040 Background: Galiximab, a primatized monoclonal antibody that binds with high affinity to CD80 and mediates antibody- dependent, cell-mediated cytotoxicity in vitro, is currently under investigation for the treatment of follicular non-Hodgkin’s lymphoma (NHL). In a phase I/II monotherapy study, galiximab produced an overall response rate of 11%, and tumor reductions were observed in 46% of patients. Initial clinical trials also demonstrate that galiximab is well tolerated and suggest that combining galiximab with rituximab (anti-CD20) provides clinical benefit. These results are consistent with preclinical studies in murine lymphoma xenograft model systems, which demonstrate the superiority of combination therapy. Methods: To further define the therapeutic potential of galiximab, the Raji subcutaneous and the SKW disseminated lymphoma murine xenograft models were used to define the in vivo efficacy of galiximab alone or in combination with fludarabine or doxorubicin. Similar studies were performed with rituximab. Results: In the Raji model, both galiximab and rituximab exhibited maximal inhibition of the growth of preestablished (150-mg) tumors at a dose of 3 mg/kg/wk. Interestingly, higher doses of galiximab (but not rituximab) showed reduced inhibition. Galiximab (3 mg/kg/wk) inhibited tumor growth alone (P<0.0001 vs. control) and showed significantly enhanced activity when combined with fludarabine (50 or 100 mg/kg daily for 5 days; P<0.0002 vs. galiximab alone and P<0.003 vs. fludarabine alone). Similar results were observed with rituximab. In the SKW model, treatment with galiximab (5 mg/kg/wk for 6 doses) significantly enhanced survival compared with a control (P<0.0001) or doxorubicin (2.5 mg/kg/day for 3 doses; P<0.0001). Studies combining fludarabine or doxorubicin with both galiximab and rituximab are ongoing. Conclusions: Studies in animal models of lymphoma indicate that galiximab may provide clinical benefit when used in combination with chemotherapeutic agents such as fludarabine and doxorubicin, and provide a rationale for the investigation of these novel chemoimmunotherapy combinations in clinical trials. No significant financial relationships to disclose.

Abstract 12518: MicroRNA 139-5p Coordinates APLNR-CXCR4 Crosstalk During Vascular Maturation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Irinna Papangeli ◽  
Jongmin Kim ◽  
Inna Maier ◽  
Yujung Kang ◽  
Keiichiro Tanaka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathways ◽  
Critical Role ◽  
Stalk Cell ◽  
Cell Populations ◽  
Branch Points ◽  
In Vitro Techniques ◽  
Vascular Maturation

Rationale: Sprouting angiogenesis is governed by the concept of tip/stalk cells that guides our understanding of the transition from vascular sprouting to maturation and ultimately quiescence. The VEGF and Notch signaling pathways have been extensively described in regulating the discrimination between these two cell populations. However, several additional tip and stalk cell specific genes have been identified. To date, unresolved questions remain, and our understanding of the mechanisms by which these signaling processes are integrated is incomplete. Objective: We set out to investigate novel mechanisms by which signaling pathways involving two G protein coupled receptors (GPCRs), expressed in a mutually exclusive fashion in the tip/stalk cell populations, are intricately linked in vascular development. Methods/Results: Using a combination of in vivo and in vitro techniques, we demonstrate the critical role of crosstalk between APLNR and CXCR4 in vascular maturation. We show robust flow induced expression of the stalk cell specific APLNR, that leads to marked suppression of CXCR4 expression, a mechanism to achieve tip cell restricted expression of the latter. Retinas from Apln (ligand), Aplnr (receptor) and endothelial specific Aplnr deleted mice show retarded vascular expansion, reduced vascularized area and fewer vascular branch points. These phenotypes are in part due to increased expression of Cxcr4 in Apln-/- and Aplnr-/- retinal vessels as Cxcr4 inhibition through a selective inhibitor can ameliorate the Aplnr phenotype. The crosstalk between the two GPCRs was found to involve a key shear responsive microRNA, miR-139-5p, which is upregulated by APLN/APLNR signaling and directly targets CXCR4 in endothelial cells. In accordance, Apln-/- and Aplnr-/- retinal endothelial cells showed depleted levels of miR-139-5p. Lastly, we demonstrate that atorvastatin, an HMG-CoA reductase inhibitor shown to enhance APLNR signaling, can induce miR-139-5p expression and rescue the vascular phenotypes associated with APLN/APLNR deficiency. Conclusions: These findings provide key mechanistic insights into a critical microRNA based crosstalk between two GPCR signaling cascades, which regulates important steps in vascular maturation.

A Comprehensive Review on Preclinical Diabetic Models

2020 ◽  
Vol 16 (2) ◽  
pp. 104-116
Author(s):  
Anshul Shakya ◽  
Sushil Kumar Chaudary ◽  
Debapriya Garabadu ◽  
Hans Raj Bhat ◽  
Bibhuti Bhusan Kakoti ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Animal Models ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Ongoing Research ◽  
Chronic Hyperglycemia ◽  
Limited Effectiveness

Background: Preclinical experimental models historically play a critical role in the exploration and characterization of disease pathophysiology. Further, these in-vivo and in-vitro preclinical experiments help in target identification, evaluation of novel therapeutic agents and validation of treatments. Introduction: Diabetes mellitus (DM) is a multifaceted metabolic disorder of multidimensional aetiologies with the cardinal feature of chronic hyperglycemia. To avoid or minimize late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic manifestations, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. Methods: The study included electronic databases such as Pubmed, Web of Science and Scopus. The datasets were searched for entries of studies up to June, 2018. Results: A large number of in-vivo and in-vitro models have been presented for evaluating the mechanism of anti-hyperglycaemic effect of drugs in hormone-, chemically-, pathogen-induced animal models of diabetes mellitus. The advantages and limitations of each model have also been addressed in this review. Conclusion: This review encompasses the wide pathophysiological and molecular mechanisms associated with diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. This review may further contribute to discover a novel drug to treat diabetes more efficaciously with minimum or no side effects. Furthermore, it also highlights ongoing research and considers the future perspectives in the field of diabetes.

The Role of VEGFA in Malignant Progression in AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 203-203 ◽  
Author(s):  
Alida C Weidenaar ◽  
Arja ter Elst ◽  
Henk-Marijn de Jonge ◽  
Tiny Meeuwsen-de Boer ◽  
Willem A Kamps ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Critical Role ◽  
Malignant Progression ◽  
Endothelial Cell Proliferation ◽  
Receptor Interaction ◽  
Apoptosis Pathway

Abstract Vascular Endothelial Growth Factor (VEGFA) at time of diagnosis is an independent prognostic factor for poor treatment outcome in (pediatric) acute myeloid leukemia (AML). Inhibition of VEGFA by Bevacizumab, a recombinant humanized monoclonal antibody, preceded by chemotherapy yields a favorable CR rate and duration in adults with refractory AML (Karp et al., 2004). VEGFA is a powerful stimulator of angiogenesis; VEGFA binds to the tyrosine kinase receptors VEGFR1 and VEGFR2 on endothelial cells, resulting in endothelial cell proliferation. Moreover, binding of VEGFA to VEGF receptors on AML cells in vitro promotes leukemic cell survival via activation of signaling pathways such as RAS/Raf/MEK/ERK and PI3K/AKT pathway. In our study a model was generated to investigate the effect of VEGFA in malignant progression in AML. An HL-60 AML cell line was transduced with VEGFA (the splice variant VEGFA165) or a control vector using a retroviral construct. With RT-PCR we found a threefold induction of VEGFA in VEGFA165 transduced cells. No difference in growth rate and drug sensitivity was found between the HL-60 VEGFA165 cells and HL-60 control cells in vitro. Thus, VEGFA165 overexpression did not result in growth benefit in vitro. To evaluate the in vivo effects of VEGFA165 overexpression, we injected 10 × 106 HL-60 VEGFA165 cells or HL-60 control cells s.c. into NOD/SCID mice (n=14). We observed that overexpression of VEGFA165 increased tumor weight (median weight: HL-60 VEGFA165 tumors 995 mg, range 670–1344; HL-60 control tumors 464 mg, range 413–646; p=0.001). So, the effects of AML overexpressed VEGFA165 are detectable in combination with its environment. Using gene expression profiles (Affymetrix) we found differentially activated signaling pathways, e.g. the PI3K/AKT (p&lt;0.001), MAPK (p&lt;0.001), Jak-STAT (p&lt;0.001) and VEGF-pathway (p&lt;0.001), as well as pathways involved in cell interaction. With GeneTrail (a web-based application that scores a sorted list of genes with respect to their enrichment of functional categories) and the transcriptional system regulator approach (De Jonge et al., 2008) we could demonstrate that the Jak-STAT pathway (p=0.02) as well as the apoptosis pathway (p=0.04) was more active in the VEGFA165 HL-60 tumors, whereas the cytokine-cytokine receptor interaction was more active in de HL-60 control tumors (p=0.02). In addition, we found differential expression of the process angiogenesis (p=0.002). Cell proliferation within the tumors was verified by staining for Ki67; the HL-60 VEGFA165 tumor cells showed more proliferation than the HL-60 control tumor cells, as a netto result of multiple signaling pathway activation (p=0.02). In conclusion, overexpression of VEGFA165 did not have a growth benefit in vitro, whereas in vivo an increase in tumor volume was seen when VEGFA165 was overexpressed. VEGFA related pro-angiogenic effects are found in the AML tumor cells as well as enhanced signaling and proliferation in AML tumor cells in vivo. Therefore, the interaction of VEGFA165 with its environment plays a critical role in the malignant progression in AML. New design drugs related to VEGF/VEGFR interaction need to be tested in context of a tumor in its environment.

scholarly journals Seeing is believing: methods to monitor vertebrate autophagy in vivo

Open Biology ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. 180106 ◽  
Author(s):  
Ana Lopez ◽  
Angeleen Fleming ◽  
David C. Rubinsztein
Keyword(s):  
Therapeutic Strategy ◽  
Critical Role ◽  
Model Systems ◽  
Protein Homeostasis ◽  
Pathological Conditions ◽  
Intracellular Regulation ◽  
Vertebrate Model ◽  
Nervous System Function

Autophagy is an intracellular clearance pathway that delivers cytoplasmic contents to the lysosome for degradation. It plays a critical role in maintaining protein homeostasis and providing nutrients under conditions where the cell is starved. It also helps to remove damaged organelles and misfolded or aggregated proteins. Thus, it is not surprising that defects in this pathway are associated with a variety of pathological conditions, such as neurodegeneration, cancer and infection. Pharmacological upregulation of autophagy is considered a promising therapeutic strategy for the treatment of neurodegenerative and infectious diseases. Studies in knockout mice have demonstrated that autophagy is essential for nervous system function, and data from invertebrate and vertebrate models suggest that the efficiency of autophagic processes generally declines with age. However, much of our understanding of the intracellular regulation of autophagy comes from in vitro studies, and there is a paucity of knowledge about how this process is regulated within different tissues and during the processes of ageing and disease. Here, we review the available tools to probe these questions in vivo within vertebrate model systems. We discuss how these tools have been used to date and consider future avenues of research.

scholarly journals Animal Studies of Colon Carcinogenesis and Altered Epithelial Cell Differentiation

1990 ◽  
Vol 4 (7) ◽  
pp. 372-377
Author(s):  
Hugh J Freeman
Keyword(s):  
Colon Cancer ◽  
Animal Models ◽  
Critical Role ◽  
Intestinal Resection ◽  
Chronic Inflammatory Bowel Disease ◽  
Human Colon Cancer ◽  
Specific Chemical ◽  
Cancer Pathogenesis

Chronic inflammatory bowel disease (IBD) appears to predispose to subsequent colon cancer. Factors that influence the degree of this risk require definition since the reported incidence of malignant change varies widely. Differing environmental factors such as diet may be critical, and several approaches have been used to explore the role of specific variables in colon cancer pathogenesis; one has employed the use of animal models. Naturally occurring models of colon cancer exist including cotton-topped tamarins with colitis. Best studied, however, are animal models of colon cancer induced with specific chemical carcinogens. Cycasin and hydrazine derivatives, eg, 1,2-dimethylhydrazine, are most widely used. After parenteral administration of an active carcinogen, metabolic activation occurs, resulting in colonic adenocarcinomas. Sessile and polypoid neoplasms may be induced, particularly in the distal colon, similar to human colon cancer. Using this model, the effect of differing dietary and therapeutic variables has been explored. Studies with purified single dietary fibres, such as microcrystalline cellulose and hemicellulose, but not pectin, have demonstrated reduced numbers of colonic tumours; these in vivo observations correlate with in vitro effects of fibres on rat luminal and fecal mutagenic activities. Specific therapies used in IBD have also been evaluated - metronidazole, for example, a bacterial mutagen, enhances the development of chemically induced rodent colon cancer. In addition, a significant increase in colonic tumour development occurs after intestinal resection or bypass, two procedures used in the surgical management of IBD. In this setting, surgical sutures, particularly nonabsorbable materials including stainless steel, may play a critical role. Although the extent and duration of disease in patients with chronic IBD may be important in colon cancer pathogenesis, other variables, including diet and treatment, may be critical modulating factors.

scholarly journals Mastomys Species as Model Systems for Infectious Diseases

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 182 ◽  
Author(s):  
Daniel Hasche ◽  
Frank Rösl
Keyword(s):  
Animal Models ◽  
Laboratory Mouse ◽  
Model Systems ◽  
Experimental Systems ◽  
Non Melanoma Skin Cancer ◽  
In Vitro Systems ◽  
Mastomys Coucha ◽  
First Time

Replacements of animal models by advanced in vitro systems in biomedical research, despite exceptions, are currently still not satisfactory in reproducing the whole complexity of pathophysiological mechanisms that finally lead to disease. Therefore, preclinical models are additionally required to reflect analogous in vivo situations as found in humans. Despite proven limitations of both approaches, only a combined experimental arrangement guarantees generalizability of results and their transfer to the clinics. Although the laboratory mouse still stands as a paradigm for many scientific discoveries and breakthroughs, it is mandatory to broaden our view by also using nontraditional animal models. The present review will first reflect the value of experimental systems in life science and subsequently describes the preclinical rodent model Mastomys coucha that—although still not well known in the scientific community—has a long history in research of parasites, bacteria, papillomaviruses and cancer. Using Mastomys, we could recently show for the first time that cutaneous papillomaviruses—in conjunction with UV as an environmental risk factor—induce squamous cell carcinomas of the skin via a “hit-and-run” mechanism. Moreover, Mastomys coucha was also used as a proof-of-principle model for the successful vaccination against non-melanoma skin cancer even under immunosuppressive conditions.

scholarly journals Phytochemicals as Anti-Inflammatory Agents in Animal Models of Prevalent Inflammatory Diseases

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5932
Author(s):  
Seong Ah Shin ◽  
Byeong Jun Joo ◽  
Jun Seob Lee ◽  
Gyoungah Ryu ◽  
Minjoo Han ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Defense Mechanism ◽  
Inflammatory Diseases ◽  
Disease Model ◽  
Model Systems ◽  
Molecular Signaling ◽  
Chronic Inflammatory Diseases ◽  
Anti Inflammatory

Phytochemicals are known to have anti-inflammatory effects in vitro and in vivo, such as in inflammatory disease model systems. Inflammation is an essential immune response to exogenous stimuli such as infection and injury. Although inflammation is a necessary host-defense mechanism, chronic inflammation is associated with the continuous local or systemic release of inflammatory mediators, non-cytokine mediators, such as ROS and NO, and inflammatory cytokines are strongly implicated in the pathogenesis of various inflammatory disorders. Phytochemicals that exhibit anti-inflammatory mechanisms that reduce sustained inflammation could be therapeutic candidates for various inflammatory diseases. These phytochemicals act by modulating several main inflammatory signaling pathways, including NF-κB, MAPKs, STAT, and Nrf-2 signaling. Here, we discuss the characteristics of phytochemicals that possess anti-inflammatory activities in various chronic inflammatory diseases and review the molecular signaling pathways altered by these anti-inflammatory phytochemicals, with a focus on transcription factor pathways. Furthermore, to evaluate the phytochemicals as drug candidates, we translate the effective doses of phytochemicals in mice or rat disease models into the human-relevant equivalent and compare the human-relevant equivalent doses of several phytochemicals with current anti-inflammatory drugs doses used in different types of chronic inflammatory diseases.

scholarly journals ADP-dependent glucokinase regulates energy metabolism via ER-localized glucose sensing

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Roland Imle ◽  
Bei-Tzu Wang ◽  
Nicolas Stützenberger ◽  
Jana Birkenhagen ◽  
Amol Tandon ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Energy Metabolism ◽  
Critical Role ◽  
Receptor Activation ◽  
Glucose Sensing ◽  
Model Systems ◽  
Jurkat T Cells

Abstract Modulation of energy metabolism to a highly glycolytic phenotype, i.e. Warburg effect, is a common phenotype of cancer and activated immune cells allowing increased biomass-production for proliferation and cell division. Endoplasmic reticulum (ER)-localized ADP-dependent glucokinase (ADPGK) has been shown to play a critical role in T cell receptor activation-induced remodeling of energy metabolism, however the underlying mechanisms remain unclear. Therefore, we established and characterized in vitro and in vivo models for ADPGK-deficiency using Jurkat T cells and zebrafish. Upon activation, ADPGK knockout Jurkat T cells displayed increased cell death and ER stress. The increase in cell death resulted from a metabolic catastrophe and knockout cells displayed severely disturbed energy metabolism hindering induction of Warburg phenotype. ADPGK knockdown in zebrafish embryos led to short, dorsalized body axis induced by elevated apoptosis. ADPGK hypomorphic zebrafish further displayed dysfunctional glucose metabolism. In both model systems loss of ADPGK function led to defective N- and O-glycosylation. Overall, our data illustrate that ADPGK is part of a glucose sensing system in the ER modulating metabolism via regulation of N- and O-glycosylation.

scholarly journals Social communication between microbes colonizing the social honey bee Apis mellifera

2018 ◽  
Author(s):  
K.I. Miller ◽  
C.D. Franklin ◽  
H. R. Mattila ◽  
I.L.G. Newton
Keyword(s):  
Apis Mellifera ◽  
Quorum Sensing ◽  
Microbial Communities ◽  
Honey Bee ◽  
Biofilm Formation ◽  
Critical Role ◽  
Model Systems ◽  
Native Flora

AbstractThe European honey bee (Apis mellifera) is a charismatic species that plays a critical role in the pollination of agriculturally important crops and native flora. One emerging field of research is that of the host-associated honey bee microbiome: a group of bacterial phylotypes consistently found within the honey bee, which may play critical roles such as protection from pathogens and nutrient acquisition. In other model systems, host-associated microbial communities are known to participate in a form of bacterial communication known as quorum sensing. This type of communication allows bacteria to sense their environment and respond with changes in gene expression, controlling a number of factors including virulence, biofilm formation, and cell motility. Here, we have investigated the production of a specific quorum sensing molecule by honey bee microbes in vivo and in vitro. We specifically focused on the inter-species signaling molecule, autoinducer-2 (AI-2). We identified the production of AI-2 by both the entire community (using honey bee gut homogenates) and by cultured isolates, using a Vibrio harveyi biosensor. By comparing newly emerged and adult bees, we showed this signal is likely coming from the core microbial community. Finally, using honey bee specific bacterial isolates, we identified changes in biofilm production when isolates are exposed to increased levels of exogenous AI-2. Altogether, these data provide multiple lines of evidence for the presence of quorum sensing inside the honey bee host. The effect of AI-2 on biofilm formation by honey bee specific bacteria identifies one potential avenue for quorum sensing to affect host health.Author summaryMicrobial communities associate with every animal on the planet and can have dramatic effects on the health of their host. The honey bee is one such animal, home to a characteristic community of bacteria, which may provide various benefits. Here, we show that these microbes are producing quorum sensing molecules which could support interactions between bacterial members and facilitate host colonization.

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