bims-bicyki 2021-10-03 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2021–10–03
27 papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases.
Retarding Progression of Chronic Kidney Disease in Autosomal Dominant Polycystic Kidney Disease with Metformin and Other Therapies: An Update of New Insights.
Cilia kinases in skeletal development and homeostasis.
Impaired Ciliary Beat Frequency and Ciliogenesis Alteration during Airway Epithelial Cell Differentiation in COPD.
Addition of ROCK inhibitors to prostaglandin derivative (PG) synergistically affects adipogenesis of the 3D spheroids of human orbital fibroblasts (HOFs).
The Transformation of the Centrosome into the Basal Body: Similarities and Dissimilarities between Somatic and Male Germ Cells and Their Relevance for Male Fertility.
Bardet-Biedl syndrome proteins modulate the release of bioactive extracellular vesicles.
Giant haemorrhagic hepatic cyst with flame-like morphology in a patient with polycystic kidney and liver disease.
Autophagy-mediated reduction of miR-345 contributes to hepatic cystogenesis in polycystic liver disease.
Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia.
Entropy Production in Electroosmotic Cilia Facilitated Stream of Thermally Radiated Nanofluid with Ohmic Heating.
Ciliary Videomicroscopy: A Long Beat from the European Respiratory Society Guidelines to the Recognition as a Confirmatory Test for Primary Ciliary Dyskinesia.
The localization of amyloid precursor protein to ependymal cilia in vertebrates and its role in ciliogenesis and brain development in zebrafish.
Current and Future Treatments in Primary Ciliary Dyskinesia.
The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes.
Vaptans or voluntary increased hydration to protect the kidney: how do they compare?
MR Brain Screening in ADPKD Patients : To Screen or not to Screen?
Design, Synthesis and Biological Evaluation of Urea-based ROCK2 inhibitors.
Soft surfaces promote astrocytic differentiation of mouse embryonic neural stem cells via dephosphorylation of MRLC in the absence of serum.
LRRC23 is a conserved component of the radial spoke that is necessary for sperm motility and male fertility in mice.
NADPH-Oxidase, Rho-Kinase and Autophagy Mediate the (Pro)renin-Induced Pro-Inflammatory Microglial Response and Enhancement of Dopaminergic Neuron Death.
Untangling the complexities of micropapillary cancer†.
A Comprehensive Approach for the Diagnosis of Primary Ciliary Dyskinesia-Experiences from the First 100 Patients of the PCD-UNIBE Diagnostic Center.
Feasibility of nasal NO screening in healthy newborns.
FAK Shutdown: Consequences on Epithelial Morphogenesis and Biomarker Expression Involving an Innovative Biomaterial for Tissue Regeneration.
Design and development of novel fasudil derivatives as potent anti-breast cancer agent that improves intestinal flora and intestinal barrier function in rats.
Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries.

Front Physiol. 2021 ;12 693130

Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases.

Valeriia Y Vasileva, Regina F Sultanova, Anastasia V Sudarikova, Daria V Ilatovskaya.

  Autosomal dominant (AD) and autosomal recessive (AR) polycystic kidney diseases (PKD) are severe multisystem genetic disorders characterized with formation and uncontrolled growth of fluid-filled cysts in the kidney, the spread of which eventually leads to the loss of renal function. Currently, there are no treatments for ARPKD, and tolvaptan is the only FDA-approved drug that alleviates the symptoms of ADPKD. However, tolvaptan has only a modest effect on disease progression, and its long-term use is associated with many side effects. Therefore, there is still a pressing need to better understand the fundamental mechanisms behind PKD development. This review highlights current knowledge about the fundamental aspects of PKD development (with a focus on ADPKD) including the PC1/PC2 pathways and cilia-associated mechanisms, major molecular cascades related to metabolism, mitochondrial bioenergetics, and systemic responses (hormonal status, levels of growth factors, immune system, and microbiome) that affect its progression. In addition, we discuss new information regarding non-pharmacological therapies, such as dietary restrictions, which can potentially alleviate PKD.

Keywords:  calcium; cilia; microbiome; mitochondria; polycystic kidney disease

DOI:  https://doi.org/10.3389/fphys.2021.693130
Int J Gen Med. 2021 ;14 5993-6000

Retarding Progression of Chronic Kidney Disease in Autosomal Dominant Polycystic Kidney Disease with Metformin and Other Therapies: An Update of New Insights.

Nazareno Carullo, Maria Teresa Zicarelli, Alessandro Casarella, Ramona Nicotera, Alberto Castagna, Alessandra Urso, Pierangela Presta, Michele Andreucci, Emilio Russo, Davide Bolignano, Giuseppe Coppolino.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent single-gene disorder leading to renal failure. Current therapies are aimed to treat renal and extrarenal complications of ADPKD, but improved knowledge of the pathophysiological mechanisms leading to the generation and growth of cysts has permitted the identification of new drug candidates for clinical trials. Among these, in this review, we will examine above all the role of metformin, hypothesized to be able to activate the AMP-activated protein kinase (AMPK) pathway and potentially modulate some mechanisms implicated in the onset and the growth of the cysts.

Keywords:  chronic renal disease; cystogenesis; metformin; renal cells; renal tubule

DOI:  https://doi.org/10.2147/IJGM.S305491
Dev Dyn. 2021 Sep 28.

Cilia kinases in skeletal development and homeostasis.

Sara P Abraham, Alexandru Nita, Pavel Krejci, Michaela Bosakova.

  Primary cilia are dynamic compartments that regulate multiple aspects of cellular signaling. The production, maintenance and function of cilia involves more than 1,000 genes in mammals, and their mutations disrupt the ciliary signaling which manifests in a plethora of pathological conditions - the ciliopathies. Skeletal ciliopathies are genetic disorders affecting development and homeostasis of the skeleton, and encompass a broad spectrum of pathologies ranging from isolated polydactyly to lethal syndromic dysplasias. The recent advances in forward genetics allowed for identification of novel regulators of skeletogenesis, and revealed a growing list of ciliary proteins that are critical for signaling pathways implicated in bone physiology. Among these, a group of protein kinases involved in cilia assembly, maintenance, signaling and disassembly has emerged. In this review, we summarize the functions of cilia kinases in skeletal development and disease, and discuss the available and upcoming treatment options. This article is protected by copyright. All rights reserved.

Keywords:  cilia kinase; ciliopathy; endochondral bone formation; primary cilia; skeletal ciliopathy; skeletal dysplasia; skeletogenesis

DOI:  https://doi.org/10.1002/dvdy.426
Diagnostics (Basel). 2021 Aug 31. pii: 1579. [Epub ahead of print]11(9):

Impaired Ciliary Beat Frequency and Ciliogenesis Alteration during Airway Epithelial Cell Differentiation in COPD.

Julien Ancel, Randa Belgacemi, Zania Diabasana, Jeanne-Marie Perotin, Arnaud Bonnomet, Maxime Dewolf, Claire Launois, Pauline Mulette, Gaëtan Deslée, Myriam Polette, Valérian Dormoy.

  Chronic obstructive pulmonary disease (COPD) is a frequent respiratory disease. However, its pathophysiology remains partially elucidated. Epithelial remodeling including alteration of the cilium is a major hallmark of COPD, but specific assessments of the cilium have been rarely investigated as a diagnostic tool in COPD. Here we explore the dysregulation of the ciliary function (ciliary beat frequency (CBF)) and differentiation (multiciliated cells formation in air-liquid interface cultures) of bronchial epithelial cells from COPD (n = 17) and non-COPD patients (n = 15). CBF was decreased by 30% in COPD (11.15 +/- 3.37 Hz vs. 7.89 +/- 3.39 Hz, p = 0.037). Ciliary differentiation was altered during airway epithelial cell differentiation from COPD patients. While the number of multiciliated cells decreased (p < 0.005), the number of primary ciliated cells increased (p < 0.05) and primary cilia were shorter (p < 0.05). Altogether, we demonstrate that COPD can be considered as a ciliopathy through both primary non-motile cilia modifications (related to airway epithelial cell repair and remodeling) and motile cilia function impairment (associated with decrease sputum clearance and clinical respiratory symptoms). These observations encourage considering cilia-associated features in the complex COPD physiopathology and highlight the potential of cilia-derived biomarkers for diagnosis.

Keywords:  CBF; CiliOPD; airway epithelial cells; chronic obstructive pulmonary disease; cilia

DOI:  https://doi.org/10.3390/diagnostics11091579
Hum Cell. 2021 Sep 30.

Addition of ROCK inhibitors to prostaglandin derivative (PG) synergistically affects adipogenesis of the 3D spheroids of human orbital fibroblasts (HOFs).

Fumihito Hikage, Hanae Ichioka, Megumi Watanabe, Araya Umetsu, Hiroshi Ohguro, Yosuke Ida.

  To study the additive effects of Rho-associated coiled-coil containing protein kinase inhibitors, ripasudil (Rip) to bimatoprost acid (BIM-A) on orbital adipose tissue, three-dimensional (3D) cultures of human orbital fibroblasts (HOFs) were prepared and the physical properties including the 3D spheroid size and stiffness, lipid staining by BODIPY and the mRNA expression of adipogenesis-related genes, PPARγ and AP2, and extracellular matrix (ECM) including collagen (COL)1, 4 and 6, and fibronectin (FN) were analyzed. Adipogenesis (DIF+) induced (1) enlargement and increasing stiffness of the 3D HOFs spheroid, (2) increased lipid staining, the expression of adipogenesis-related gene expressions, and (3) the down-regulation of COL1 and FN and up-regulation of COL4 and COL6. In the presence of BIM-A, (1) such DIF+-induced changes in 3D spheroid size and stiffness were significantly inhibited or enhanced, respectively, (2) the lipid staining and its related gene expressions were significantly down-regulated, and (3) the expression of COL1 and COL6 were up-regulated. By the addition of Rip to BIM-A, the above BIM-A-induced effects were all inhibited, except for the up-regulation of COL6 and FN expression, that is, enlarging and decreasing stiffness, enhancement of lipid staining and its related gene expression, and down-regulation of COL1 expression. Our present study indicates that Rip significantly suppressed BIM-A-induced effects toward 3D HOFs spheroids.

Keywords:  Deepening of the upper eyelid sulcus (DUES); Human orbital fibroblasts (HOFs); ROCK; ROCK inhibitor; Rho-kinase; Three-dimensional (3D) tissue culture

DOI:  https://doi.org/10.1007/s13577-021-00623-y
Cells. 2021 Aug 31. pii: 2266. [Epub ahead of print]10(9):

The Transformation of the Centrosome into the Basal Body: Similarities and Dissimilarities between Somatic and Male Germ Cells and Their Relevance for Male Fertility.

Constanza Tapia Contreras, Sigrid Hoyer-Fender.

  The sperm flagellum is essential for the transport of the genetic material toward the oocyte and thus the transmission of the genetic information to the next generation. During the haploid phase of spermatogenesis, i.e., spermiogenesis, a morphological and molecular restructuring of the male germ cell, the round spermatid, takes place that includes the silencing and compaction of the nucleus, the formation of the acrosomal vesicle from the Golgi apparatus, the formation of the sperm tail, and, finally, the shedding of excessive cytoplasm. Sperm tail formation starts in the round spermatid stage when the pair of centrioles moves toward the posterior pole of the nucleus. The sperm tail, eventually, becomes located opposed to the acrosomal vesicle, which develops at the anterior pole of the nucleus. The centriole pair tightly attaches to the nucleus, forming a nuclear membrane indentation. An articular structure is formed around the centriole pair known as the connecting piece, situated in the neck region and linking the sperm head to the tail, also named the head-to-tail coupling apparatus or, in short, HTCA. Finally, the sperm tail grows out from the distal centriole that is now transformed into the basal body of the flagellum. However, a centriole pair is found in nearly all cells of the body. In somatic cells, it accumulates a large mass of proteins, the pericentriolar material (PCM), that together constitute the centrosome, which is the main microtubule-organizing center of the cell, essential not only for the structuring of the cytoskeleton and the overall cellular organization but also for mitotic spindle formation and chromosome segregation. However, in post-mitotic (G1 or G0) cells, the centrosome is transformed into the basal body. In this case, one of the centrioles, which is always the oldest or mother centriole, grows the axoneme of a cilium. Most cells of the body carry a single cilium known as the primary cilium that serves as an antenna sensing the cell's environment. Besides, specialized cells develop multiple motile cilia differing in substructure from the immotile primary cilia that are essential in moving fluids or cargos over the cellular surface. Impairment of cilia formation causes numerous severe syndromes that are collectively subsumed as ciliopathies. This comparative overview serves to illustrate the molecular mechanisms of basal body formation, their similarities, and dissimilarities, in somatic versus male germ cells, by discussing the involved proteins/genes and their expression, localization, and function. The review, thus, aimed to provide a deeper knowledge of the molecular players that is essential for the expansion of clinical diagnostics and treatment of male fertility disorders.

Keywords:  HTCA; acephalic spermatozoa syndrome; capitulum; centriole; centrosome; connecting piece; male fertility; proteome; segmented columns; sperm decapitation

DOI:  https://doi.org/10.3390/cells10092266
Nat Commun. 2021 Sep 27. 12(1): 5671

Bardet-Biedl syndrome proteins modulate the release of bioactive extracellular vesicles.

Ann-Kathrin Volz, Alina Frei, Viola Kretschmer, António M de Jesus Domingues, Rene F Ketting, Marius Ueffing, Karsten Boldt, Eva-Maria Krämer-Albers, Helen L May-Simera.

Primary cilia are microtubule based sensory organelles important for receiving and processing cellular signals. Recent studies have shown that cilia also release extracellular vesicles (EVs). Because EVs have been shown to exert various physiological functions, these findings have the potential to alter our understanding of how primary cilia regulate specific signalling pathways. So far the focus has been on lgEVs budding directly from the ciliary membrane. An association between cilia and MVB-derived smEVs has not yet been described. We show that ciliary mutant mammalian cells demonstrate increased secretion of small EVs (smEVs) and a change in EV composition. Characterisation of smEV cargo identified signalling molecules that are differentially loaded upon ciliary dysfunction. Furthermore, we show that these smEVs are biologically active and modulate the WNT response in recipient cells. These results provide us with insights into smEV-dependent ciliary signalling mechanisms which might underly ciliopathy disease pathogenesis.

DOI: https://doi.org/10.1038/s41467-021-25929-1
Ultrasound. 2021 Aug;29(3): 187-192

Giant haemorrhagic hepatic cyst with flame-like morphology in a patient with polycystic kidney and liver disease.

Ana Brusic, June Oo, Damien L Stella, Paul M Simkin, Benjamin Pt Loveday.

   Introduction: Intracystic haemorrhage is a rare complication of hepatic cysts, and is often mistaken for a malignant lesion.
Case Report: A 55-year-old female with a history of polycystic kidney and liver disease presented with a six-month history of abdominal distension, abdominal pain, early satiety, shortness of breath and 5 kg of weight loss. Imaging revealed a 20 cm mixed solid-cystic hepatic lesion containing peripheral avascular mobile echogenic material with a flame-like morphology. After experiencing symptomatic relief from ultrasound-guided aspiration, the patient underwent cyst fenestration for more definitive treatment.
Discussion: Haemorrhagic hepatic cysts are uncommon and may present on imaging as having lace-like retractile clot, internal layering or shading of separating blood products or avascular mobile flame-like excrescences. The presence of avascular mobile flame-like excrescences appears to be a unique feature of haemorrhagic hepatic cysts.
Conclusion: While haemorrhagic hepatic cysts are rare and commonly mistaken for biliary cystadenomas or adenocarcinomas, the identification of particular features on high-resolution magnetic resonance imaging and contrast-enhanced ultrasound can lead to the correct diagnosis.

Keywords:  Hepatic cyst; haemorrhagic cyst; polycystic liver disease

DOI:  https://doi.org/10.1177/1742271X20987263
JHEP Rep. 2021 Oct;3(5): 100345

Autophagy-mediated reduction of miR-345 contributes to hepatic cystogenesis in polycystic liver disease.

Tatyana Masyuk, Anatoliy Masyuk, Christy Trussoni, Brynn Howard, Jingyi Ding, Bing Huang, Nicholas LaRusso.

   Background & Aims: Polycystic liver disease (PLD) is characterised by increased autophagy and reduced miRNA levels in cholangiocytes. Given that autophagy has been implicated in miRNA regulation, we tested the hypothesis that increased autophagy accounts for miRNA reduction in PLD cholangiocytes (PLDCs) and accelerated hepatic cystogenesis.
Methods: We assessed miRNA levels in cultured normal human cholangiocytes (NHCs), PLDCs, and isolated PLDC autophagosomes by miRNA-sequencing (miRNA-seq), and miRNA targets by mRNA-seq. Levels of miR-345 and miR-345-targeted proteins in livers of animals and humans with PLD, in NHCs and PLDCs, and in PLDCs transfected with pre-miR-345 were assessed by in situ hybridisation (ISH), quantitative PCR, western blotting, and fluorescence confocal microscopy. We also assessed cell proliferation and cyst growth in vitro, and hepatic cystogenesis in vivo.
Results: In total, 81% of miRNAs were decreased in PLDCs, with levels of 10 miRNAs reduced by more than 10 times; miR-345 was the most-reduced miRNA. In silico analysis and luciferase reporter assays showed that miR-345 targets included cell-cycle and cell-proliferation-related genes [i.e. cell division cycle 25A (CDC25A), cyclin-dependent kinase 6 (CDK6), E2F2, and proliferating cell nuclear antigen (PCNA)]; levels of 4 studied miR-345 targets were increased in PLDCs at both the mRNA and protein levels. Transfection of PLDCs with pre-miR-345 increased miR-345 and decreased the expression of miR-345-targeted proteins, cell proliferation, and cyst growth in vitro. MiR-345 accumulated in autophagosomes in PLDCs but not NHCs. Inhibition of autophagy increased miR-345 levels, decreased the expression of miR-345-targeted proteins, and reduced hepatic cystogenesis in vitro and in vivo.
Conclusion: Autophagy-mediated reduction of miR-345 in PLDCs (i.e. miRNAutophagy) accelerates hepatic cystogenesis. Inhibition of autophagy restores miR-345 levels, decreases cyst growth, and is beneficial for PLD.
Lay summary: Polycystic liver disease (PLD) is an incurable genetic disorder characterised by the progressive growth of hepatic cysts. We found that hepatic cystogenesis is increased when the levels of miR-345 in PLD cholangiocytes (PLDCs) are reduced by autophagy. Restoration of miR-345 in PLDCs via inhibition of autophagy decreases hepatic cystogenesis and thus, is beneficial for PLD.

Keywords:  ADPKD, autosomal dominant polycystic kidney disease; ADPLD, autosomal dominant polycystic liver disease; AGO2, Argonaute 2; ALG8, alpha-1,3-glucosyltransferase; ALG9, alpha-1,2-mannosyltransferase; ARPKD, autosomal recessive polycystic kidney disease; CDC25A, cell division cycle 25A; CDK6, cyclin-dependent kinase 6; Cell cycle-related proteins; Cholangiocyte proliferation; Cholangiocytes; DNAJB11, DnaJ heat shock protein family (Hsp40) member B11; DZIP1L, DAZ interacting zinc finger protein 1 like; FDR, false discovery rate; GANAB, glucosidase II alpha subunit; GO, Gene Ontology; Genetic liver diseases; HCQ, hydroxychloroquine; ISH, in situ hybridisation; KEGG, Kyoto Encyclopedia of Genes and Genomes; LRP5, low-density lipoprotein receptor-related protein 5; NHC, normal human cholangiocyte; NRC, normal rat cholangiocyte; PCK, polycystic kidney; PCKC, polycystic kidney rat cholangiocyte; PCNA, proliferating cell nuclear antigen; PKD1/2, polycystic kidney disease 1/2; PKHD1, polycystic kidney and hepatic disease 1; PLD treatment; PLD, polycystic liver disease; PLDC, polycystic liver disease cholangiocyte; PRKCSH, protein kinase C substrate 80K-H; RPM, reads per million; SEC61B, SEC61 translocon subunit beta; SEC63, SEC63 homolog, protein translocation regulator; WT, wild type; mTOR, mammalian target of rapamycin; miRISC, RNA-induced silencing complex; miRNA-seq, miRNA-sequencing; snRNA, small nuclear RNA

DOI:  https://doi.org/10.1016/j.jhepr.2021.100345
Diagnostics (Basel). 2021 Aug 26. pii: 1550. [Epub ahead of print]11(9):

Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia.

Channa N Jayasena, Anu Sironen.

  Primary ciliary dyskinesia (PCD), a disease caused by the malfunction of motile cilia, manifests mainly with chronic recurrent respiratory infections. In men, PCD is also often associated with infertility due to immotile sperm. Since causative mutations for PCD were identified in over 50 genes, the role of these genes in sperm development should be investigated in order to understand the effect of PCD mutations on male fertility. Previous studies showed that different dynein arm heavy chains are present in respiratory cilia and sperm flagellum, which may partially explain the variable effects of mutations on airways and fertility. Furthermore, recent studies showed that male reproductive tract motile cilia may play an important part in sperm maturation and transport. In some PCD patients, extremely low sperm counts were reported, which may be due to motile cilia dysfunction in the reproductive tract rather than problems with sperm development. However, the exact roles of PCD genes in male fertility require additional studies, as do the treatment options. In this review, we discuss the diagnostic and treatment options for men with PCD based on the current knowledge.

Keywords:  ICSI; PCD; male fertility; sperm

DOI:  https://doi.org/10.3390/diagnostics11091550
Micromachines (Basel). 2021 Aug 24. pii: 1004. [Epub ahead of print]12(9):

Entropy Production in Electroosmotic Cilia Facilitated Stream of Thermally Radiated Nanofluid with Ohmic Heating.

Najma Saleem, Sufian Munawar, Ahmer Mehmood, Ibtisam Daqqa.

  No thermal process, even the biological systems, can escape from the long arms of the second law. All living things preserve entropy since they obtain energy from the nutrition they consume and gain order by producing disorder. The entropy generation in a biological and thermally isolated system is the main subject of current investigation. The aim is to examine the entropy generation during the convective transport of a ciliated nano-liquid in a micro-channel under the effect of a uniform magnetic field. Joint effects of electroosmosis and thermal radiation are also brought into consideration. To attain mathematical simplicity, the governing equations are transformed to wave frame where the inertial parts of the transport equations are dropped with the use of a long-wavelength approximation. This finally produces the governing equations in the form of ordinary differential equations which are solved numerically by a shooting technique. The analysis reports that the cilia motion contributes to enhance the flow and heat transfer phenomena. An enhancement in the flow is observed near the channel surface for higher cilia length and for smaller values of the electroosmotic parameter. The entropy generation in the ciliated channel is observed to be lessened by intensifying the thermal radiation and decreasing the Ohmic heating. The extended and flexible cilia structure contributes to augment the volumetric flow rate and to drop the total entropy generation in the channel.

Keywords:  Carreau nanofluid; Joule heating; electroosmotic ciliary flow; entropy analysis; magnetic field; thermal radiation

DOI:  https://doi.org/10.3390/mi12091004
Diagnostics (Basel). 2021 Sep 17. pii: 1700. [Epub ahead of print]11(9):

Ciliary Videomicroscopy: A Long Beat from the European Respiratory Society Guidelines to the Recognition as a Confirmatory Test for Primary Ciliary Dyskinesia.

Noemie Bricmont, Mihaela Alexandru, Bruno Louis, Jean-François Papon, Céline Kempeneers.

  Primary ciliary dyskinesia (PCD) is a rare inherited ciliopathy in which respiratory cilia are stationary or dyskinetic. The clinical presentation of PCD is highly non-specific since it includes infections and disorders of the upper (otitis and rhinosinusitis) and lower (neonatal respiratory distress, bronchitis, pneumonia and bronchiectasis) airways, starting in early life. Clinical examination alone does not allow a PCD diagnosis, which relies on several concordant tests, since none are sensitive or specific enough alone. Despite being the most sensitive and specific test to diagnose PCD, digital high-speed videomicroscopy (DHSV) is not sufficiently standardized, preventing its use with complete confidence as a confirmatory diagnostic test for PCD, or its inclusion in a diagnostic algorithm. Since the 2017 ERS recommendations for PCD diagnosis, three main issues remain to be solved in order to optimize DHSV ciliary beating evaluation: the problem in defining an accurate sensitivity and specificity as there is no gold standard method to diagnose all PCD cases, a lack of standardization in the operating procedure for processing respiratory samples, and in the choice of measured parameters (self-operating or not). The development of new automated analysis approaches is promising and will require full clinical validation.

Keywords:  ciliary beat frequency (CBF); ciliary beat pattern (CBP); diagnostic; digital high-speed videomicroscopy (DHSV); primary ciliary dyskinesia (PCD); standardization

DOI:  https://doi.org/10.3390/diagnostics11091700
Sci Rep. 2021 Sep 27. 11(1): 19115

The localization of amyloid precursor protein to ependymal cilia in vertebrates and its role in ciliogenesis and brain development in zebrafish.

Jasmine Chebli, Maryam Rahmati, Tammaryn Lashley, Brigitta Edeman, Anders Oldfors, Henrik Zetterberg, Alexandra Abramsson.

Amyloid precursor protein (APP) is expressed in many tissues in human, mice and in zebrafish. In zebrafish, there are two orthologues, Appa and Appb. Interestingly, some cellular processes associated with APP overlap with cilia-mediated functions. Whereas the localization of APP to primary cilia of in vitro-cultured cells has been reported, we addressed the presence of APP in motile and in non-motile sensory cilia and its potential implication for ciliogenesis using zebrafish, mouse, and human samples. We report that Appa and Appb are expressed by ciliated cells and become localized at the membrane of cilia in the olfactory epithelium, otic vesicle and in the brain ventricles of zebrafish embryos. App in ependymal cilia persisted in adult zebrafish and was also detected in mouse and human brain. Finally, we found morphologically abnormal ependymal cilia and smaller brain ventricles in appa-/-appb-/- mutant zebrafish. Our findings demonstrate an evolutionary conserved localisation of APP to cilia and suggest a role of App in ciliogenesis and cilia-related functions.

DOI: https://doi.org/10.1038/s41598-021-98487-7
Int J Mol Sci. 2021 Sep 11. pii: 9834. [Epub ahead of print]22(18):

Current and Future Treatments in Primary Ciliary Dyskinesia.

Tamara Paff, Heymut Omran, Kim G Nielsen, Eric G Haarman.

  Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.

Keywords:  genetic; primary ciliary dyskinesia; treatment

DOI:  https://doi.org/10.3390/ijms22189834
Int J Mol Sci. 2021 Sep 12. pii: 9854. [Epub ahead of print]22(18):

The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes.

Christine K C Loo, Michael A Pearen, Grant A Ramm.

  The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using examples of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. SHH mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed.

Keywords:  Sonic Hedgehog; human holoprosencephaly; short-rib polydactyly syndromes

DOI:  https://doi.org/10.3390/ijms22189854
Nephrol Dial Transplant. 2021 Sep 29. pii: gfab278. [Epub ahead of print]

Vaptans or voluntary increased hydration to protect the kidney: how do they compare?

Lise Bankir, Dominique Guerrot, Daniel G Bichet.

  The adverse effects of vasopressin (AVP) in diverse forms of chronic kidney disease have been well described. They depend on the antidiuretic action of AVP mediated by V2 receptors (V2R). Treatment with tolvaptan, a selective V2R antagonist, is now largely used for the treatment of patients with ADPKD. Another way to reduce the adverse effects of AVP is to reduce endogenous AVP secretion by voluntary increase in fluid intake. These two approaches differ in several ways, including the level of thirst and AVP. With voluntary increased drinking plasma osmolality will decline and so will AVP secretion. Thus, not only will V2R-mediated effects be reduced, but also those mediated by V1a (V1aR) and V1b receptors. In contrast, selective V2R antagonism will induce a loss of fluid that will stimulate AVP secretion and thus, increase AVP's influence on V1a and V1b receptors. V1aR are expressed in the luminal side of the collecting duct and in inner medullary interstitial cells, and their activation induces the production of prostaglandins, mostly PGE2. Intrarenal PGE2 have been shown to reduce sodium and water reabsorption in the collecting duct and to increase blood flow in the renal medulla, both effects contributing to increase sodium and water excretion and reduce urine concentrating activity. Conversely, non-steroidal anti-inflammatory drugs have been shown to induce a significant water and sodium retention and potentiate the antidiuretic effects of AVP. Thus, during V2R antagonism, V1aR-mediated actions may be responsible for part of the diuresis observed with this drug. These V1aR-dependent effects do not take place with voluntary increase in fluid intake. In summary, while both strategies may have beneficial effects, the information reviewed here lead us to assume that the pharmacological V2R antagonism, with resulting stimulation of V1aR and increased PGE2 production, may provide greater benefit than voluntary HWI. The influence of tolvaptan on PGE2 excretion rate and the possibility to use somewhat lower tolvaptan doses than presently prescribed remain to be evaluated.

Keywords:  chronic kidney disease; medullary insterstitial cells; polycystic kidney disease; prostaglandin; sodium excretion; thirst

DOI:  https://doi.org/10.1093/ndt/gfab278
Clin Neuroradiol. 2021 Sep 29.

MR Brain Screening in ADPKD Patients : To Screen or not to Screen?

I Capelli, M Zoli, M Righini, L Faccioli, V Aiello, L Spinardi, D Gori, F Friso, A Rustici, C Bortolotti, C Graziano, V Mantovani, N Sciascia, D Mazzatenta, M Seri, M Pastore Trossello, G La Manna.

   BACKGROUND: Adult polycystic kidney disease (ADPKD) still represents a major cause of renal failure and intracranial aneurisms (IA) have a higher prevalence in ADPKD than in the general population. Current guidelines suggest performing brain MRI only in the subjects with a positive familiar history of IAs or subarachnoid hemorrhage (SAH). This is a retrospective case-control analysis to evaluate the usefulness of a MR screening program in ADPKD patients.
METHODS: We retrospectively analyzed all ADPKD patients followed in our outpatient clinic between 2016 and 2019 who underwent a brain MRI screening. We evaluated the presence of IAs and others brain abnormalities and compared our results with a non-ADPKD population (n = 300). We performed univariate and multivariate regression analysis to evaluate if general and demographic features, laboratory findings, clinical parameters and genetic test results correlated with IAs or other brain abnormalities presence.
RESULTS: Among the patients evaluated 17 out of 156 (13.6%) ADPKD patients had IAs, compared to 16 out of 300 (5.3%) non-ADPKD controls (p < 0.005). Considering ADPKD patients presenting IAs, 12 (70.6%) had no family history for IAs or SAH. Genetic analysis was available for 97 patients: in the sub-population with IAs, 13 (76.5%) presented a PKD1 mutation and none a PKD2 mutation. We found that arachnoid cysts (AC) (p < 0.001) and arterial anatomical variants (p < 0.04) were significantly more frequent in ADPKD patients.
CONCLUSION: In our population ADPKD patients showed a higher prevalence of IAs, AC and arterial variants compared to non-ADPKD. Most of the IAs were found in patients presenting a PKD1 mutation. We found a significant number of alterations even in those patients without a family history of IAs or SAH. The practice of submitting only patients with familial IAs or kidney transplantation candidates to MRI scan should be re-evaluated.

Keywords:  Acute complications screening; Arachnoid cysts; Genetic nephropathies; Intracranial aneurysms; Polycystic disease

DOI:  https://doi.org/10.1007/s00062-021-01050-0
Chem Biol Drug Des. 2021 Sep 28.

Design, Synthesis and Biological Evaluation of Urea-based ROCK2 inhibitors.

Linan Wang, Junhui Qi, Meixia Fan, Lei Yao.

  A series of urea-based ROCK2 inhibitors were design and synthesized. The inhibitory activity on ROCK2 was screened by enzyme-linked immunosorbent assay (ELISA). The study results showed that the urea derivatives exhibited certain ROCK2 inhibitory activity. The most potent compound 10p showed ROCK2 inhibitory activity with the IC50 value of 0.03 μM. A preliminary structure-activity relationship was then summarized. The molecular docking studies showed that further optimization needs to conduct to obtain more potent ROCK inhibitors.

Keywords:  ROCK inhibitors; Rho kinase; molecular docking; synthesis; urea

DOI:  https://doi.org/10.1111/cbdd.13961
Sci Rep. 2021 Oct 01. 11(1): 19574

Soft surfaces promote astrocytic differentiation of mouse embryonic neural stem cells via dephosphorylation of MRLC in the absence of serum.

Hiroshi Oyama, Akihiro Nukuda, Seiichiro Ishihara, Hisashi Haga.

Astrocytes, which can be obtained from neural stem cells (NSCs) by adding serum and/or recombinant proteins in culture media or by passaging NSCs repeatedly, are expected to be applicable in regenerative medicine for the treatment of neurodegenerative diseases. However, astrocytes obtained using existing methods are costly and have poor quality. The stiffness of culture surfaces has been reported to affect astrocytic differentiation of adult NSCs. However, the influence of surface stiffness on astrocytic differentiation of embryonic NSCs has not yet been reported. In this study, we showed that astrocytic differentiation of embryonic NSCs was increased on soft surfaces (1 kPa and 12 kPa) compared with the NSCs on stiff surfaces (2.8 GPa) in serum-free condition. Furthermore, di-phosphorylated myosin regulatory light chain (PP-MRLC) was decreased in embryonic NSCs cultured on the soft surfaces than the cells on the stiff surfaces. Additionally, astrocytic differentiation of embryonic NSCs was induced by a Ras homolog associated kinase (ROCK) inhibitor, which decreased PP-MRLC in NSCs. These results suggest that decreasing the PP-MRLC of embryonic NSCs on soft surfaces or treating NSCs with a ROCK inhibitor is a good method to prepare astrocytes for application in regenerative medicine.

DOI: https://doi.org/10.1038/s41598-021-99059-5
J Cell Sci. 2021 Sep 29. pii: jcs.259381. [Epub ahead of print]

LRRC23 is a conserved component of the radial spoke that is necessary for sperm motility and male fertility in mice.

Xin Zhang, Jiang Sun, Yonggang Lu, Jintao Zhang, Keisuke Shimada, Taichi Noda, Shuqin Zhao, Takayuki Koyano, Makoto Matsuyama, Shushu Zhou, Jiayan Wu, Masahito Ikawa, Mingxi Liu.

  Cilia and flagella are ancient structures that achieve controlled motor functions through the coordinated interaction based on microtubules, and some attached projections. Radial spokes (RSs) facilitate the beating motion of these organelles by mediating signal transduction between dyneins and a central pair (CP) of singlet microtubules. RS complex isolation from Chlamydomonas axonemes enabled the detection of 23 radial spoke proteins (RSP1-23), with the roles of some radial spoke proteins remained unknown. Recently, RSP15 has been reported to be located to the stalk of RS2, but its homolog in mammals has not been explored. Herein, we show that Lrrc23 is an evolutionarily conserved testis-enriched gene encoding an RSP15 homolog in mice. We found that LRRC23 localizes to the RS complex within murine sperm flagella and interacts with RSPH3A/B. The knockout of Lrrc23 resulted in male infertility due to RS disorganization and impaired motility in murine spermatozoa, whereas the ciliary beating was unaffected significantly. These data indicate that LRRC23 is a key regulator underpinning the integrity of RS complex within the flagella of mammalian spermatozoa, whereas it is dispensable in cilia.

Keywords:  Flagella; LRRC23; Male infertility; Radial spoke; Sperm

DOI:  https://doi.org/10.1242/jcs.259381
Antioxidants (Basel). 2021 Aug 25. pii: 1340. [Epub ahead of print]10(9):

NADPH-Oxidase, Rho-Kinase and Autophagy Mediate the (Pro)renin-Induced Pro-Inflammatory Microglial Response and Enhancement of Dopaminergic Neuron Death.

Andrea Lopez-Lopez, Begoña Villar-Cheda, Aloia Quijano, Pablo Garrido-Gil, María Garcia-Garrote, Carmen Díaz-Ruiz, Ana Muñoz, José L Labandeira-Garcia.

  Dysregulation of the tissue renin-angiotensin system (RAS) is involved in tissue oxidative and inflammatory responses. Among RAS components, renin, its precursor (pro)renin and its specific receptor (PRR) have been less investigated, particularly in the brain. We previously showed the presence of PRR in neurons and glial cells in the nigrostriatal system of rodents and primates, including humans. Now, we used rat and mouse models and cultures of BV2 and primary microglial cells to study the role of PRR in microglial pro-inflammatory responses. PRR was upregulated in the nigral region, particularly in microglia during the neuroinflammatory response. In the presence of the angiotensin type-1 receptor blocker losartan, to exclude angiotensin-related effects, treatment of microglial cells with (pro)renin induces the expression of microglial pro-inflammatory markers, which is mediated by upregulation of NADPH-oxidase and Rho-kinase activities, downregulation of autophagy and upregulation of inflammasome activity. Conditioned medium from (pro)renin-treated microglia increased dopaminergic cell death relative to medium from non-treated microglia. However, these effects were blocked by pre-treatment of microglia with the Rho-kinase inhibitor fasudil. Activation of microglial PRR enhances the microglial pro-inflammatory response and deleterious effects of microglia on dopaminergic cells, and microglial NADPH-oxidase, Rho-Kinase and autophagy are involved in this process.

Keywords:  Parkinson; ROCK; angiotensin; autophagy; dopamine; microglia; neurodegeneration; neuroinflammation; prorenin; renin

DOI:  https://doi.org/10.3390/antiox10091340
J Pathol. 2021 Sep 26.

Untangling the complexities of micropapillary cancer†.

Frederick Charles Campbell.

  Distinct morphological subtypes of colorectal cancer (CRC) confer a bleak clinical outlook. In a recent issue of The Journal of Pathology, Onuma et al. investigated morphological evolution of a highly fatal CRC subtype known as micropapillary cancer (MPC). This study enhances understanding of MPC biology including essential regulatory signals, cellular and multicellular phenotypes as well as cancer behaviour. Iterative modelling in three-dimensional (3D) patient-derived CRC tissue-originated spheroids (CTOS) revealed spatiotemporal oscillations of Rho-ROCK hyperactivity underlying reversal of membrane polarity and suppression of lumen formation during development of multicellular MPC morphology. Corroborative studies in CTOS, xenografts and archival human CRCs confirm human disease relevance. Although cancer morphology has previously been considered irreversible, targeted inhibition of Rho-ROCK activity restored membrane polarity, lumenized multicellular assembly and suppressed MPC morphology in 3D CTOS cultures and xenografts. Collectively, the study identifies molecular, biophysical and multicellular mechanisms implicated in morphological evolution of micropapillary CRC. This article is protected by copyright. All rights reserved.

Keywords:  Colorectal neoplasms; cell polarity; morphogenesis; organoids

DOI:  https://doi.org/10.1002/path.5809
Diagnostics (Basel). 2021 Aug 25. pii: 1540. [Epub ahead of print]11(9):

A Comprehensive Approach for the Diagnosis of Primary Ciliary Dyskinesia-Experiences from the First 100 Patients of the PCD-UNIBE Diagnostic Center.

Loretta Müller, Sibel T Savas, Stefan A Tschanz, Andrea Stokes, Anaïs Escher, Mirjam Nussbaumer, Marina Bullo, Claudia E Kuehni, Sylvain Blanchon, Andreas Jung, Nicolas Regamey, Beat Haenni, Martin Schneiter, Jonas Ingold, Elisabeth Kieninger, Carmen Casaulta, Philipp Latzin, On Behalf Of The Swiss Pcd Research Group.

  Primary ciliary dyskinesia (PCD) is a rare genetic disease characterized by dyskinetic cilia. Respiratory symptoms usually start at birth. The lack of diagnostic gold standard tests is challenging, as PCD diagnostics requires different methods with high expertise. We founded PCD-UNIBE as the first comprehensive PCD diagnostic center in Switzerland. Our diagnostic approach includes nasal brushing and cell culture with analysis of ciliary motility via high-speed-videomicroscopy (HSVM) and immunofluorescence labeling (IF) of structural proteins. Selected patients undergo electron microscopy (TEM) of ciliary ultrastructure and genetics. We report here on the first 100 patients assessed by PCD-UNIBE. All patients received HSVM fresh, IF, and cell culture (success rate of 90%). We repeated the HSVM with cell cultures and conducted TEM in 30 patients and genetics in 31 patients. Results from cell cultures were much clearer compared to fresh samples. For 80 patients, we found no evidence of PCD, 17 were diagnosed with PCD, two remained inconclusive, and one case is ongoing. HSVM was diagnostic in 12, IF in 14, TEM in five and genetics in 11 cases. None of the methods was able to diagnose all 17 PCD cases, highlighting that a comprehensive approach is essential for an accurate diagnosis of PCD.

Keywords:  air-liquid interface cell culture; airways; ciliopathy; high-speed videomicroscopy; immunofluorescence; transmission electron microscopy

DOI:  https://doi.org/10.3390/diagnostics11091540
Pediatr Pulmonol. 2021 Sep 27.

Feasibility of nasal NO screening in healthy newborns.

Flurina Buechel, Jakob Usemann, A Aline, Peter Salfeld, Alexander Moeller, Andreas Jung.

   BACKGROUND: Nasal nitric oxide (nNO) measurement is recommended as a first line screening test for primary ciliary dyskinesia (PCD). While reliable velum- and non-velum-closure techniques exist for preschool children and older individuals, no data are available for neonates.
AIMS: To determine feasibility of nNO screening and nNO concentration in healthy newborns in the first week of life.
METHODS: Nasal NO was analyzed in tidal breathing during natural sleep using a CLD-88 sp NO analyzer (chemoluminescence sensor) and a NIOX MINO (electrochemical sensor). Test success and nNO concentration were determined and compared between the two devices.
RESULTS: Nasal NO was measured in 62 healthy neonates within the first week of life. Feasibility of nNO measurement was 100% for at least one nostril and 85.5% for both nostrils using the chemoluminescence device, but significantly lower with the electrochemical device (85.5% and 53.2%; p < .001). Median nNO concentration was 38 ppb (interquartile range, 27-55; range, 9-100) with the ECOMEDICS device and 23 (15-33, 8-59) with the NIOX MINO (p < .001), with a trend towards higher values for older subjects. None of the subjects exceeded nNO levels of 100 ppb.
CONCLUSION: Measurement of nNO using a chemoluminescence device is highly feasible in newborns during natural sleep. However, nNO levels are considerably lower compared to the published data for older individuals and in the range of a PCD reference group of infants between 4 and 8 weeks of age, potentially resulting in a great overlap with subjects with PCD in this age group. Therefore, screening for PCD using nasal NO might not be useful in the first week of life. Upon clinical suspicion, other diagnostic tests such as high-speed video analysis of the cilia should be applied.

Keywords:  chemoluminescence; electrochemical sensor; nasal nitric oxide; newborns; primary ciliary dyskinesia; screening

DOI:  https://doi.org/10.1002/ppul.25702
Int J Mol Sci. 2021 Sep 10. pii: 9774. [Epub ahead of print]22(18):

FAK Shutdown: Consequences on Epithelial Morphogenesis and Biomarker Expression Involving an Innovative Biomaterial for Tissue Regeneration.

Xiaoling Wang, Thorsten Steinberg, Martin P Dieterle, Imke Ramminger, Ayman Husari, Pascal Tomakidi.

  By employing an innovative biohybrid membrane, the present study aimed at elucidating the mechanistic role of the focal adhesion kinase (FAK) in epithelial morphogenesis in vitro over 4, 7, and 10 days. The consequences of siRNA-mediated FAK knockdown on epithelial morphogenesis were monitored by quantifying cell layers and detecting the expression of biomarkers of epithelial differentiation and homeostasis. Histologic examination of FAK-depleted samples showed a significant increase in cell layers resembling epithelial hyperplasia. Semiquantitative fluorescence imaging (SQFI) revealed tissue homeostatic disturbances by significantly increased involucrin expression over time, persistence of yes-associated protein (YAP) and an increase of keratin (K) 1 at day 4. The dysbalanced involucrin pattern was underscored by ROCK-IISer1366 activity at day 7 and 10. SQFI data were confirmed by quantitative PCR and Western blot analysis, thereby corroborating the FAK shutdown-related expression changes. The artificial FAK shutdown was also associated with a significantly higher expression of filaggrin at day 10, sustained keratinocyte proliferation, and the dysregulated expression of K19 and vimentin. These siRNA-induced consequences indicate the mechanistic role of FAK in epithelial morphogenesis by simultaneously considering prospective biomaterial-based epithelial regenerative approaches.

Keywords:  biomaterial; differentiation; epithelial hyperplasia; epithelial morphogenesis; filaggrin; focal adhesion kinase (FAK); involucrin; keratins; proliferation; siRNA

DOI:  https://doi.org/10.3390/ijms22189774
Chem Biol Drug Des. 2021 Sep 29.

Design and development of novel fasudil derivatives as potent anti-breast cancer agent that improves intestinal flora and intestinal barrier function in rats.

Jinghui Liang, Mu Tang, Lieliang Wang, Rui Huang, Ailong Fu, Juying Zhou.

  The present study was conducted to develop novel fasudil derivatives after incorporation of substituted thiazoles as potent anti-breast cancer agents. The compounds were developed using a facile synthetic route in excellent yields. The entire set of developed compounds was tested for inhibitory activity against ROCK (ROCK1 and ROCK2) kinase, where they exhibit potent and selective inhibition of ROCK1 as compared to ROCK2. The most potent ROCK2 inhibitor, compound 6h significantly inhibited the viability of breast cancer cells (MCF-7). It also causes inhibition of migration and invasion of MCF-7 cells. Moreover, the anti-breast cancer activity of compound 6h was studied in 7,12 dimethyl Benz(a)anthracene (DMBA)-induced breast cancer in female Sprague Dawley rats. Results suggest that it causes significant improvement in the bodyweight of the animals with a reduction in oxidative stress in the liver and mammary tissues of rats. It showed improvement in the intestinal barrier function of rats by restoring the level of Diamine oxidase (DAO), D-lactate, and endotoxin (ETX). In western blot analysis, it showed improvement in (ZO-1), occludin, and claudin-1 in the colon tissue of the rat as compared to the DMBA group. Our study demonstrated the development of the novel class of fasudil derivatives potent anti-breast cancer agent that improves intestinal flora and intestinal barrier function in rats.

Keywords:  Breast cancer; ROCK; fasudil; invasion; microbiota; migration

DOI:  https://doi.org/10.1111/cbdd.13963
Biomolecules. 2021 Sep 01. pii: 1301. [Epub ahead of print]11(9):

Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries.

Melissa L D Rayner, Jess Healy, James B Phillips.

  The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regeneration safely, restoring connections before the target tissues deteriorate irreversibly. The identification that the Rho/Rho-associated kinase (ROCK) pathway acts to limit neuronal growth rate is a promising advancement towards the development of drugs. Targeting Rho or ROCK directly can act to suppress the activity of this pathway; however, the pathway can also be modulated through the activation of upstream receptors; one of particular interest being peroxisome proliferator-activated receptor gamma (PPAR-γ). The connection between the PPAR-γ receptor and the Rho/ROCK pathway is the suppression of the conversion of inactive guanosine diphosphate (GDP)-Rho to active guanosine triphosphate GTP-Rho, resulting in the suppression of Rho/ROCK activity. PPAR-γ is known for its role in cellular metabolism that leads to cell growth and differentiation. However, more recently there has been a growing interest in targeting PPAR-γ in peripheral nerve injury (PNI). The localisation and expression of PPAR-γ in neural cells following a PNI has been reported and further in vitro and in vivo studies have shown that delivering PPAR-γ agonists following injury promotes nerve regeneration, leading to improvements in functional recovery. This review explores the potential of repurposing PPAR-γ agonists to treat PNI and their prospective translation to the clinic.

Keywords:  PPAR-γ; Rho/ROCK pathway; drug repurposing; nerve regeneration; peripheral nerve injury; small molecules

DOI:  https://doi.org/10.3390/biom11091301