bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022‒01‒23
twenty-two papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. [A Case of Laparoscopic High Anterior Resection for Rectal Cancer with Autosomal Dominant Polycystic Kidney Disease].
  2. The renal inflammatory network of nephronophthisis.
  3. Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2.
  4. The genetics of autosomal recessive polycystic kidney disease (ARPKD).
  5. cAMP-Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.
  6. Metabolic reprogramming in a slowly developing orthologous model of polycystic kidney disease.
  7. Abnormal Iron and Lipid Metabolism Mediated Ferroptosis in Kidney Diseases and Its Therapeutic Potential.
  8. Weight loss and cystic disease progression in autosomal dominant polycystic kidney disease.
  9. Rho Kinases in Embryonic Development and Stem Cell Research.
  10. Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via Sonic Hedgehog signaling.
  11. Primary cilia direct murine articular cartilage tidemark patterning through Hedgehog signaling and ambulatory load.
  12. Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease.
  13. The role of Rho-associated kinase inhibitor, Y-27632 on primary culture of ovine spermatogonial stem cells.
  14. Enhanced β-adrenergic response in mice with dominant-negative expression of the PKD2L1 channel.
  15. Effects of Tolvaptan on Oxidative Stress in ADPKD: A Molecular Biological Approach.
  16. Erianin Controls Collagen-Mediated Retinal Angiogenesis via the RhoA/ROCK1 Signaling Pathway Induced by the alpha2/beta1 Integrin-Collagen Interaction.
  17. Axonemal Symmetry Break, a New Ultrastructural Diagnostic Tool for Primary Ciliary Dyskinesia?
  18. Ciliary IFT88 protects coordinated adolescent growth plate ossification from disruptive physiological mechanical forces.
  19. The NEK family of serine/threonine kinases as a biomarker for cancer.
  20. A multiscale biophysical model gives quantized metachronal waves in a lattice of beating cilia.
  21. Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development.
  22. Variations in infection control practices suggest a need for guidelines in primary ciliary dyskinesia patient care.
  1. Gan To Kagaku Ryoho. 2021 Dec;48(13): 1807-1809
    [A Case of Laparoscopic High Anterior Resection for Rectal Cancer with Autosomal Dominant Polycystic Kidney Disease].
    Yujiro Nishizawa, Yoshinori Kagawa, Akira Inoue, Norihiro Aomatsu, Takuro Takeuchi, Yoshito Tsuji, Masataka Hirano, Yusuke Nakano, Hisateru Komatsu, Yasuhiro Miyazaki, Akira Tomokuni, Masaaki Motoori, Mitsukazu Goto, Kazuhiro Iwase, Kazumasa Fujitani.
      The case was a 61-year-old woman. She was diagnosed with autosomal dominant polycystic kidney disease(ADPKD)at the age of 38 and started hemodialysis at the age of 42. She was diagnosed with rectal cancer(RS)at the age of 61. Laparoscopic high anterior resection and D3 lymphadenectomy were carried out. Although the intra-abdominal space was limited by the huge renal cysts, laparoscopic surgery can be safely performed by arranging the port closer to the midline, taking the patient's position sufficiently, and using some useful tips. Laparoscopic surgery for the patient with ADPKD was considered a useful approach.
  2. Hum Mol Genet. 2022 Jan 19. pii: ddac014. [Epub ahead of print]
    The renal inflammatory network of nephronophthisis.
    Marceau Quatredeniers, Frank Bienaimé, Giulia Ferri, Pierre Isnard, Esther Porée, Katy Billot, Eléonore Birgy, Manal Mazloum, Salomé Ceccarelli, Flora Silbermann, Simone Braeg, Thao Nguyen-Khoa, Rémi Salomon, Marie-Claire Gubler, E Wolfgang Kuehn, Sophie Saunier, Amandine Viau.
      Renal ciliopathies are the leading cause of inherited kidney failure. In autosomal dominant polycystic kidney disease (ADPKD), mutations in the ciliary gene PKD1 lead to the induction of CCL2, which promotes macrophage infiltration in the kidney. Whether or not mutations in genes involved in other renal ciliopathies also lead to immune cells recruitment is controversial. Through the parallel analysis of patients derived material and murine models, we investigated the inflammatory components of nephronophthisis (NPH), a rare renal ciliopathy affecting children and adults. Our results show that NPH mutations lead to kidney infiltration by neutrophils, macrophages and T cells. Contrary to ADPKD, this immune cell recruitment does not rely on the induction of CCL2 in mutated cells, which is dispensable for disease progression. Through an unbiased approach, we identified a set of inflammatory cytokines that are upregulated precociously and independently of CCL2 in murine models of NPH. The majority of these transcripts is also upregulated in NPH patient renal cells at a level exceeding those found in common non-immune chronic kidney diseases. This study reveals that inflammation is a central aspect in NPH and delineates a specific set of inflammatory mediators that likely regulates immune cell recruitment in response to NPH genes mutations.
    DOI:  https://doi.org/10.1093/hmg/ddac014
  3. Antioxidants (Basel). 2021 Dec 24. pii: 38. [Epub ahead of print]11(1):
    Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2.
    Zhiwei Qiu, Jinzhao He, Guangying Shao, Jiaqi Hu, Xiaowei Li, Hong Zhou, Min Li, Baoxue Yang.
      Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The purpose of this study was to discover an effective therapeutic drug for ADPKD. With virtual screening, Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney-specific Pkd1 knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library. In vitro experiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner. In vivo, obacunone treatment significantly reduced the renal cyst development in PKD mice. Western blot and morphological analysis revealed that obacunone served as a NRF2 activator in ADPKD, which suppressed lipid peroxidation by up-regulating GPX4 and finally restrained excessive cell proliferation by down-regulating mTOR and MAPK signaling pathways. Experimental data demonstrated obacunone as an effective renal cyst inhibitor for ADPKD, indicating that obacunone might be developed into a therapeutic drug for ADPKD treatment.
    Keywords:  MAPK; NRF2; autosomal dominant polycystic kidney disease; glutathione peroxidase; lipid peroxidation; mTOR; obacunone
    DOI:  https://doi.org/10.3390/antiox11010038
  4. Biochim Biophys Acta Mol Basis Dis. 2022 Jan 12. pii: S0925-4439(22)00011-4. [Epub ahead of print] 166348
    The genetics of autosomal recessive polycystic kidney disease (ARPKD).
    Paraskevi Goggolidou, Taylor Richards.
      ARPKD is a genetically inherited kidney disease that manifests by bilateral enlargement of cystic kidneys and liver fibrosis. It shows a range of severity, with 30% of individuals dying early on and the majority having good prognosis if they survive the first year of life. The reasons for this variability remain unclear. Two genes have been shown to cause ARPKD when mutated, PKHD1, mutations in which lead to most of ARPKD cases and DZIP1L, which is associated with moderate ARPKD. This mini review will explore the genetics of ARPKD and discuss potential genetic modifiers and phenocopies that could affect diagnosis.
    Keywords:  Autosomal recessive polycystic kidney disease (ARPKD); DZIP1L; Fibrocystin; Modifier genes; PKHD1; Phenocopy
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166348
  5. Adv Sci (Weinh). 2022 Jan 17. e2104578
    cAMP-Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.
    Zeyun Mi, Yandong Song, Jiuchen Wang, Zhiheng Liu, Xinyi Cao, Lin Dang, Yumei Lu, Yongzhan Sun, Hui Xiong, Lirong Zhang, Yupeng Chen.
      Formation of biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signal transduction and gene activation through condensate formation, and how dysregulation of these mechanisms contributes to disease progression, remain elusive. Here, the authors report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to the nucleus and forms phase-separated condensates upon activation of cAMP signaling. They show that intranuclear CRTC2 interacts with positive transcription elongation factor b (P-TEFb) and activates P-TEFb by disrupting the inhibitory 7SK snRNP complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). They find that CRTC2 localizes to the nucleus and forms condensates in cystic epithelial cells of both mouse and human ADPKD kidneys. Genetic depletion of CRTC2 suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, they identify CRTC2-regulated cystogenesis-associated genes, whose activation depends on CRTC2 condensate-facilitated P-TEFb recruitment and the release of paused RNA polymerase II. Together, their findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and thereby promotes cystogenesis in ADPKD.
    Keywords:  ADPKD; CRTC2; P-TEFb; cAMP; condensate; phase separation
    DOI:  https://doi.org/10.1002/advs.202104578
  6. Am J Physiol Renal Physiol. 2022 Jan 17.
    Metabolic reprogramming in a slowly developing orthologous model of polycystic kidney disease.
    Katharina Hopp, Emily K Kleczko, Berenice Y Gitomer, Michel Chonchol, Jost Klawitter, Uwe Christians, Jelena Klawitter.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. There is accumulating evidence suggesting that there are shared cellular mechanisms responsible for cystogenesis in human and murine PKD and that reprograming of metabolism is a key disease feature. In this study we utilized a targeted metabolomics approach in an orthologous mouse model of PKD (Pkd1RC/RC) to investigate the metabolic modifications a cystic kidney undergoes during disease progression. Using the KEGG pathway database, we identified several biologically relevant metabolic pathways which were altered early in this disease (in 3-month-old Pkd1RC/RC mice), the most highly represented being arginine biosynthesis and metabolism and tryptophan and phenylalanine metabolism. During the next 6 months of disease progression, multiple uremic solutes accumulated in the kidney of cystic mice including several established markers of oxidative stress and endothelial dysfunction (allantoin, asymmetric dimethylarginine (ADMA), homocysteine, malondialdehyde, methionine sulfoxide, and S-adenosylhomocysteine (SAH)). Levels of kynurenines and polyamines were also augmented in kidneys of Pkd1RC/RC versus wildtype mice, as were the levels of bacteria-produced indoles whose increase within PKD kidneys suggests microbial dysbiosis. In summary, we confirmed previously published and identified novel metabolic markers and pathways of PKD progression that may prove helpful for diagnosis and monitoring of cystic kidney disease in patients. Furthermore, they provide targets for novel therapeutic approaches that deserve further study and hint towards currently understudied pathomechanism.
    Keywords:  ADPKD; Metabolomics; kidney-gut axis; tryptophan metabolism
    DOI:  https://doi.org/10.1152/ajprenal.00262.2021
  7. Metabolites. 2022 Jan 10. pii: 58. [Epub ahead of print]12(1):
    Abnormal Iron and Lipid Metabolism Mediated Ferroptosis in Kidney Diseases and Its Therapeutic Potential.
    Xiaoqin Zhang, Xiaogang Li.
      Ferroptosis is a newly identified form of regulated cell death driven by iron-dependent phospholipid peroxidation and oxidative stress. Ferroptosis has distinct biological and morphology characteristics, such as shrunken mitochondria when compared to other known regulated cell deaths. The regulation of ferroptosis includes different molecular mechanisms and multiple cellular metabolic pathways, including glutathione/glutathione peroxidase 4(GPX4) signaling pathways, which are involved in the amino acid metabolism and the activation of GPX4; iron metabolic signaling pathways, which are involved in the regulation of iron import/export and the storage/release of intracellular iron through iron-regulatory proteins (IRPs), and lipid metabolic signaling pathways, which are involved in the metabolism of unsaturated fatty acids in cell membranes. Ferroptosis plays an essential role in the pathology of various kidneys diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), autosomal dominant polycystic kidney disease (ADPKD), and renal cell carcinoma (RCC). Targeting ferroptosis with its inducers/initiators and inhibitors can modulate the progression of kidney diseases in animal models. In this review, we discuss the characteristics of ferroptosis and the ferroptosis-based mechanisms, highlighting the potential role of the main ferroptosis-associated metabolic pathways in the treatment and prevention of various kidney diseases.
    Keywords:  abnormal metabolism; ferroptosis; kidney disease; therapeutic
    DOI:  https://doi.org/10.3390/metabo12010058
  8. iScience. 2022 Jan 21. 25(1): 103697
    Weight loss and cystic disease progression in autosomal dominant polycystic kidney disease.
    Katharina Hopp, Victoria A Catenacci, Nidhi Dwivedi, Timothy L Kline, Wei Wang, Zhiying You, Dustin T Nguyen, Kristen Bing, Bhavya Poudyal, Ginger C Johnson, Matthew R Jackman, Marsha Miller, Cortney N Steele, Natalie J Serkova, Paul S MacLean, Raphael A Nemenoff, Berenice Gitomer, Michel Chonchol, Kristen L Nowak.
      Progression of autosomal dominant polycystic kidney disease (ADPKD) is modified by metabolic defects and obesity. Indeed, reduced food intake slows cyst growth in preclinical rodent studies. Here, we demonstrate the feasibility of daily caloric restriction (DCR) and intermittent fasting (IMF) in a cohort of overweight or obese patients with ADPKD. Clinically significant weight loss occurred with both DCR and IMF; however, weight loss was greater and adherence and tolerability were better with DCR. Further, slowed kidney growth correlated with body weight and visceral adiposity loss independent of dietary regimen. Similarly, we compared the therapeutic efficacy of DCR, IMF, and time restricted feeding (TRF) using an orthologous ADPKD mouse model. Only ADPKD animals on DCR lost significant weight and showed slowed cyst growth compared to ad libitum, IMF, or TRF feeding. Collectively, this supports therapeutic feasibility of caloric restriction in ADPKD, with potential efficacy benefits driven by weight loss.
    Keywords:  Activities of daily living; Nephrology; Nutrition related to disease
    DOI:  https://doi.org/10.1016/j.isci.2021.103697
  9. Arch Immunol Ther Exp (Warsz). 2022 Jan 19. 70(1): 4
    Rho Kinases in Embryonic Development and Stem Cell Research.
    Jianjian Shi, Lei Wei.
      The Rho-associated coiled-coil containing kinases (ROCKs or Rho kinases) belong to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and are major downstream effectors of small GTPase RhoA, a key regulator of actin-cytoskeleton reorganization. The ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in kinase domain. ROCK1 and ROCK2 were assumed to be functionally redundant, based largely on their major common activators, their high degree kinase domain homology, and study results from overexpression with kinase constructs or chemical inhibitors. ROCK signaling research has expanded to all areas of biology and medicine since its discovery in 1996. The rapid advance is befitting ROCK's versatile functions in modulating various cell behavior, such as contraction, adhesion, migration, proliferation, polarity, cytokinesis, and differentiation. The rapid advance is noticeably driven by an extensive linking with clinical medicine, including cardiovascular abnormalities, aberrant immune responsive, and cancer development and metastasis. The rapid advance during the past decade is further powered by novel biotechnologies including CRISPR-Cas and single cell omics. Current consensus, derived mainly from gene targeting and RNA interference approaches, is that the two ROCK isoforms have overlapping and distinct cellular, physiological and pathophysiology roles. In this review, we present an overview of the milestone discoveries in ROCK research. We then focus on the current understanding of ROCK signaling in embryonic development, current research status using knockout and knockin mouse models, and stem cell research.
    Keywords:  Development; Inhibitor; Isoform; ROCK; Stem cell
    DOI:  https://doi.org/10.1007/s00005-022-00642-z
  10. JCI Insight. 2022 Jan 18. pii: e149626. [Epub ahead of print]
    Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via Sonic Hedgehog signaling.
    Hairong Shi, Hongshun Wang, Cheng Zhang, Yajie Lu, Jun Yao, Zhibin Chen, Guangqian Xing, Qinjun Wei, Xin Cao.
      Defective primary cilia cause a range of diseases called ciliopathies, which include hearing loss (HL). Variants in human oxysterol binding protein like 2 (OSBPL2/ORP2) are responsible for autosomal dominant nonsyndromic HL (DFNA67). However, the pathogenesis of OSBPL2 deficiency has not been fully elucidated. In this study, we showed that the Osbpl2-knockout (KO) mice exhibited progressive HL and abnormal cochlea development with defective cilia. Further research revealed that OSBPL2 was located at the base of kinocilia in hair cells (HCs) and primary cilia in supporting cells (SCs), and functioned in the maintenance of ciliogenesis by regulating the homeostasis of PI(4,5)P2 on the cilia membrane. OSBPL2 deficiency led to a significant increase of PI(4,5)P2 on the cilia membrane, which could be partially rescued by the overexpression of INPP5E. In addition, the key molecules in Sonic Hedgehog (Shh) signaling pathway (SMO and GLI3) were detected to be down-regulated in Osbpl2-KO HEI-OC1 cells. Our findings revealed that OSBPL2 deficiency resulted in ciliary defects and abnormal Shh signaling transduction in auditory cells, which helped to elucidate the underlying mechanism of OSBPL2 deficiency in HL.
    Keywords:  Cytoskeleton; Genetic variation; Genetics; Otology
    DOI:  https://doi.org/10.1172/jci.insight.149626
  11. J Bone Miner Res. 2022 Jan 21.
    Primary cilia direct murine articular cartilage tidemark patterning through Hedgehog signaling and ambulatory load.
    Danielle Rux, Kimberly Helbig, Biao Han, Courtney Cortese, Eiki Koyama, Lin Han, Maurizio Pacifici.
      Articular cartilage (AC) is essential for body movement but is highly susceptible to degenerative diseases and has poor self-repair capacity. To improve current subpar regenerative treatments, developmental mechanisms of AC should be clarified and, specifically, how its postnatal multi-zone organization is acquired. Primary cilia are cell surface organelles crucial for mammalian tissue morphogenesis. While their importance for chondrocyte functioning is appreciated, their specific roles in postnatal AC morphogenesis remain unclear. To explore these mechanisms, we used a murine conditional loss-of-function approach (Ift88-flox) targeting joint-lineage progenitors (Gdf5Cre) and monitored postnatal knee AC development. Joint formation and growth up to juvenile stages were largely unaffected. However, mature AC (aged 2 months) exhibited disorganized extracellular matrix, decreased aggrecan and collagen II due to reduced gene expression (not increased catabolism), and marked reduction of AC modulus by 30-50%. In addition, and unexpectedly, we discovered that tidemark patterning was severely disrupted, as was hedgehog signaling, and exhibited specificity based on regional load-bearing functions of AC. Interestingly, Prg4 expression was markedly increased in highly loaded sites in mutants. Together, our data provide evidence that primary cilia orchestrate postnatal AC morphogenesis including tidemark topography, zonal matrix composition and ambulation load responses. This article is protected by copyright. All rights reserved.
    Keywords:  IFT88; Prg4; articular cartilage development; hedgehog; primary cilia; tidemark
    DOI:  https://doi.org/10.1002/jbmr.4506
  12. Int J Mol Sci. 2022 Jan 14. pii: 884. [Epub ahead of print]23(2):
    Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease.
    Sonja Djudjaj, Panagiotis Kavvadas, Niki Prakoura, Roman D Bülow, Tiffany Migeon, Sandrine Placier, Christos E Chadjichristos, Peter Boor, Christos Chatziantoniou.
      BACKGROUND: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to be regulated by Notch signaling.METHODS: We found increased Notch3 expression in human PKD and renal cell carcinoma biopsies. To obtain insight into the underlying mechanisms and the functional consequences of this abnormal expression, we developed a transgenic mouse model with conditional overexpression of the intracellular Notch3 (ICN3) domain specifically in renal tubules. We evaluated the alterations in renal function (creatininemia, BUN) and structure (cysts, fibrosis, inflammation) and measured the expression of several genes involved in Notch signaling and the mechanisms of inflammation, proliferation, dedifferentiation, fibrosis, injury, apoptosis and regeneration.
    RESULTS: After one month of ICN3 overexpression, kidneys were larger with tubules grossly enlarged in diameter, with cell hypertrophy and hyperplasia, exclusively in the outer stripe of the outer medulla. After three months, mice developed numerous cysts in proximal and distal tubules. The cysts had variable sizes and were lined with a single- or multilayered, flattened, cuboid or columnar epithelium. This resulted in epithelial hyperplasia, which was observed as protrusions into the cystic lumen in some of the renal cysts. The pre-cystic and cystic epithelium showed increased expression of cytoskeletal filaments and markers of epithelial injury and dedifferentiation. Additionally, the epithelium showed increased proliferation with an aberrant orientation of the mitotic spindle. These phenotypic tubular alterations led to progressive interstitial inflammation and fibrosis.
    CONCLUSIONS: In summary, Notch3 signaling promoted tubular cell proliferation, the alignment of cell division, dedifferentiation and hyperplasia, leading to cystic kidney diseases and pre-neoplastic lesions.
    Keywords:  Notch3; chronic kidney disease; polycystic kidney disease; renal cell carcinoma; renal fibrosis; renal inflammation
    DOI:  https://doi.org/10.3390/ijms23020884
  13. Anim Reprod. 2021 ;18(4): e20200257
    The role of Rho-associated kinase inhibitor, Y-27632 on primary culture of ovine spermatogonial stem cells.
    Fatemeh Emamdoust, Mehdi Aminafshar, Mohammad Zandi, Mohammad Reza Sanjabi.
      The access to sufficient numbers of spermatogonial stem cells (SSCs) is a prerequisite for the study of their regulation and further biomanipulation. Rho kinase (ROCK) belongs to a family of serine/threonine kinases and involves in a wide range of fundamental cellular functions. The aim of the present study was to study the effect of ROCK inhibitor, Y-27632 (0.1-40 µM), during the primary culture of ovine SSCs. SSCs were collected from 3-5-month-old's lamb testes. The viability of SSCs, the apoptosis assay of SSCs, the intracellular reactive oxygen species (ROS) analysis, and the SSCs markers and apoptosis-related gene expressions were detected by MTT reduction assay, Annexin V-FITC/ Propidium Iodide (PI) dual staining, flow cytometry and real-time-PCR studies, respectively. Morphological analyses indicated that the 5-10 µM Y-27632 had an optimal effect on the number of presumptive SSCs colonies and the area covered by them after a 10 days culture. The cell viability, apoptosis and necrosis of SSCs after 10 days' culture were not affected in comparison with the control group, and the 20 µM of Y-27632 resulted in significantly decreased cell viability (P<0.05) and an increased necrosis of cells. On day 10 after culture, the expression of P53 was decreased with an increase from 0 to 10 µM in the Y-27632 dose. In the 20 µM Y-27632 group, the expressions of P53 and Bax were higher and the Bcl-2 was lower than other groups and these values were significantly different from 5 and 10 µM Y-27632 groups (P<0.05). The level of intracellular ROS was decreased with an increase in the Y-27632 dose from 5 to 20 µM in comparison with the control group. In conclusion, the present study demonstrated that Y-27632 at a concentration of 5-10 µM provided optimal culture conditions for the primary culture of ovine SSCs.
    Keywords:  Y-27632; primary culture; sheep; spermatogonial stem cells
    DOI:  https://doi.org/10.1590/1984-3143-AR2020-0257
  14. PLoS One. 2022 ;17(1): e0261668
    Enhanced β-adrenergic response in mice with dominant-negative expression of the PKD2L1 channel.
    Manabu Murakami, Agnieszka M Murakami, Takayuki Nemoto, Takayoshi Ohba, Manabu Yonekura, Yuichi Toyama, Hirofumi Tomita, Yasushi Matsuzaki, Daisuke Sawamura, Kazuyoshi Hirota, Shirou Itagaki, Yujiro Asada, Ichiro Miyoshi.
      Polycystic kidney disease (PKD) is the most common genetic cause of kidney failure in humans. Among the various PKD-related molecules, PKD2L1 forms cation channels, but its physiological importance is obscure. In the present study, we established a transgenic mouse line by overexpressing the dominant-negative form of the mouse PKD2L1 gene (i.e., lacking the pore-forming domain). The resulting PKD2L1del-Tg mice exhibited supraventricular premature contraction, as well as enhanced sensitivity to β-adrenergic stimulation and unstable R-R intervals in electrocardiography. During spontaneous atrial contraction, PKD2L1del-Tg atria showed enhanced sensitivity to isoproterenol, norepinephrine, and epinephrine. Action potential recording revealed a shortened action potential duration in PKD2L1del-Tg atria in response to isoproterenol. These findings indicated increased adrenergic sensitivity in PKD2L1del-Tg mice, suggesting that PKD2L1 is involved in sympathetic regulation.
    DOI:  https://doi.org/10.1371/journal.pone.0261668
  15. J Clin Med. 2022 Jan 13. pii: 402. [Epub ahead of print]11(2):
    Effects of Tolvaptan on Oxidative Stress in ADPKD: A Molecular Biological Approach.
    Matteo Rigato, Gianni Carraro, Irene Cirella, Silvia Dian, Valentina Di Vico, Lucia Federica Stefanelli, Verdiana Ravarotto, Giovanni Bertoldi, Federico Nalesso, Lorenzo A Calò.
      Autosomal dominant polycystic disease (ADPKD) is the most frequent monogenic kidney disease. It causes progressive renal failure, endothelial dysfunction, and hypertension, all of which are strictly linked to oxidative stress (OxSt). Treatment with tolvaptan is known to slow the renal deterioration rate, but not all the molecular mechanisms involved in this effect are well-established. We evaluated the OxSt state in untreated ADPKD patients compared to that in tolvaptan-treated ADPKD patients and healthy subjects. OxSt was assessed in nine patients for each group in terms of mononuclear cell p22phox protein expression, NADPH oxidase key subunit, MYPT-1 phosphorylation state, marker of Rho kinase activity (Western blot) and heme oxygenase (HO)-1, induced and protective against OxSt (ELISA). p22phox protein expression was higher in untreated ADPKD patients compared to treated patients and controls: 1.42 ± 0.11 vs. 0.86 ± 0.15 d.u., p = 0.015, vs. 0.53 ± 0.11 d.u., p < 0.001, respectively. The same was observed for phosphorylated MYPT-1: 0.96 ± 0.28 vs. 0.68 ± 0.09 d.u., p = 0.013 and vs. 0.47 ± 0.13 d.u., p < 0.001, respectively, while the HO-1 expression of untreated patients was significantly lower compared to that of treated patients and controls: 5.33 ± 3.34 vs. 2.08 ± 0.79 ng/mL, p = 0.012, vs. 1.97 ± 1.22 ng/mL, p = 0.012, respectively. Tolvaptan-treated ADPKD patients have reduced OxSt levels compared to untreated patients. This effect may contribute to the slowing of renal function loss observed with tolvaptan treatment.
    Keywords:  ADPKD; oxidative stress; tolvaptan
    DOI:  https://doi.org/10.3390/jcm11020402
  16. Invest Ophthalmol Vis Sci. 2022 Jan 03. 63(1): 27
    Erianin Controls Collagen-Mediated Retinal Angiogenesis via the RhoA/ROCK1 Signaling Pathway Induced by the alpha2/beta1 Integrin-Collagen Interaction.
    Xueke Li, Xiaoxue Liu, Yue Xing, Lingyan Zeng, Xin Liu, Huangxuan Shen, Jin Ma.
      Purpose: Erianin has been reported to inhibit tumor activity by suppressing the expression of integrins. It is hypothesized that erianin can inhibit retinal neovascularization in collagen by suppressing the expression of integrins. With an aim to test this hypothesis, the regulation of erianin on collagen-mediated retinal angiogenesis via the Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil containing protein kinase 1 (ROCK1) signaling pathway induced by α2 and β1 integrin-collagen interactions was investigated.Methods: The effects of erianin on human retinal vascular endothelial cells (HRVECs) were assessed in vitro using a hypoxia model in a three-dimensional cell culture induced by cobalt (II) chloride (CoCl2). A hypoxia-induced retinopathy model in adult zebrafish and zebrafish embryos was established to assess the antiangiogenic effect of erianin with and without vitreous collagen in vivo. The expression of α2 and β1 integrin and RhoA/ROCK1 pathway in HRVECs and zebrafish retinas were analyzed.
    Results: In vitro, collagen improved the angiogenic potential of HRVECs, including migration, adhesion, and tube formation, in a three-dimensional cell culture model. Erianin suppressed the angiogenic processes of the CoCl2-induced hypoxia HRVEC model in a concentration-dependent manner. In vivo, erianin reduced retinal angiogenesis in the hypoxia-induced retinopathy model in adult and embryo zebrafish. Erianin inhibited the expression of α2 and β1 integrin and RhoA/ROCK1 in a hypoxia-induced model in vitro in three-dimensional cell culture and in vivo in adult zebrafish.
    Conclusions: Collagen-mediated retinal angiogenesis may be regulated by erianin via the RhoA/ROCK1 signaling pathway induced by α2 and β1 integrin-collagen interactions. These findings suggest that erianin has the therapeutic potential on intraocular collagen-mediated retinal angiogenesis.
    DOI:  https://doi.org/10.1167/iovs.63.1.27
  17. Diagnostics (Basel). 2022 Jan 06. pii: 129. [Epub ahead of print]12(1):
    Axonemal Symmetry Break, a New Ultrastructural Diagnostic Tool for Primary Ciliary Dyskinesia?
    Rosana Blanco-Máñez, Miguel Armengot-Carceller, Teresa Jaijo, Francisco Vera-Sempere.
      Diagnosis testing for primary ciliary dyskinesia (PCD) requires a combination of investigations that includes study of ciliary beat pattern by high-speed video-microscopy, genetic testing and assessment of the ciliary ultrastructure by transmission electron microscopy (TEM). Historically, TEM was considered to be the "gold standard" for the diagnosis of PCD. However, with the advances in molecular genetic techniques, an increasing number of PCD variants show normal ultrastructure and cannot be diagnosed by TEM. During ultrastructural assessment of ciliary biopsies of patients with suspicion of PCD, we observed an axonemal defect not previously described that affects peripheral doublets tilting. To further characterize this defect of unknown significance, we studied the ciliary axonemes by TEM from both PCD-confirmed patients and patients with other sino-pulmonary diseases. We detected peripheral doublets tilting in all the PCD patients, without any significant difference in the distribution of ciliary beat pattern or mutated gene. This defect was also present in those patients with normal ultrastructure PCD subtypes. We believe that the performance of axonemal asymmetry analysis would be helpful to enhance diagnosis of PCD.
    Keywords:  ciliary axoneme; diagnosis; primary ciliary dyskinesia; transmission electron microscopy
    DOI:  https://doi.org/10.3390/diagnostics12010129
  18. J Bone Miner Res. 2022 Jan 17.
    Ciliary IFT88 protects coordinated adolescent growth plate ossification from disruptive physiological mechanical forces.
    C R Coveney, H J Samvelyan, J Miotla-Zarebska, J Carnegie, E Chang, C J Corrin, T Coveney, B Stott, I Parisi, C Duarte, T L Vincent, K A Staines, A K T Wann.
      In comparison to our understanding of endochondral ossification, much less is known about the coordinated arrest of growth defined by the narrowing and fusion of the cartilaginous growth plate. Throughout the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. It remains unclear how mechanical cues are integrated into many biological programmes including those coordinating the ossification of the adolescent growth plate at the cessation of growth. Primary cilia are microtubule-based organelles tuning a range of cell activities, including signalling cascades activated or modulated by extracellular biophysical cues. Cilia have been proposed to directly facilitate cell mechanotransduction. To explore the influence of primary cilia in the mouse adolescent limb, we conditionally targeted the ciliary gene Intraflagellar transport protein 88 (Ift88fl/fl ) in the juvenile and adolescent skeleton using a cartilage-specific, inducible, Cre (AggrecanCreERT2 Ift88fl/fl ). Deletion of IFT88 in cartilage, which reduced ciliation in the growth plate, disrupted chondrocyte differentiation, cartilage resorption and mineralisation. These effects were largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. These regions were typified by an enlarged population of hypertrophic chondrocytes. While normal patterns of hedgehog signalling were maintained, targeting IFT88 inhibited hypertrophic chondrocyte VEGF expression and downstream vascular recruitment, osteoclastic activity and the replacement of cartilage with bone. In control mice, increases to physiological loading also impair ossification in the peripheral growth plate, mimicking the effects of IFT88 deletion. Limb immobilisation inhibited changes to VEGF expression and epiphyseal morphology in Ift88cKO mice, indicating the effects of depletion of IFT88 in the adolescent growth plate are mechano-dependent. We propose that during this pivotal phase in adolescent skeletal maturation, ciliary IFT88 protects uniform, coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/jbmr.4502
  19. Clin Exp Med. 2022 Jan 17.
    The NEK family of serine/threonine kinases as a biomarker for cancer.
    Nagesh Kishan Panchal, Sabina Evan Prince.
      Cancer is defined by unrestrained cell proliferation due to impaired protein activity. Cell cycle-related proteins are likely to play a role in human cancers, including proliferation, invasion, and therapeutic resistance. The serine/threonine NEK kinases are the part of Never In Mitosis A Kinases (NIMA) family, which are less explored kinase family involved in the cell cycle, checkpoint regulation, and cilia biology. They comprise of eleven members, namely NEK1, NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK8, NEK9, NEK10, and NEK11, located in different cellular regions. Recent research has shown the role of NEK family in various cancers by perversely expressing. Therefore, this review aimed to provide a systematic account of our understanding of NEK kinases; structural details; and its role in the cell cycle regulation. Furthermore, we have comprehensively reviewed the NEK kinases in terms of their expression and regulation in different cancers. Lastly, we have emphasized on some of the potential NEK inhibitors reported so far.
    Keywords:  Breast cancer; Cell cycle; Lung cancer; NEK kinases; Ovarian cancer; Pancreatic cancer
    DOI:  https://doi.org/10.1007/s10238-021-00782-0
  20. Proc Natl Acad Sci U S A. 2022 Jan 25. pii: e2113539119. [Epub ahead of print]119(4):
    A multiscale biophysical model gives quantized metachronal waves in a lattice of beating cilia.
    Brato Chakrabarti, Sebastian Fürthauer, Michael J Shelley.
      Motile cilia are slender, hair-like cellular appendages that spontaneously oscillate under the action of internal molecular motors and are typically found in dense arrays. These active filaments coordinate their beating to generate metachronal waves that drive long-range fluid transport and locomotion. Until now, our understanding of their collective behavior largely comes from the study of minimal models that coarse grain the relevant biophysics and the hydrodynamics of slender structures. Here we build on a detailed biophysical model to elucidate the emergence of metachronal waves on millimeter scales from nanometer-scale motor activity inside individual cilia. Our study of a one-dimensional lattice of cilia in the presence of hydrodynamic and steric interactions reveals how metachronal waves are formed and maintained. We find that, in homogeneous beds of cilia, these interactions lead to multiple attracting states, all of which are characterized by an integer charge that is conserved. This even allows us to design initial conditions that lead to predictable emergent states. Finally, and very importantly, we show that, in nonuniform ciliary tissues, boundaries and inhomogeneities provide a robust route to metachronal waves.
    Keywords:  active matter; cilia; metachronal waves
    DOI:  https://doi.org/10.1073/pnas.2113539119
  21. Molecules. 2022 Jan 06. pii: 347. [Epub ahead of print]27(2):
    Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development.
    Dibyendu Dana, Tuhin Das, Athena Choi, Ashif I Bhuiyan, Tirtha K Das, Tanaji T Talele, Sanjai K Pathak.
      Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. Its activity is tightly regulated during the cell cycle with the help of other kinases and phosphatases and via proteasomal degradation. Increased levels of Nek2 kinase can promote centrosome amplification (CA), mitotic defects, chromosome instability (CIN), tumor growth, and cancer metastasis. While it remains a highly attractive target for the development of anti-cancer therapeutics, several new roles of the Nek2 enzyme have recently emerged: these include drug resistance, bone, ciliopathies, immune and kidney diseases, and parasitic diseases such as malaria. Therefore, Nek2 is at the interface of multiple cellular processes and can influence numerous cellular signaling networks. Herein, we provide a critical overview of Nek2 kinase biology and discuss the signaling roles it plays in both normal and diseased human physiology. While the majority of research efforts over the last two decades have focused on the roles of Nek2 kinase in tumor development and cancer metastasis, the signaling mechanisms involving the key players associated with several other notable human diseases are highlighted here. We summarize the efforts made so far to develop Nek2 inhibitory small molecules, illustrate their action modalities, and provide our opinion on the future of Nek2-targeted therapeutics. It is anticipated that the functional inhibition of Nek2 kinase will be a key strategy going forward in drug development, with applications across multiple human diseases.
    Keywords:  Nek2 PROTACS; Nek2 in cancer metastasis; Nek2 inhibitors; Nek2 kinase review; Nek2 kinase signaling; centrosomal kinase; mitotic kinase; small molecule inhibitors of Nek2 kinase
    DOI:  https://doi.org/10.3390/molecules27020347
  22. Pediatr Pulmonol. 2022 Jan 18.
    Variations in infection control practices suggest a need for guidelines in primary ciliary dyskinesia patient care.
    Ayse Bahar Caliskan, Amjad Horani, Michele Manion, Steven L Brody.
      Primary ciliary dyskinesis (PCD) is an autosomal recessive disorder associated with impaired mucociliary clearance caused by defects in ciliary structure and function. The major clinical feature of PCD is recurring or persistent respiratory tract infection. Respiratory tract colonization with drug-resistant organisms impacts the frequency of infections and lung function decline. Protective gear has been employed by caregivers in an attempt to control respiratory tract bacterial spread between patients with cystic fibrosis, but use in PCD is not known. We conducted a web-based survey to investigate infection control and prevention practices of PCD centers in North America, and how practices have been influenced by the COVID-19 pandemic. The response rate was 87.0%. Prior to the COVID-19 pandemic, glove, gown and mask use was variable, and only 3.7% of centers used masks during encounters with PCD outpatients. After COVID-19 mandates are lifted, 48.1% of centers plan to continue to use masks during outpatient care, while the practice regarding use of gloves and gowns was not influenced by the current pandemic. There is no uniform practice for infection control in PCD care indicating the need for practice guidelines. Mitigation of respiratory virus transmission learned during the COVID-19 pandemic may impact future infection control approaches used for patients with PCD and other lung diseases. This article is protected by copyright. All rights reserved.
    Keywords:  COVID-19; Infection control; Personal protective equipment; Primary ciliary dyskinesia; Survey
    DOI:  https://doi.org/10.1002/ppul.25836
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