bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–03–12
seventeen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Drug repurposing in ADPKD.
  2. Effect of Kidney transplantation on cyst growth in autosomal dominant polycystic kidney disease.
  3. Ameliorating liver disease in an autosomal recessive polycystic kidney disease (ARPKD) mouse model.
  4. Metabolism-based approaches for autosomal dominant polycystic kidney disease.
  5. Efficacy and Safety of Tolvaptan for Patients With Autosomal Dominant Polycystic Kidney Disease in Real-world Practice: A Single Institution Retrospective Study.
  6. Clinical features and prognosis of autosomal dominant polycystic kidney disease with cerebrovascular complications.
  7. Mucociliary Wnt signaling promotes cilia biogenesis and beating.
  8. Schmidtea mediterranea as a Model Organism to Study the Molecular Background of Human Motile Ciliopathies.
  9. Phenotypes and genetic etiology of spontaneous polycystic kidney and liver disease in cynomolgus monkey.
  10. Blood pressure response to exercise in unaffected relatives of autosomal dominant polycystic kidney disease patients: an observational study.
  11. Primary cilia sense glutamine availability and respond via asparagine synthetase.
  12. Fluid-structure interaction modelling of neighboring tubes with primary cilium analysis.
  13. Cooperation between primary cilia signaling and integrin receptor extracellular matrix engagement regulates progenitor proliferation and neuronal differentiation in the developing cerebellum.
  14. Light-sheet laser speckle imaging for cilia motility assessment.
  15. TSC2/PKD1 contiguous deletion syndrome in a pregnant woman: A case report.
  16. The effects of acute hydrogen peroxide exposure on respiratory cilia motility and viability.
  17. The role of lipotoxicity in kidney disease: From molecular mechanisms to therapeutic prospects.
  1. Kidney Int. 2023 Mar 02. pii: S0085-2538(23)00133-3. [Epub ahead of print]
    Drug repurposing in ADPKD.
    Julie Xia Zhou, Vicente E Torres.
      Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive renal cyst formation that leads to kidney failure. Tolvaptan, a vasopressin 2 receptor (V2R) antagonist, is the only drug approved to treat ADPKD patients with rapid disease progression. The use of tolvaptan is limited by reduced tolerability from aquaretic effects and potential hepatotoxicity. Thus, the search for more effective drugs to slow down the progression of ADPKD is urgent and challenging. Drug repurposing is a strategy for identifying new clinical indications for approved or investigational medications. Drug repurposing is increasingly becoming an attractive proposition due to its cost- and time-efficiencies and known pharmacokinetic and safety profiles. In this review, we focus on the repurposing approaches to identify suitable drug candidates to treat ADPKD and prioritization and implementation of candidates with high probability of success. Identification of drug candidates through understanding of disease pathogenesis and signaling pathways is highlighted.
    Keywords:  ADPKD; animal model
    DOI:  https://doi.org/10.1016/j.kint.2023.02.010
  2. Clin Nephrol. 2023 Mar 07.
    Effect of Kidney transplantation on cyst growth in autosomal dominant polycystic kidney disease.
    Jorge E Gaytan-Arocha, Aaron Pérez-Segovia, Estefania Reul-Linares, Elisa Naomi Hernández-Paredes, Mónica Chapa-Ibargüengoitia, Ricardo Correa-Rotter, Luis E Morales-Buenrostro, Juan C Ramirez-Sandoval.
       BACKGROUND: In patients with autosomal dominant polycystic kidney disease (ADPKD), there is limited evidence of the rate of cyst progression after kidney transplantation.
    AIMS: To compare the height-adjusted total kidney volume (Ht-TKV) before and after transplantation in kidney transplant recipients (KTR) with -ADPKD.
    MATERIALS AND METHODS: Retrospective cohort study. The estimate of Ht-TKV was calculated by the ellipsoid volume equation using measurements from CT or yearly MRI scans before and after transplantation.
    RESULTS: We included 30 patients with -ADPKD who underwent kidney transplantation (age 49 ± 10.1 years, 11 (37%) females, dialysis vintage 3 (1 - 6) years, and 4 (13%) underwent unilateral nephrectomy during the peritransplant period). The median follow-up time was 5 years (range 2 - 16 years). Transplantation was associated with a significant decrease in Ht-TKV after transplantation in 27 (90%) KTR. Median Ht-TKV decreased from 1,708 (IQR 1,100 - 2,350) mL/m to 710 (IQR 420 - 1,380) mL/m after 6 years of follow-up (p < 0.001), with a mean Ht-TKV change rate per year after transplantation of -1.4, -11.8, -9.7, -12.7, -7.0, and -9.4% after 1, 2, 3, 4, 5, and 6 years, respectively. Even in 2 (7%) KTR without regression, the annual growth was < 1.5% per year after transplantation.
    CONCLUSION: Kidney transplantation reduced Ht-TKV after the first 2 years of transplantation, and this decline was continuous for more than 6 years of follow-up.
    DOI:  https://doi.org/10.5414/CN111036
  3. Am J Physiol Gastrointest Liver Physiol. 2023 Mar 07.
    Ameliorating liver disease in an autosomal recessive polycystic kidney disease (ARPKD) mouse model.
    Murali K Yanda, Adi Zeidan, Liudmila Cebotaru.
      Systemic and portal hypertension, liver fibrosis, and hepatomegaly are manifestations associated with autosomal recessive polycystic kidney disease (ARPKD), which is caused by malfunctions of fibrocystin/polyductin. The goal is to understand how liver pathology occurs and to devise therapeutic strategies to treat it. We injected 5-day old Pkhd1del3-4/del3-4 mice for one month with the CFTR modulator, VX-809, designed to rescue processing and trafficking of CFTR folding mutants (1). We used immunostaining and immunofluorescence techniques to evaluate liver pathology. We assessed protein expression via western blotting. We detected abnormal biliary ducts consistent with ductal plate abnormalities, as well as a greatly increased proliferation of cholangiocytes in the Pkhd1del3-4/del3-4 mice. CFTR was present in the apical membrane of cholangiocytes and increased in the Pkhd1del3-4/del3-4 mice, consistent with a role for apically located CFTR in enlarged bile ducts. Interestingly, we also found CFTR in the primary cilium, in association with PC2. Localization of CFTR and PC2 and overall length of the cilia were increased in the Pkhd1del3-4/del3-4mice. In addition, several of the heat shock proteins (27, 70, and 90) were upregulated, suggesting that global changes in protein processing and trafficking had occurred. We found that a deficit of FPC leads to bile duct abnormalities, enhanced cholangiocyte proliferation, and misregulation of heat shock proteins, which all returned toward wt. values following VX-809 treatment. These data suggest that CFTR correctors can be useful as therapeutics for ARPKD. Given that these drugs are already approved for use in humans, they can be fast-tracked for clinical use.
    Keywords:  Biliary Ducts; CFTR; Heat Shock Protein; Polcystin 2; fibrocystin/polyductin
    DOI:  https://doi.org/10.1152/ajpgi.00255.2022
  4. Front Mol Biosci. 2023 ;10 1126055
    Metabolism-based approaches for autosomal dominant polycystic kidney disease.
    Ivona Bakaj, Alessandro Pocai.
      Autosomal Dominant Polycystic Kidney Disease (ADPKD) leads to end stage kidney disease (ESKD) through the development and expansion of multiple cysts throughout the kidney parenchyma. An increase in cyclic adenosine monophosphate (cAMP) plays an important role in generating and maintaining fluid-filled cysts because cAMP activates protein kinase A (PKA) and stimulates epithelial chloride secretion through the cystic fibrosis transmembrane conductance regulator (CFTR). A vasopressin V2 receptor antagonist, Tolvaptan, was recently approved for the treatment of ADPKD patients at high risk of progression. However additional treatments are urgently needed due to the poor tolerability, the unfavorable safety profile, and the high cost of Tolvaptan. In ADPKD kidneys, alterations of multiple metabolic pathways termed metabolic reprogramming has been consistently reported to support the growth of rapidly proliferating cystic cells. Published data suggest that upregulated mTOR and c-Myc repress oxidative metabolism while enhancing glycolytic flux and lactic acid production. mTOR and c-Myc are activated by PKA/MEK/ERK signaling so it is possible that cAMPK/PKA signaling will be upstream regulators of metabolic reprogramming. Novel therapeutics opportunities targeting metabolic reprogramming may avoid or minimize the side effects that are dose limiting in the clinic and improve on the efficacy observed in human ADPKD with Tolvaptan.
    Keywords:  ADPKD (autosomal dominant polycystic kidney disease); GLP-1; glucagon; metabolic reprograming; metabolism & obesity; therapeutic approaches; tolvaptan
    DOI:  https://doi.org/10.3389/fmolb.2023.1126055
  5. In Vivo. 2023 Mar-Apr;37(2):37(2): 801-805
    Efficacy and Safety of Tolvaptan for Patients With Autosomal Dominant Polycystic Kidney Disease in Real-world Practice: A Single Institution Retrospective Study.
    Hiroshi Masuda, Nobuhiko Shimizu, Keita Sekine, Atsushi Okato, Kyokusin Hou, Takahito Suyama, Kazuhiro Araki, Satoko Kojima, Yukio Naya.
       BACKGROUND/AIM: We evaluated the efficacy and safety of tolvaptan for autosomal dominant polycystic kidney disease (ADPKD) in real-world practice.
    PATIENTS AND METHODS: We retrospectively reviewed the cases of 27 patients who had been diagnosed with ADPKD between January 2014 and December 2022. Among them, 14 patients received tolvaptan (60 mg/day; morning: 45 mg, night: 15 mg) after being admitted for 2 days. In the outpatient clinic, blood and urine samples were taken monthly.
    RESULTS: The mean age, pretreatment estimated glomerular filtration rate (eGFR), treatment duration, and total kidney volume were 60 years, 45.6 ml/min/1.73 m2, 2.8 years, and 2,390 ml, respectively. One month later, the patients' renal dysfunction had worsened slightly, and their serum sodium concentrations had significantly increased. After one year, the mean reduction in the eGFR was -5.5 ml/min/1.73 m2 Moreover, at 3 years the patients' renal function was stable. No hepatic dysfunction or electrolyte abnormalities were noted, although discontinuation occurred in two cases. Tolvaptan treatment is considered to be safe.
    CONCLUSION: Tolvaptan was effective against ADPKD in a real-world setting. Moreover, the safety of tolvaptan was confirmed.
    Keywords:  Autosomal dominant polycystic kidney disease; TKV; Tolvaptan; eGFR
    DOI:  https://doi.org/10.21873/invivo.13144
  6. Clin Nephrol. 2023 Mar 07.
    Clinical features and prognosis of autosomal dominant polycystic kidney disease with cerebrovascular complications.
    Zhe Li, Song Luo, Yang Wang, Yuchao Zhou, Shutian Xu, Ke Zuo, Shijun Li.
       OBJECTIVES: This retrospective study was used to evaluate the clinical and imaging characteristics and the prognosis of autosomal dominant polycystic kidney disease (ADPKD) with cerebrovascular complications.
    MATERIALS AND METHODS: We retrospectively analyzed 30 patients with ADPKD complicated with intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), unruptured intracranial aneurysms (UIAs), or Moyamoya disease (MMD) who were admitted to Jinling Hospital from January 2001 to January 2022. We analyzed the clinical manifestations and imaging characteristics of ADPKD patients with cerebrovascular complications and followed up on their long-term outcomes.
    RESULTS: 30 patients, 17 men and 13 women, with an average age of 47.5 (40.0, 54.0) years were included in this study, including 12 cases of ICH, 12 cases of SAH, 5 cases of UIA, and 1 case of MMD. The 8 patients who died during follow-up had a lower Glasgow Coma Scale (GCS) on admission (p = 0.024) and a significantly higher serum creatinine (p = 0.004) and blood urea nitrogen (p = 0.006) than the 22 patients with long-term survival.
    CONCLUSION: Intracranial aneurysms, SAH, and ICH are the most common cerebrovascular diseases in ADPKD. Patients with low GCS score or worse renal function have a poor prognosis, which can lead to disability and even death.
    DOI:  https://doi.org/10.5414/CN110959
  7. Nat Commun. 2023 Mar 06. 14(1): 1259
    Mucociliary Wnt signaling promotes cilia biogenesis and beating.
    Carina Seidl, Fabio Da Silva, Kaiqing Zhang, Kai Wohlgemuth, Heymut Omran, Christof Niehrs.
      It is widely thought that Wnt/Lrp6 signaling proceeds through the cytoplasm and that motile cilia are signaling-inert nanomotors. Contrasting both views, we here show in the mucociliary epidermis of X. tropicalis embryos that motile cilia transduce a ciliary Wnt signal that is distinct from canonical β-catenin signaling. Instead, it engages a Wnt-Gsk3-Ppp1r11-Pp1 signaling axis. Mucociliary Wnt signaling is essential for ciliogenesis and it engages Lrp6 co-receptors that localize to cilia via a VxP ciliary targeting sequence. Live-cell imaging using a ciliary Gsk3 biosensor reveals an immediate response of motile cilia to Wnt ligand. Wnt treatment stimulates ciliary beating in X. tropicalis embryos and primary human airway mucociliary epithelia. Moreover, Wnt treatment improves ciliary function in X. tropicalis ciliopathy models of male infertility and primary ciliary dyskinesia (ccdc108, gas2l2). We conclude that X. tropicalis motile cilia are Wnt signaling organelles that transduce a distinct Wnt-Pp1 response.
    DOI:  https://doi.org/10.1038/s41467-023-36743-2
  8. Int J Mol Sci. 2023 Feb 24. pii: 4472. [Epub ahead of print]24(5):
    Schmidtea mediterranea as a Model Organism to Study the Molecular Background of Human Motile Ciliopathies.
    Alicja Rabiasz, Ewa Ziętkiewicz.
      Cilia and flagella are evolutionarily conserved organelles that form protrusions on the surface of many growth-arrested or differentiated eukaryotic cells. Due to the structural and functional differences, cilia can be roughly classified as motile and non-motile (primary). Genetically determined dysfunction of motile cilia is the basis of primary ciliary dyskinesia (PCD), a heterogeneous ciliopathy affecting respiratory airways, fertility, and laterality. In the face of the still incomplete knowledge of PCD genetics and phenotype-genotype relations in PCD and the spectrum of PCD-like diseases, a continuous search for new causative genes is required. The use of model organisms has been a great part of the advances in understanding molecular mechanisms and the genetic basis of human diseases; the PCD spectrum is not different in this respect. The planarian model (Schmidtea mediterranea) has been intensely used to study regeneration processes, and-in the context of cilia-their evolution, assembly, and role in cell signaling. However, relatively little attention has been paid to the use of this simple and accessible model for studying the genetics of PCD and related diseases. The recent rapid development of the available planarian databases with detailed genomic and functional annotations prompted us to review the potential of the S. mediterranea model for studying human motile ciliopathies.
    Keywords:  RNA interference (RNAi); candidate genes; flatworms; motile cilia; planarians; primary ciliary dyskinesia (PCD)
    DOI:  https://doi.org/10.3390/ijms24054472
  9. Front Vet Sci. 2023 ;10 1106016
    Phenotypes and genetic etiology of spontaneous polycystic kidney and liver disease in cynomolgus monkey.
    Ruo Wu, Bing Bai, Feng Li, Raoxian Bai, Yan Zhuo, Zhengna Zhu, Rongfang Jia, Shangang Li, Yongchang Chen, Xiaoping Lan.
       Introduction: Polycystic kidney disease (PKD) is a common autosomal dominant or recessive genetic disease, often accompanied by polycystic liver disease (PLD). Many cases of PKD in animals have been reported. However, little is known about the genes that cause PKD in animals.
    Methods: In this study, we evaluated the clinical phenotypes of PKD in two spontaneously aged cynomolgus monkeys and explored the genetic etiology using whole-genome sequencing (WGS). Ultrasonic and histological consequences were further investigated in PKD- and PLD-affected monkeys.
    Results: The results indicated that the kidneys of the two monkeys had varying degrees of cystic changes, and the renal cortex was thinned and accompanied by fluid accumulation. As for hepatopathy, inflammatory cell infiltration, cystic effusion, steatosis of hepatocytes, and pseudo-lobular were found. Based on WGS results, the variants of PKD1:(XM_015442355: c.1144G>C p. E382Q) and GANAB: (NM_001285075.1: c.2708T>C/p. V903A) are predicted to be likely pathogenic heterozygous mutations in PKD- and PLD-affected monkeys.
    Discussion: Our study suggests that the cynomolgus monkey PKD and PLD phenotypes are very similar to those in humans, and are probably caused by pathogenic genes homologous to humans. The results indicate that cynomolgus monkeys can be used as the most appropriate animal model for human PKD pathogenesis research and therapeutic drug screening.
    Keywords:  cynomolgus monkey; genetic etiology; phenotype; polycystic kidney disease; polycystic liver disease; whole-genome sequencing
    DOI:  https://doi.org/10.3389/fvets.2023.1106016
  10. Int Urol Nephrol. 2023 Mar 06.
    Blood pressure response to exercise in unaffected relatives of autosomal dominant polycystic kidney disease patients: an observational study.
    Ezgi Coskun Yenigun, Didem Turgut, Simal Koksal Cevher, Cigdem Yucel, Cenk Aypak, Fatih Dede.
       INTRODUCTION: Hypertension is an early finding of autosomal dominant polycystic kidney disease (ADPKD) and is related to different mechanisms. Cyst expansion-related renin secretion or early endothelial dysfunctions are some of these hypotheses. In addition, the underlying genetic factor is thought to play a role in the inheritance of hypertension. The differential course of hypertension in ADPKD preoccupies that relatives of ADPKD patients may also be at risk for this underlying mechanisms with a genetically determined abnormal endothelial-vascular state. In this study, we aimed to evaluate blood pressure response to exercise as an initial vascular problem in unaffected and normotensive relatives of hypertensive ADPKD patients.
    METHODS: This is an observational study including unaffected and normotensive relatives (siblings and children) of ADPKD patients (relative group) and healthy controls (control group) who performed an exercise stress test. A 6-lead electrocardiogram was recorded and blood pressure was measured automatically with a cuff worn on the right arm, immediately before the test and every 3 min during the exercise and the recovery phase. Participants continued the test until their age-specific target heart rate was reached or symptoms occurred that required discontinuation of the test. The highest blood pressure and pulse values during exercise were noted. In addition, as a marker for endothelial function, nitric oxide (NO) and asymmetric dimethylarginine (ADMA) levels were measured at baseline and post-exercise.
    RESULTS: There were 24 participants in the relative group (16 female, mean age 38.45 years) and 30 participants in the control group (15 female, mean age 37.96 years). Two groups were similar in terms of age, gender, body mass index (BMI), smoking status, resting systolic blood pressure (SBP)/diastolic blood pressure (DBP) and biochemical parameters. Mean SBP and DBP were similar in both groups during 1st, 3rd and 9th minutes of exercise (1st minute: 136.25 ± 19.71 mmHg vs 140.36 ± 30.79 mmHg for SBP, p = 0.607, 84.05 ± 14.75 mmHg vs 82.60 ± 21.60 mmHg for DBP, p = 0.799; 3rd minute: 150.75 ± 30.39 mmHg vs 148.54 ± 27.30 mmHg for SBP, p = 0.801, 98.95 ± 26.92 mmHg vs 85.92 ± 17.93 mmHg for DBP, p = 0.062; 9th minute: 156.35 ± 30.84 mmHg vs 166.43 ± 31.90 mmHg for SBP, p = 0.300, 96.25 ± 21.99 mmHg vs 101.78 ± 33.11 mmHg for DBP, p = 0.529 for control and relatives, respectively). During the recovery phase, SBP decreased in both groups in 6th minute (119.85 ± 14.06 mmHg vs 122.86 ± 16.76 mmHg, p = 0.538 for control and relatives respectively); however, in the relatives of ADPKD patients DBP remained high at the end of the 6th minute (78.95 ± 11.29 mmHg vs 86.67 ± 9.81 mmHg p = 0.025 for control and relatives, respectively). Baseline and post-exercise NO and ADMA levels were similar in both groups (Baseline p = 0.214 and p = 0.818, post-exercise p = 0.652 and p = 0.918 for NO and ADMA, respectively).
    CONCLUSION: Abnormal blood pressure response to exercise was observed in unaffected normotensive relatives of ADPKD. Although its clinical significance needs to be demonstrated by additional research, it is an important finding that unaffected relatives of ADPKD may be at risk for an altered arterial vascular network. Furthermore, these data are the first to demonstrate that relatives of ADPKD patients may also be under risk with a genetically determined abnormal vascular state.
    Keywords:  ADMA; ADPKD; Endothelial dysfunction; Exercise stress test; Hypertension; NO; Unaffected relative
    DOI:  https://doi.org/10.1007/s11255-023-03535-y
  11. Nat Metab. 2023 Mar 06.
    Primary cilia sense glutamine availability and respond via asparagine synthetase.
    Maria Elena Steidl, Elisa A Nigro, Anne Kallehauge Nielsen, Roberto Pagliarini, Laura Cassina, Matteo Lampis, Christine Podrini, Marco Chiaravalli, Valeria Mannella, Gianfranco Distefano, Ming Yang, Mariam Aslanyan, Giovanna Musco, Ronald Roepman, Christian Frezza, Alessandra Boletta.
      Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.
    DOI:  https://doi.org/10.1038/s42255-023-00754-6
  12. Math Biosci Eng. 2023 Jan;20(2): 3677-3699
    Fluid-structure interaction modelling of neighboring tubes with primary cilium analysis.
    Nerion Zekaj, Shawn D Ryan, Andrew Resnick.
      We have developed a numerical model of two osculating cylindrical elastic renal tubules to investigate the impact of neighboring tubules on the stress applied to a primary cilium. We hypothesize that the stress at the base of the primary cilium will depend on the mechanical coupling of the tubules due to local constrained motion of the tubule wall. The objective of this work was to determine the in-plane stresses of a primary cilium attached to the inner wall of one renal tubule subject to the applied pulsatile flow, with a neighboring renal tube filled with stagnant fluid in close proximity to the primary tubule. We used the commercial software COMSOLⓇ to model the fluid-structure interaction of the applied flow and tubule wall, and we applied a boundary load to the face of the primary cilium during this simulation to produces a stress at its base. We confirm our hypothesis by observing that on average the in-plane stresses are greater at the base of the cilium when there is a neighboring renal tube versus if there is no neighboring tube at all. In combination with the hypothesized function of a cilium as a biological fluid flow sensor, these results indicate that flow signaling may also depend on how the tubule wall is constrained by neighboring tubules. Our results may be limited in their interpretation due to the simplified nature of our model geometry, and further improvements to the model may potentially lead to the design of future experiments.
    Keywords:   biophysics ; fluid flow ; fluid-structure interactions ; kidney ; modeling ; primary cilia ; renal tubules
    DOI:  https://doi.org/10.3934/mbe.2023172
  13. Front Cell Dev Biol. 2023 ;11 1127638
    Cooperation between primary cilia signaling and integrin receptor extracellular matrix engagement regulates progenitor proliferation and neuronal differentiation in the developing cerebellum.
    Anna E Pittman, David J Solecki.
      Neural progenitors and their neuronal progeny are bathed in extrinsic signals that impact critical decisions like the mode of cell division, how long they should reside in specific neuronal laminae, when to differentiate, and the timing of migratory decisions. Chief among these signals are secreted morphogens and extracellular matrix (ECM) molecules. Among the many cellular organelles and cell surface receptors that sense morphogen and ECM signals, the primary cilia and integrin receptors are some of the most important mediators of extracellular signals. Despite years of dissecting the function of cell-extrinsic sensory pathways in isolation, recent research has begun to show that key pathways work together to help neurons and progenitors interpret diverse inputs in their germinal niches. This mini-review utilizes the developing cerebellar granule neuron lineage as a model that highlights evolving concepts on the crosstalk between primary cilia and integrins in the development of the most abundant neuronal type in the brains of mammals.
    Keywords:  cell polarity; germinal zone; integrin; morphogen; niche; pard complex; primary cilia
    DOI:  https://doi.org/10.3389/fcell.2023.1127638
  14. Comput Struct Biotechnol J. 2023 ;21 1661-1669
    Light-sheet laser speckle imaging for cilia motility assessment.
    Kai Long, Jing Liu, Shuhao Shen, Mark Thong, Deyun Wang, Nanguang Chen.
      Mucociliary clearance is an important innate defense mechanism predominantly mediated by ciliated cells in the upper respiratory tract. Ciliary motility on the respiratory epithelium surface and mucus pathogen trapping assist in maintaining healthy airways. Optical imaging methods have been used to obtain several indicators for assessing ciliary movement. Light-sheet laser speckle imaging (LSH-LSI) is a label-free and non-invasive optical technique for three-dimensional and quantitative mapping of velocities of microscopic scatterers. Here, we propose to use an inverted LSH-LSI platform to study cilia motility. We have experimentally confirmed that LSH-LSI can reliably measure the ciliary beating frequency and has the potential to provide many additional quantitative indicators for characterizing the ciliary beating pattern without labeling. For example, the asymmetry between the power stroke and the recovery stroke is apparent in the local velocity waveform. PIV (particle imaging velocimetry) analysis of laser speckle data could determine the cilia motion directions in different phases.
    Keywords:  Autocorrelation; Cilia; Laser speckle imaging; Motility; PIV
    DOI:  https://doi.org/10.1016/j.csbj.2023.02.036
  15. Front Med (Lausanne). 2023 ;10 1101079
    TSC2/PKD1 contiguous deletion syndrome in a pregnant woman: A case report.
    Shaofang Huang, Kangxiang Xu, Yuqi Xu, Lu Zhao, Xiaoju He.
      TSC2/PKD1 contiguous gene deletion syndrome is a disease caused by the deletions of the TSC2 and PKD1 genes. This is a rare contiguous genomic disease with clinical manifestations of tuberous sclerosis and polycystic kidney disease. To our knowledge, this case report is the first known case of TSC2/PKD1 contiguous gene deletions in a pregnant woman. The patient had multiple renal cysts, angiomyolipoma, hypomelanotic macules, shagreen patch, subependymal giant cell astrocytoma, multiple cortical tubers, and subependymal nodules. The patient underwent genetic testing. To exclude genetic defects in the fetus, prenatal fetal genetic testing was performed after obtaining the patient's consent. We found an increasing trend in the size of renal cysts and renal angiomyolipomas in patients with polycystic kidney with tuberous sclerosis during pregnancy. Through enhanced clinical monitoring of patients and prenatal genetic testing of the fetus, timely and effective clinical intervention for the mother may be achieved, thus obtaining the best possible outcome for both mother and fetus.
    Keywords:  TSC2/PKD1 contiguous gene deletions; polycystic kidney disease; pregnant woman; prenatal diagnosis; renal angiomyolipoma; tuberous sclerosis
    DOI:  https://doi.org/10.3389/fmed.2023.1101079
  16. PeerJ. 2023 ;11 e14899
    The effects of acute hydrogen peroxide exposure on respiratory cilia motility and viability.
    Richard Francis.
      COVID-19 has seen the propagation of alternative remedies to treat respiratory disease, such as nebulization of hydrogen peroxide (H2O2). As H2O2 has known cytotoxicity, it was hypothesised that H2O2 inhalation would negatively impact respiratory cilia function. To test this hypothesis, mouse tracheal samples were incubated with different H2O2 concentrations (0.1-1%) then cilia motility, cilia generated flow, and cell death was assessed 0-120 min following H2O2 treatment. 0.1-0.2% H2O2 caused immediate depression of cilia motility and complete cessation of cilia generated flow. Higher H2O2 concentrations (≥0.5%) caused immediate complete cessation of cilia motility and cilia generated flow. Cilia motility and flow was restored 30 min after 0.1% H2O2 treatment. Cilia motility and flow remained depressed 120 min after 0.2-0.5% H2O2 treatment. No recovery was seen 120 min after treatment with ≥1% H2O2. Live/dead staining revealed that H2O2 treatment caused preferential cell death of ciliated respiratory epithelia over non-ciliated epithelia, with 1% H2O2 causing 35.3 ± 7.0% of the ciliated epithelia cells to die 120 min following initial treatment. This study shows that H2O2 treatment significantly impacts respiratory cilia motility and cilia generated flow, characterised by a significant impairment in cilia motility even at low concentrations, the complete cessation of cilia motility at higher doses, and a significant cytotoxic effect on ciliated respiratory epithelial cells by promoting cell death. While this data needs further study using in vivo models, it suggests that extreme care should be taken when considering treating respiratory diseases with nebulised H2O2.
    Keywords:  Alternative medicine; Cilia; Hydrogen peroxide; Respiratory epithelium
    DOI:  https://doi.org/10.7717/peerj.14899
  17. Biomed Pharmacother. 2023 Mar 03. pii: S0753-3322(23)00253-6. [Epub ahead of print]161 114465
    The role of lipotoxicity in kidney disease: From molecular mechanisms to therapeutic prospects.
    Linan Ren, Haiying Cui, Yao Wang, Feng Ju, Yunjia Cai, Xiaokun Gang, Guixia Wang.
      Lipotoxicity is the dysregulation of the lipid environment and/or intracellular composition that leads to accumulation of harmful lipids and ultimately to organelle dysfunction, abnormal activation of intracellular signaling pathways, chronic inflammation and cell death. It plays an important role in the development of acute kidney injury and chronic kidney disease, including diabetic nephropathy, obesity-related glomerulopathy, age-related kidney disease, polycystic kidney disease, and the like. However, the mechanisms of lipid overload and kidney injury remain poorly understood. Herein, we discuss two pivotal aspects of lipotoxic kidney injury. First, we analyzed the mechanism of lipid accumulation in the kidney. Accumulating data indicate that the mechanisms of lipid overload in different kidney diseases are inconsistent. Second, we summarize the multiple mechanisms by which lipotoxic species affect the kidney cell behavior, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, dysregulated autophagy, and inflammation, highlighting the central role of oxidative stress. Blocking the molecular pathways of lipid accumulation in the kidney and the damage of the kidney by lipid overload may be potential therapeutic targets for kidney disease, and antioxidant drugs may play a pivotal role in the treatment of kidney disease in the future.
    Keywords:  Acute kidney injury; Chronic kidney disease; Lipid overload; Lipotoxicity; Molecular mechanism
    DOI:  https://doi.org/10.1016/j.biopha.2023.114465
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