bims-bicyki 2021-07-11 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2021–07–11
nineteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Autosomal Dominant Polycystic Kidney Disease in which the Polycystic Liver Volume was Reduced by Rigorous Blood Pressure Control.
Clinical and genetic characteristics of Korean autosomal dominant polycystic kidney disease patients.
Safety and efficacy of Tolvaptan in real-world patients with autosomal dominant polycystic kidney disease- interim results of SLOW-PKD surveillance.
Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease.
Drug repurposing in autosomal dominant polycystic kidney disease: back to the future with pioglitazone.
Founding mutations explains hotspots of polycystic kidney disease in Southern Spain.
A randomized phase 1b cross-over study of the safety of low-dose pioglitazone for treatment of autosomal dominant polycystic kidney disease.
Y-27632, a ROCK inhibitor, improved laser-induced shock wave (LISW)-induced cochlear synaptopathy in mice.
The vasopressin-aquaporin-2 pathway syndromes.
Twitchy, the Drosophila orthologue of the ciliary gating protein FBF1/dyf-19, is required for coordinated locomotion and male fertility.
A ciliopathy complex builds distal appendages to initiate ciliogenesis.
Primary Cilia in Amacrine Cells in Retinal Development.
RhoA/ROCK-1 Signaling Pathway and Oxidative Stress in Coronary Artery Disease Patients.
The regulatory roles of motile cilia in CSF circulation and hydrocephalus.
Exercise Counterbalances Rho/ROCK2 Signaling Impairment in the Skeletal Muscle and Ameliorates Insulin Sensitivity in Obese Mice.
Impact of plasma 5-hydroxyindoleacetic acid, a serotonin metabolite, on clinical outcome in septic shock, and its effect on vascular permeability.
Ciliogenesis is Not Directly Regulated by LRRK2 Kinase Activity in Neurons.
Betulin alleviates cisplatin-induced hepatic injury in rats: Targeting apoptosis and Nek7-independent NLRP3 inflammasome pathways.
Diagnostic imaging of the ciliary body: Technologies, outcomes, and future perspectives.

Intern Med. 2021 Jul 03.

Autosomal Dominant Polycystic Kidney Disease in which the Polycystic Liver Volume was Reduced by Rigorous Blood Pressure Control.

Tatsuya Suwabe, Yoshifumi Ubara, Daisuke Ikuma, Hiroki Mizuno, Noriko Hayami, Masayuki Yamanouchi, Naoki Sawa.

  Polycystic liver disease (PLD) is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). However, current treatments for PLD are only supportive. We experienced a case of enlarged kidneys and liver in a 53-year-old Japanese man with ADPKD who was on hemodialysis. He underwent renal transcatheter arterial embolization (TAE) for enlarged kidneys. His blood pressure (BP) decreased after renal TAE, and his liver volume decreased from 5,259 mL to 4,647 mL (11.6% reduction) within 1 year after renal TAE. This case suggests that rigorous blood pressure control may be beneficial for ameliorating enlarged PLD.

Keywords:  ADPKD; PLD; blood pressure; polycystic kidney disease; polycystic liver disease

DOI:  https://doi.org/10.2169/internalmedicine.7441-21
Korean J Intern Med. 2021 Jul;36(4): 767-779

Clinical and genetic characteristics of Korean autosomal dominant polycystic kidney disease patients.

Yun Kyu Oh, Hayne Cho Park, Hyunjin Ryu, Yong-Chul Kim, Kook-Hwan Oh.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It is characterized by cyst growth in the kidneys, resulting in kidney enlargement and end-stage kidney disease. The polycystic kidney disease 1 (PKD1) and PKD2 have been identified as genes related to ADPKD and their significance in the molecular pathology of the disease has been studied. A disease-modifying drug has been approved; therefore, it has become important to identify patients at a high risk of kidney disease progression. Genetic tests, image analysis methods, and clinical factors for kidney disease progression prediction have been established. This review describes genetic and clinical characteristics, and discusses ongoing studies in Korean ADPKD patients.

Keywords:  Autosomal dominant polycystic kidney disease; Disease progression; PKD1; PKD2; Tolvaptan

DOI:  https://doi.org/10.3904/kjim.2021.176
Clin Exp Nephrol. 2021 Jul 06.

Safety and efficacy of Tolvaptan in real-world patients with autosomal dominant polycystic kidney disease- interim results of SLOW-PKD surveillance.

Toshio Mochizuki, Satoru Muto, Masateru Miyake, Toshiki Tanaka, Wenchyi Wang.

   BACKGROUND: Tolvaptan is a vasopressin type 2 receptor antagonist and has been used to treat autosomal dominant polycystic kidney disease (ADPKD) since 2014. There has been limited real-world data on the safety and efficacy of tolvaptan.
METHODS: This post-marketing surveillance was conducted to evaluate the long-term safety and the efficacy of tolvaptan in Japanese patients with ADPKD in real-world clinical settings. The baseline characteristics of 1630 patients treated with tolvaptan are reported. Safety analysis comprises evaluation of adverse drug reactions (ADRs). The efficacy evaluation includes percent change in total kidney volume (TKV) and change in estimated glomerular filtration rate (eGFR) before and after tolvaptan treatment.
RESULTS: Mean age was 49.7 ± 11.2 years and 843 (51.7%) patients were male. Baseline TKV was 2158 ± 1346 mL and eGFR was 44.4 ± 21.7 mL/min/1.73 m2. The majority of CKD patients were stage G3b (27.0%) and G4 (30.1%). Frequently reported ADRs were hepatic function abnormal (8.3%), thirst (8.2%), and hyperuricaemia (6.9%). The frequency of ALT elevation (> 30 and > 90 IU/L) was slightly high (32.9 and 8.3%) to previous studies. After tolvaptan treatment, the annual rate of percentage change in TKV reduced from 11.68%/year to 2.73%/year (P < 0.0001). Similar results were also obtained for the effect on change in eGFR from - 3.31 to - 2.28 mL/min/1.73 m2/year after initiation of tolvaptan treatment (P = 0.0403).
CONCLUSION: There were no major problems with safety of tolvaptan treatment and comparable efficacy for TKV and eGFR was observed in relation to the previous pivotal two randomized control trials in this post-marketing surveillance.

Keywords:  Autosomal dominant polycystic kidney disease; Glomerular filtration rate; Post-marketing survey; Safety profile; Tolvaptan; Total kidney volume

DOI:  https://doi.org/10.1007/s10157-021-02100-0
Ther Clin Risk Manag. 2021 ;17 649-656

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease.

Ioannis Bellos.

  Autosomal dominant polycystic kidney disease constitutes the most prevalent hereditary kidney disease, associated with high rates of morbidity leading eventually to end-stage renal disease. Tolvaptan is a selective vasopressin antagonist and has emerged as a promising therapeutic option for patients with autosomal dominant polycystic kidney disease. The present review summarized current evidence regarding the safety profile of tolvaptan in patients with the disease. Consistent with its pharmacological action, aquaretic adverse events represent the most common side effects of tolvaptan, consisting of polyuria, pollakiuria and polydipsia. Gradual dose titration based on urinary osmolality, as well as dietary interventions aiming to reduce solute excretion, have been proposed as potential strategies to mitigate polyuria. In addition, tolvaptan administration may be complicated by liver injury, characterized by alanine aminotransferase and bilirubin elevations. Hepatotoxicity has been suggested to be triggered by impaired biliary clearance, activation of innate immunity and increased oxidative stress. Frequent monitoring of liver function tests has been shown to be effective in preventing Hy's Law and liver failure cases. Uric acid elevation due to reduced renal excretion may lead to hyperuricemia and gout, although no drug discontinuations have been linked to these events. Future studies should confirm the safety profile of tolvaptan in large-scale real-world studies, clarify the pathogenetic pathways leading to hepatotoxicity and define its role in special populations, especially pediatric patients.

Keywords:  ADPKD; adverse effect; hepatotoxicity; liver; toxicity; vaptan

DOI:  https://doi.org/10.2147/TCRM.S286952
Clin Kidney J. 2021 Jul;14(7): 1715-1718

Drug repurposing in autosomal dominant polycystic kidney disease: back to the future with pioglitazone.

Zhiguo Mao, Manoj K Valluru, Albert C M Ong.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney failure. At present, only one drug, tolvaptan, has been approved for use to slow disease progression, but its use is limited by reduced tolerability and idiosyncratic liver toxicity. Thiazolidinediones were first developed as insulin-sensitizers but also regulate gene transcription in multiple tissues, leading to systemic effects on metabolism, inflammation and vascular reactivity. In this issue, Blazer-Yost et al. report the results of a single-centre Phase 1b double-blind placebo-controlled crossover study of the peroxisome proliferator-activated receptor γ (PPAR-γ) agonist pioglitazone in 18 ADPKD patients. Encouragingly, there were no major safety signals, although evidence of efficacy could not be demonstrated due to the small sample size. We review the preclinical evidence for the use of PPAR-γ agonists in ADPKD and speculate on the likely beneficial and adverse clinical effects of this interesting class of compounds in a future trial.

Keywords:  ADPKD; clinical trial; diabetes mellitus; magnetic resonance imaging; polycystic kidney disease

DOI:  https://doi.org/10.1093/ckj/sfab062
Clin Kidney J. 2021 Jul;14(7): 1845-1847

Founding mutations explains hotspots of polycystic kidney disease in Southern Spain.

Carmen García Rabaneda, Francisco Perea, María Luz Bellido Díaz, Ana I Morales García, Margarita Martínez Atienza, Lisbeth Sousa Silva, Miguel Ángel García González, Francisco Ruiz Cabello, Rafael J Esteban de la Rosa.

  Our group identified two pathogenic variants on the PKD1 gene, c.10527_10528delGA and c.7292T>A, from unrelated families. They came from two small counties in Granada, with 61 and 26 autosomal dominant polycystic kidney disease (ADPKD) individuals affected. To determine a common ancestor, healthy and ADPKD individuals from these families were genotyped by analysing four microsatellites located on chromosome 16. Our study identified a common haplotype in all ADPKD individuals. These findings underpin our hypothesis of the founder effect and explain why there is a high frequency of ADPKD in small regions. Determining hotspots of ADPKD will help to better plan healthcare in the future.

Keywords:  ADPKD; Southern Spain; common ancestor; disease-associated haplotype; founding mutation; hotspots

DOI:  https://doi.org/10.1093/ckj/sfaa261
Clin Kidney J. 2021 Jul;14(7): 1738-1746

A randomized phase 1b cross-over study of the safety of low-dose pioglitazone for treatment of autosomal dominant polycystic kidney disease.

Bonnie L Blazer-Yost, Robert L Bacallao, Bradley J Erickson, Michelle L LaPradd, Marie E Edwards, Nehal Sheth, Kim Swinney, Kristen M Ponsler-Sipes, Ranjani N Moorthi, Susan M Perkins, Vicente E Torres, Sharon M Moe.

   Background: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD.
Methods: This Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function.
Results: Eighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24-2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of -3.5% (95% CI -8.4-1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio.
Conclusions: In this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.

Keywords:  MRI; PPARγ; agonists; anti-hypertensive; crossover design; total kidney volume

DOI:  https://doi.org/10.1093/ckj/sfaa232
Mol Brain. 2021 Jul 03. 14(1): 105

Y-27632, a ROCK inhibitor, improved laser-induced shock wave (LISW)-induced cochlear synaptopathy in mice.

Yutaka Koizumi, Kunio Mizutari, Satoko Kawauchi, Shunichi Sato, Akihiro Shiotani, Seiji Kakehata.

  Recently, a pathological condition called cochlear synaptopathy has been clarified, and as a disorder of the auditory nerve synapses that occurs prior to failure of hair cells, it has been recognized as a major cause of sensorineural hearing loss. However, cochlear synaptopathy is untreatable. Inhibition of rho-associated coiled-coil containing protein kinase (ROCK), a serine-threonine protein kinase, has been reported to have neuroprotective and regenerative effects on synaptic pathways in the nervous system, including those in the inner ear. We previously demonstrated the regenerative effect of the ROCK inhibitor, Y-27632, on an excitotoxic cochlear nerve damage model in vitro. In this study, we aimed to validate the effect of ROCK inhibition on mice with cochlear synaptopathy induced by laser-induced shock wave (LISW) in vivo. After the elevation of ROCK1/2 expression in the damaged cochlea was confirmed, we administered Y-27632 locally via the middle ear. The amplitude of wave I in the auditory brainstem response and the number of synapses in the Y-27632-treated cochlea increased significantly. These results clearly demonstrate that ROCK inhibition has a promising clinical application in the treatment of cochlear synaptopathy, which is the major pathology of sensorineural hearing loss.

Keywords:  Cochlea; Hearing loss; Inner ear; Regeneration; Rho-associated coiled-coil containing protein kinase (ROCK); Synapse; Y-27632

DOI:  https://doi.org/10.1186/s13041-021-00819-1
Handb Clin Neurol. 2021 ;pii: B978-0-12-820683-6.00018-X. [Epub ahead of print]181 249-259

The vasopressin-aquaporin-2 pathway syndromes.

Giovanna Valenti, Grazia Tamma.

  Vasopressin is the key hormone involved in water conservation and regulation of water balance, essential for life. In the renal collecting duct, vasopressin binds to the V2 receptor, increasing water permeability through activation of aquaporin-2 redistribution to the luminal membrane. This mechanism promotes rapid water reabsorption, important for immediate survival; however, only recently it has become clear that long-term adverse effects are associated with alterations of the vasopressin-aquaporin-2 pathway, leading to several syndromes associated with water balance disorders. The kidney resistance to the vasopressin action may cause severe dehydration for patients and, conversely, nonosmotic release of vasopressin is associated with water retention and increasing the circulatory blood volume. This chapter discusses the relevance of the altered vasopressin-aquaporin-2 pathway in some diseases associated with water balance disorders, including congenital nephrogenic diabetes insipidus, syndrome of inappropriate secretion of antidiuretic hormone, nephrogenic syndrome of inappropriate antidiuresis, and autosomal dominant polycystic kidney disease. The emerging picture suggests that targeting the vasopressin-AQP2 axis can provide therapeutic benefits in those patients.

Keywords:  ADPKD; AQP2; Kidney; NDI; NSIAD; SIADH; Vaptans; Vasopressin; Water balance

DOI:  https://doi.org/10.1016/B978-0-12-820683-6.00018-X
Biol Open. 2021 Jul 07. pii: bio.058531. [Epub ahead of print]

Twitchy, the Drosophila orthologue of the ciliary gating protein FBF1/dyf-19, is required for coordinated locomotion and male fertility.

Suzanne H Hodge, Amy Watts, Richard Marley, Richard A Baines, Ernst Hafen, Lindsay K MacDougall.

  Primary cilia are compartmentalised from the rest of the cell by a ciliary gate comprising transition fibres and a transition zone. The ciliary gate allows the selective import and export of molecules such as transmembrane receptors and transport proteins. These are required for the assembly of the cilium, its function as a sensory and signalling centre and to maintain its distinctive composition. Certain motile cilia can also form within the cytosol as exemplified by human and Drosophila sperm. The role of transition fibre proteins has not been well described in the cytoplasmic cilia. Drosophila have both compartmentalized primary cilia, in sensory neurons, and sperm flagella that form within the cytosol. Here, we describe phenotypes for twitchy the Drosophila orthologue of a transition fibre protein, mammalian FBF1/C. elegans dyf-19. Loss-of-function mutants in twitchy are adult lethal and display a severely uncoordinated phenotype. Twitchy flies are too uncoordinated to mate but RNAi-mediated loss of twitchy specifically within the male germline results in coordinated but infertile adults. Examination of sperm from twitchy RNAi-knockdown flies shows that the flagellar axoneme forms, elongates and is post-translationally modified by polyglycylation but the production of motile sperm is impaired. These results indicate that twitchy is required for the function of both sensory cilia that are compartmentalized from the rest of the cell and sperm flagella that are formed within the cytosol of the cell. Twitchy is therefore likely to function as part of a molecular gate in sensory neurons but may have a distinct function in sperm cells.

Keywords:  Cilia; Distal appendage; Drosophila; Spermiogenesis; Transition fibre proteins

DOI:  https://doi.org/10.1242/bio.058531
J Cell Biol. 2021 Sep 06. pii: e202011133. [Epub ahead of print]220(9):

A ciliopathy complex builds distal appendages to initiate ciliogenesis.

Dhivya Kumar, Addison Rains, Vicente Herranz-Pérez, Quanlong Lu, Xiaoyu Shi, Danielle L Swaney, Erica Stevenson, Nevan J Krogan, Bo Huang, Christopher Westlake, Jose Manuel Garcia-Verdugo, Bradley K Yoder, Jeremy F Reiter.

Cells inherit two centrioles, the older of which is uniquely capable of generating a cilium. Using proteomics and superresolved imaging, we identify a module that we term DISCO (distal centriole complex). The DISCO components CEP90, MNR, and OFD1 underlie human ciliopathies. This complex localizes to both distal centrioles and centriolar satellites, proteinaceous granules surrounding centrioles. Cells and mice lacking CEP90 or MNR do not generate cilia, fail to assemble distal appendages, and do not transduce Hedgehog signals. Disrupting the satellite pools does not affect distal appendage assembly, indicating that it is the centriolar populations of MNR and CEP90 that are critical for ciliogenesis. CEP90 recruits the most proximal known distal appendage component, CEP83, to root distal appendage formation, an early step in ciliogenesis. In addition, MNR, but not CEP90, restricts centriolar length by recruiting OFD1. We conclude that DISCO acts at the distal centriole to support ciliogenesis by restraining centriole length and assembling distal appendages, defects in which cause human ciliopathies.

DOI: https://doi.org/10.1083/jcb.202011133
Invest Ophthalmol Vis Sci. 2021 Jul 01. 62(9): 15

Primary Cilia in Amacrine Cells in Retinal Development.

Ke Ning, Brent E Sendayen, Tia J Kowal, Biao Wang, Bryan W Jones, Yang Hu, Yang Sun.

Purpose: Primary cilia are conserved organelles found in polarized cells within the eye that regulate cell growth, migration, and differentiation. Although the role of cilia in photoreceptors is well-studied, the formation of cilia in other retinal cell types has received little attention. In this study, we examined the ciliary profile focused on the inner nuclear layer of retinas in mice and rhesus macaque primates.
Methods: Retinal sections or flatmounts from Arl13b-Cetn2 tg transgenic mice were immunostained for cell markers (Pax6, Sox9, Chx10, Calbindin, Calretinin, ChaT, GAD67, Prox1, TH, and vGluT3) and analyzed by confocal microscopy. Primate retinal sections were immunostained for ciliary and cell markers (Pax6 and Arl13b). Optical coherence tomography (OCT) and ERGs were used to assess visual function of Vift88 mice.
Results: During different stages of mouse postnatal eye development, we found that cilia are present in Pax6-positive amacrine cells, which were also observed in primate retinas. The cilia of subtypes of amacrine cells in mice were shown by immunostaining and electron microscopy. We also removed primary cilia from vGluT3 amacrine cells in mouse and found no significant vision defects. In addition, cilia were present in the outer limiting membrane, suggesting that a population of Müller glial cells forms cilia.
Conclusions: We report that several subpopulations of amacrine cells in inner nuclear layers of the retina form cilia during early retinal development in mice and primates.

DOI: https://doi.org/10.1167/iovs.62.9.15
Braz J Cardiovasc Surg. 2021 Jul 07.

RhoA/ROCK-1 Signaling Pathway and Oxidative Stress in Coronary Artery Disease Patients.

Eda Dokumacioglu, Ibrahim Duzcan, Hatice Iskender, Arzu Sahin.

   INTRODUCTION: Coronary artery disease (CAD) is an ischemic condition that occurs as a result of partial or complete interruption of blood flow by narrowing or complete blockage of the vessels supplying the heart, which are called coronary arteries. Our objective in this study is to investigate the RhoA/Rho-associated kinase (ROCK)-1 signaling pathway and oxidative stress in CAD patients.
METHODS: A total of 81 individuals aged between 40-70 years - including 45 patients (15 females and 30 males) who were admitted to the Artvin State Hospital Cardiovascular Surgery Clinic and were diagnosed with CAD and 36 healthy volunteers (15 females and 21 males) - participated in this study. Serum samples were tested for total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, malondialdehyde (MDA), superoxide dismutase (SOD), RhoA, and ROCK-1 values.
RESULTS: Serum RhoA, MDA levels, and ROCK-1 activity in the CAD group were found to be statistically significantly higher than in the control group (P<0.001). Concordantly, serum SOD activity was found to be statistically significantly lower in the CAD group than in the control group (P<0.001).
CONCLUSION: Inhibition of the activity of RhoA/ROCK-1 pathway would be beneficial in treating cardiovascular diseases since this pathway plays an important role in the development of these diseases.

Keywords:  Coronary Artery Disease; Malondialdehyde; Oxidative Stress; RHOA protein, human; Rho-Associated Kinases; Signal Transduction; Superoxide Dismutase

DOI:  https://doi.org/10.21470/1678-9741-2020-0525
Fluids Barriers CNS. 2021 Jul 07. 18(1): 31

The regulatory roles of motile cilia in CSF circulation and hydrocephalus.

Vijay Kumar, Zobia Umair, Shiv Kumar, Ravi Shankar Goutam, Soochul Park, Jaebong Kim.

   BACKGROUND: Cerebrospinal fluid (CSF) is an ultra-filtrated colorless brain fluid that circulates within brain spaces like the ventricular cavities, subarachnoid space, and the spine. Its continuous flow serves many primary functions, including nourishment, brain protection, and waste removal.
MAIN BODY: The abnormal accumulation of CSF in brain cavities triggers severe hydrocephalus. Accumulating evidence had indicated that synchronized beats of motile cilia (cilia from multiciliated cells or the ependymal lining in brain ventricles) provide forceful pressure to generate and restrain CSF flow and maintain overall CSF circulation within brain spaces. In humans, the disorders caused by defective primary and/or motile cilia are generally referred to as ciliopathies. The key role of CSF circulation in brain development and its functioning has not been fully elucidated.
CONCLUSIONS: In this review, we briefly discuss the underlying role of motile cilia in CSF circulation and hydrocephalus. We have reviewed cilia and ciliated cells in the brain and the existing evidence for the regulatory role of functional cilia in CSF circulation in the brain. We further discuss the findings obtained for defective cilia and their potential involvement in hydrocephalus. Furthermore, this review will reinforce the idea of motile cilia as master regulators of CSF movements, brain development, and neuronal diseases.

Keywords:  Brain development; Brain ventricular system; Cerebrospinal fluid; Cilia; Ciliary motility; Ciliopathies; Ependymal cells; Hydrocephalus

DOI:  https://doi.org/10.1186/s12987-021-00265-0
Front Immunol. 2021 ;12 702025

Exercise Counterbalances Rho/ROCK2 Signaling Impairment in the Skeletal Muscle and Ameliorates Insulin Sensitivity in Obese Mice.

Vitor R Muñoz, Rafael C Gaspar, Matheus B Severino, Ana P A Macêdo, Fernando M Simabuco, Eduardo R Ropelle, Dennys E Cintra, Adelino S R da Silva, Young-Bum Kim, José Rodrigo Pauli.

  Physical exercise is considered a fundamental strategy in improving insulin sensitivity and glucose uptake in skeletal muscle. However, the molecular mechanisms underlying this regulation, primarily on skeletal muscle glucose uptake, are not fully understood. Recent evidence has shown that Rho-kinase (ROCK) isoforms play a pivotal role in regulating skeletal muscle glucose uptake and systemic glucose homeostasis. The current study evaluated the effect of physical exercise on ROCK2 signaling in skeletal muscle of insulin-resistant obese animals. Physiological (ITT) and molecular analysis (immunoblotting, and RT-qPCR) were performed. The contents of RhoA and ROCK2 protein were decreased in skeletal muscle of obese mice compared to control mice but were restored to normal levels in response to physical exercise. The exercised animals also showed higher phosphorylation of insulin receptor substrate 1 (IRS1 Serine 632/635) and protein kinase B (Akt) in the skeletal muscle. However, phosphatase and tensin homolog (PTEN) and protein-tyrosine phosphatase-1B (PTP-1B), both inhibitory regulators for insulin action, were increased in obesity but decreased after exercise. The impact of ROCK2 action on muscle insulin signaling is further underscored by the fact that impaired IRS1 and Akt phosphorylation caused by palmitate in C2C12 myotubes was entirely restored by ROCK2 overexpression. These results suggest that the exercise-induced upregulation of RhoA-ROCK2 signaling in skeletal muscle is associated with increased systemic insulin sensitivity in obese mice and further implicate that muscle ROCK2 could be a potential target for treating obesity-linked metabolic disorders.

Keywords:  Rho-kinase (ROCK); exercise; insulin sensitivity; obesity; skeletal muscle

DOI:  https://doi.org/10.3389/fimmu.2021.702025
Sci Rep. 2021 Jul 08. 11(1): 14146

Impact of plasma 5-hydroxyindoleacetic acid, a serotonin metabolite, on clinical outcome in septic shock, and its effect on vascular permeability.

Takeshi Tanaka, Masahiko Mori, Motohiro Sekino, Ushio Higashijima, Masahiro Takaki, Yoshiro Yamashita, Satoshi Kakiuchi, Masato Tashiro, Konosuke Morimoto, Osamu Tasaki, Koichi Izumikawa.

Septic shock is characterized by dysregulated vascular permeability. We hypothesized that the vascular permeability of endothelial cells (ECs) would be regulated by serotonin via serotonin-Rho-associated kinase (ROCK) signaling. We aimed to determine the impact of 5-hydroxyindoleacetic acid (5-HIAA) on septic shock as a novel biomarker. Plasma 5-HIAA levels and disease severity indices were obtained from 47 patients with sepsis. The association between 5-HIAA levels and severity indices was analyzed. Permeability upon serotonin stimulation was determined using human pulmonary microvascular ECs. 5-HIAA were significantly higher in septic shock patients than in patients without shock or healthy controls (p = 0.004). These elevated levels were correlated with severity indexes (SOFA score [p < 0.001], APACHE II [p < 0.001], and PaO2:FiO2 [p = 0.02]), and longitudinally associated with worse clinical outcomes (mechanical ventilation duration [p = 0.009] and ICU duration [p = 0.01]). In the experiment, serotonin increased the permeability of ECs, which was inhibited by the ROCK inhibitor (p < 0.001). Serotonin increases vascular permeability of ECs via ROCK signaling. This suggests a novel mechanism by which serotonin disrupts endothelial barriers via ROCK signaling and causes the pathogenesis of septic shock with a vascular leak. Serotonin serves as a novel biomarker of vascular permeability.

DOI: https://doi.org/10.1038/s41598-021-93649-z
Exp Neurobiol. 2021 Jun 30. 30(3): 232-243

Ciliogenesis is Not Directly Regulated by LRRK2 Kinase Activity in Neurons.

Hyejung Kim, Hyuna Sim, Joo-Eun Lee, Mi Kyoung Seo, Juhee Lim, Yeojin Bang, Daleum Nam, Seo-Young Lee, Sun-Ku Chung, Hyun Jin Choi, Sung Woo Park, Ilhong Son, Janghwan Kim, Wongi Seol.

  Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent cause of familial Parkinson's disease (PD). The increase in LRRK2 kinase activity observed in the pathogenic G2019S mutation is important for PD development. Several studies have reported that increased LRRK2 kinase activity and treatment with LRRK2 kinase inhibitors decreased and increased ciliogenesis, respectively, in mouse embryonic fibroblasts (MEFs) and retinal pigment epithelium (RPE) cells. In contrast, treatment of SH-SY5Y dopaminergic neuronal cells with PD-causing chemicals increased ciliogenesis. Because these reports were somewhat contradictory, we tested the effect of LRRK2 kinase activity on ciliogenesis in neurons. In SH-SY5Y cells, LRRK2 inhibitor treatment slightly increased ciliogenesis, but serum starvation showed no increase. In rat primary neurons, LRRK2 inhibitor treatment repeatedly showed no significant change. Little difference was observed between primary cortical neurons prepared from wild-type (WT) and G2019S+/- mice. However, a significant increase in ciliogenesis was observed in G2019S+/- compared to WT human fibroblasts, and this pattern was maintained in neural stem cells (NSCs) differentiated from the induced pluripotent stem cells (iPSCs) prepared from the same WT/G2019S fibroblast pair. NSCs differentiated from G2019S and its gene-corrected WT counterpart iPSCs were also used to test ciliogenesis in an isogenic background. The results showed no significant difference between WT and G2019S regardless of kinase inhibitor treatment and B27-deprivation-mimicking serum starvation. These results suggest that LRRK2 kinase activity may be not a direct regulator of ciliogenesis and ciliogenesis varies depending upon the cell type or genetic background.

Keywords:  Ciliogenesis; LRRK2 kinase; Neuron; Parkinson’s disease; Primary cilia

DOI:  https://doi.org/10.5607/en21003
Int Immunopharmacol. 2021 Jul 01. pii: S1567-5769(21)00561-0. [Epub ahead of print]99 107925

Betulin alleviates cisplatin-induced hepatic injury in rats: Targeting apoptosis and Nek7-independent NLRP3 inflammasome pathways.

Nada H Eisa, Mohamed El-Sherbiny, Nada F Abo El-Magd.

  Cisplatin is a chemotherapeutic agent that induces multiorgan toxicity side effect due to induction of inflammation, apoptosis and disruption of intracellular antioxidant pathways. Betulin is a natural triterpenoid that has been shown to counteract cisplatin-induced nephrotoxicity. In this study, we investigated the ameliorative effect of betulin against cisplatin-promoted hepatotoxicity in rats. Moreover, we studied the molecular mechanism underlying betulin's effect. Single intraperitoneal injection (i.p.) of 10 mg/kg of cisplatin, was used to induce acute liver injury in rats. To assess betulin effect, a dose of 8 mg/kg (i.p.) was daily administered for 10 days. Betulin significantly improved serum Aspartate transaminase (AST), Alanine transaminase (ALT), albumin and total bilirubin levels in comparison with cisplatin group. Histopathologically, betulin restored cisplatin-deteriorated liver structural features and hepatic fibrosis. Mechanistically, betulin reduced hepatic oxidative stress as indicated by increased total antioxidant capacity and decreased malondialdehyde levels compared to cisplatin group. In addition, betulin reduced hepatic inflammation via significant inhibition of NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, caspase-1 and interleukin-1β (IL-1β) levels. Intriguingly, betulin did not affect the expression levels of the mitotic kinase NIMA-related kinase 7 (Nek7), an NLRP3 interacting/activating protein. Last, Betulin induced anti-apoptotic effects as denoted by significant downregulation of P53 and Bax apoptotic proteins, upregulation of the anti-apoptotic protein, BCL2 and reduction of caspases 8, -9 and -3. This study is the first to provide evidence that betulin might be beneficial as a safe therapeutic approach to manage cisplatin-induced hepatotoxicity via targeting inflammatory and apoptotic pathways.

Keywords:  Apoptosis; Betulin; Cisplatin; Hepatotoxicity; NLRP3

DOI:  https://doi.org/10.1016/j.intimp.2021.107925
Eur J Ophthalmol. 2021 Jul 07. 11206721211031409

Diagnostic imaging of the ciliary body: Technologies, outcomes, and future perspectives.

José Ignacio Fernández-Vigo, Bachar Kudsieh, Hang Shi, Lucía De-Pablo-Gómez-de-Liaño, José Ángel Fernández-Vigo, Julián García-Feijóo.

  The ciliary body (CB) is part of the uvea and is a complex, highly specialized structure with multiple functions and significant relationships with nearby structures. Its functions include the aqueous humor (AH) production in the ciliary processes, the regulation of the AH output through the uveoscleral pathway, and accommodation, which depends on the ciliary muscle. Also, the CB is an important determinant of angle width as it forms part of the ciliary sulcus. Until recently, knowledge of the CB was based on histological studies. However, this structure can currently be assessed in vivo using imaging techniques such as ultrasound biomicroscopy (UBM) and optical coherence tomography (OCT). Both techniques have shown good reproducibility of their measurements allowing for quantification of CB dimensions and their localization. In effect, studies have shown a larger CB in myopia and its diminishing size with age. Swept-source OCT devices offer fast, non-invasive high-resolution imaging allowing the identification of multiple structures. UBM requires contact and is uncomfortable for the patient. However, this technique offers deeper imaging and therefore remains the gold standard for assessing the posterior chamber, ciliary processes, or zonula. The clinical utility of CB imaging includes its assessment in different types of glaucoma such as angle-closure, malignant or plateau iris. Diagnostic CB imaging is also invaluable for the assessment of ciliochoroidal detachment when suspected, the position after the implantation of a pre-crystalline or sulcus-sutured lenses, diagnosis or monitoring of cysts or tumors, sclerotomies after retinal surgery, intermediate uveitis, or accommodation.

Keywords:  Ciliary body; accommodation; ciliary muscle; glaucoma; optical coherence tomography; ultrasound biomicroscopy

DOI:  https://doi.org/10.1177/11206721211031409