bims-bicyki 2022-05-01 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–05–01
nineteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Polycystic Kidney/Liver Disease.
Hand-assisted laparoscopic bilateral native nephrectomy for autosomal dominant polycystic kidney disease post-renal transplant.
Automated measurement of total kidney volume from 3D ultrasound images of patients affected by polycystic kidney disease and comparison to MR measurements.
[Reduced oxidative stress in ADPKD patients treated with tolvaptan].
Reverse Phenotyping Maternal Cystic Kidney Disease by Diagnosis in a Newborn: Case Report and Literature Review on Neonatal Cystic Kidney Diseases.
Relationship Between Disease Awareness and Severity of Kidney Disease in Autosomal Dominant Polycystic Kidney Disease Patients.
Mitochondrial pharmacotherapy during pregnancy and lactation in an ADPKD mouse model: a win for both mothers and their offspring.
[Lymphocytic leukopenia in two patients affected by polycystic kidney disease waiting for renal transplantation].
INPP5E and Coordination of Signaling Networks in Cilia.
Contribution of Afferent Renal Nerves to Cystogenesis and Arterial Pressure Regulation in a Preclinical Model of Autosomal Recessive Polycystic Kidney Disease.
Ciliary signaling in stem cells in health and disease: Hedgehog pathway and beyond.
Modelling ciliopathy phenotypes in human tissues derived from pluripotent stem cells with genetically ablated cilia.
[Interleukin 33 inhibits lipopolysaccharide-induced high permeability of cardiac microvascular endothelial cells].
Cadmium exposure enhances VE-cadherin expression in endothelial cells via suppression of ROCK signaling.
Kidney epithelial cells are active mechano-biological fluid pumps.
Mechanical stimulation promotes enthesis injury repair by mobilizing Prrx1+ cells via ciliary TGF-β signaling.
Delineating and sparing functional nephrons for radiotherapy in the case of lymphoma with polycystic kidney disease.
Lysophosphatidylcholine induces azurophil granule translocation via Rho/Rho kinase/F-actin polymerization in human neutrophils.
Pyrogallol-Phloroglucinol-6, 6-Bieckol Restored Primary Cilia Length, Which Was Decreased by High-Fat Diet in Visceral Adipose Tissue, and Decreased Adipogenesis.

Clin Liver Dis. 2022 May;pii: S1089-3261(22)00009-5. [Epub ahead of print]26(2): 229-243

Polycystic Kidney/Liver Disease.

Rebecca Roediger, Douglas Dieterich, Pramodh Chanumolu, Priya Deshpande.

  Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder that leads to chronic kidney disease and end-stage kidney disease (ESKD). Polycystic liver disease (PCLD) is the most common extrarenal manifestation of ADPKD. Though isolated PCLD and PCLD due to ADPKD are genetically distinct, they follow a similar clinical course of hepatomegaly from multiple cysts with preserved liver function. Tolvaptan use in ADPKD can slow down the deterioration of renal function and growth of cysts. Somatostatin analogs can slow the growth of polycystic livers but the effect is short-lived. The only curative therapy for PCLD is liver transplantation. Renal transplantation can significantly improve survival in patients with ESKD due to ADPKD.

Keywords:  Autosomal dominant polycystic kidney disease; End-stage kidney disease; Polycystic liver disease; Polycystic renal disease

DOI:  https://doi.org/10.1016/j.cld.2022.01.009
Int J Urol. 2022 Apr 25.

Hand-assisted laparoscopic bilateral native nephrectomy for autosomal dominant polycystic kidney disease post-renal transplant.

Christopher Gwydion Chalklin, Georgios Koimtzis, Elijah Ablorsu.

DOI: https://doi.org/10.1111/iju.14906
Abdom Radiol (NY). 2022 Apr 27.

Automated measurement of total kidney volume from 3D ultrasound images of patients affected by polycystic kidney disease and comparison to MR measurements.

Jaidip M Jagtap, Adriana V Gregory, Heather L Homes, Darryl E Wright, Marie E Edwards, Zeynettin Akkus, Bradley J Erickson, Timothy L Kline.

   PURPOSE: Total kidney volume (TKV) is the most important imaging biomarker for quantifying the severity of autosomal-dominant polycystic kidney disease (ADPKD). 3D ultrasound (US) can accurately measure kidney volume compared to 2D US; however, manual segmentation is tedious and requires expert annotators. We investigated a deep learning-based approach for automated segmentation of TKV from 3D US in ADPKD patients.
METHOD: We used axially acquired 3D US-kidney images in 22 ADPKD patients where each patient and each kidney were scanned three times, resulting in 132 scans that were manually segmented. We trained a convolutional neural network to segment the whole kidney and measure TKV. All patients were subsequently imaged with MRI for measurement comparison.
RESULTS: Our method automatically segmented polycystic kidneys in 3D US images obtaining an average Dice coefficient of 0.80 on the test dataset. The kidney volume measurement compared with linear regression coefficient and bias from human tracing were R2 = 0.81, and - 4.42%, and between AI and reference standard were R2 = 0.93, and - 4.12%, respectively. MRI and US measured kidney volumes had R2 = 0.84 and a bias of 7.47%.
CONCLUSION: This is the first study applying deep learning to 3D US in ADPKD. Our method shows promising performance for auto-segmentation of kidneys using 3D US to measure TKV, close to human tracing and MRI measurement. This imaging and analysis method may be useful in a number of settings, including pediatric imaging, clinical studies, and longitudinal tracking of patient disease progression.

Keywords:  ADPKD; Kidney segmentation; MRI; TKV; U-Net; Ultrasound images

DOI:  https://doi.org/10.1007/s00261-022-03521-5
G Ital Nefrol. 2022 Apr 21. pii: 2022-vol2. [Epub ahead of print]39(2):

[Reduced oxidative stress in ADPKD patients treated with tolvaptan].

Matteo Rigato, Gianni Carraro, Irene Cirella, Silvia Dian, Valentina Di Vico, Verdiana Ravarotto, Giovanni Bertoldi, Lorenzo A Calò.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic kidney disease. It causes hypertension and progressive renal failure, both strictly linked to oxidative stress (OxSt). Treatment with tolvaptan is a consolidate option which slows renal deterioration rate, although the molecular mechanisms involved are not fully clarified. We evaluated the OxSt state in tolvaptan-treated ADPKD patients, untreated patients and healthy subjects. OxSt was assessed in 9 patients for each group as mononuclear cell protein expression, MYPT-1 phosphorylation state (Western blot) and heme oxygenase (HO-1) (ELISA). p22 phox protein expression was lower in tolvaptan treated ADPKD and controls compared to untreated patients: 0.86 ±0.15 d.u. p=0.015; 0.53 ±0.11, p<0.001; 1.42 ±0.11 respectively. The same was observed for phosphorylated MYPT-1: 0.68 ±0.09, p=0.013 and vs 0.47 ±0.13, p<0.001, 0.96 ±0.28, while HO-1 of untreated patients was significantly lower compared to treated and controls: 5.33 ±3.34 ng/mL, 2.08 ±0.79, p=0.012, 1.97 ±1.22, p=0.012. Tolvaptan-treated ADPKD patients have reduced OxSt, which might contribute to slowing down the loss of renal function.

Keywords: Rho kinase; autosomal dominant polycystic kidney disease; oxidative stress; tolvaptan
Acta Med Litu. 2021 ;28(2): 308-316

Reverse Phenotyping Maternal Cystic Kidney Disease by Diagnosis in a Newborn: Case Report and Literature Review on Neonatal Cystic Kidney Diseases.

Dovilė Ruzgienė, Meda Sutkevičiūtė, Birutė Burnytė, Kristina Grigalionienė, Augustina Jankauskienė.

   Kidney cysts are the most common kidney lesion, while congenital kidney cysts are mostly found in pediatric population. Neonatal kidney cysts can develop due to fetal malformations, rare genetic disorders or can be acquired which is very rare. Kidney cysts may be the only isolated finding or be part of the overall phenotype. They can be asymptomatic, found by ultrasound accidentally or can manifest from mild to life-threatening symptoms. Therefore, early diagnosis is very important. Autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease are the most common causes of kidney cysts in the neonatal population. This review highlights the most common kidney cystic diseases during the neonatal period and a rare clinical case of HNF1B-associated disease.

Keywords:  HNF1B; diabetes; family history; kidney cysts

DOI:  https://doi.org/10.15388/Amed.2021.28.2.5
Ther Apher Dial. 2022 Apr 26.

Relationship Between Disease Awareness and Severity of Kidney Disease in Autosomal Dominant Polycystic Kidney Disease Patients.

Ege Dogan, Necmi Eren, Seyda Gul Ozcan, Orcun Altunoren, Ozkan Gungor, Hamad Dheir, Mehmet Tanrisev, Hafsa Kociyigit, Abdülmecit Yıldız, İsmail Kocyigit, Nurhan Seyahi, Erhan Tatar.

   INTRODUCTION: Polycystic kidney disease (PKD) is responsible for 5-10% of end-stage renal disease. We examined the relationship between renal and extrarenal findings, disease severity, and the level of consciousness of PKD patients.
MATERIALS AND METHODS: Patients were asked to answer the questionnaire about PKD. Disease severity was determined according to estimated glomerular filtration rate, and disease awareness was assessed by adapting the Disease Perception Scale to PKD. Awareness of patients was evaluated comparatively with chronic kidney disease stage, age, region, and symptoms.
RESULTS: One out of five patients does not know that this disease is inherited. Mean awareness scores of the patients decreased significantly with increasing age. Awareness scores were significantly higher in patients with flank pain, hematuria, and urinary tract stones.
CONCLUSION: Although PKD is the most common hereditary kidney disease, the rate of patients' knowledge on this subject is low. Increased awareness might lead to better treatment in those patients. This article is protected by copyright. All rights reserved.

Keywords:  Autosomal dominant polycystic kidney disease; chronic kidney disease; dialysis; disease awareness

DOI:  https://doi.org/10.1111/1744-9987.13860
Kidney Int. 2022 May;pii: S0085-2538(22)00112-0. [Epub ahead of print]101(5): 870-872

Mitochondrial pharmacotherapy during pregnancy and lactation in an ADPKD mouse model: a win for both mothers and their offspring.

Wei Wang, Pamela V Tran.

Pharmacotherapies that are safe during pregnancy are lacking for patients with autosomal dominant polycystic kidney disease. In this issue, Daneshgar et al. reveal that administration of the mitochondrial-protective peptide, elamipretide, during pregnancy and lactation in a mouse model with autosomal dominant polycystic kidney disease, is nonteratogenic and attenuates disease severity in both mothers and their affected offspring. This finding suggests therapeutic potential of elamipretide during pregnancy, in utero, and in early postnatal life.

DOI: https://doi.org/10.1016/j.kint.2022.02.008
G Ital Nefrol. 2022 Apr 21. pii: 2022-vol2. [Epub ahead of print]39(2):

[Lymphocytic leukopenia in two patients affected by polycystic kidney disease waiting for renal transplantation].

Elisa Costa, Anna Giuliani, Valentina Corradi, Carlotta Caprara, Matteo Rigato, Sabrina Milan Manani, Ilaria Tantillo, Claudio Ronco, Fiorella Gastaldon, Monica Zanella.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, responsible for 10% of patients on renal replacement therapy. The disease is well known to be associated with many extrarenal manifestations. Leukopenia may also be present, even if it is not commonly identified as a typical extrarenal manifestation. Herein we describe two case reports of ADPKD patients with leukopenia. The first case is about a 47-year-old patient affected by ADPKD, regularly treated with peritoneal dialysis, who showed a progressive reduction of white blood cell count, mostly of lymphocytes. Lymphocytic leukopenia was so severe that, when he was called for transplantation from a deceased donor, he was considered temporarily not eligible. We then describe a second ADPKD patient regularly treated with peritoneal dialysis, who had stable lymphopenia for years. Six years after starting PD, it was necessary to perform bone marrow aspirate to investigate the simultaneous presence of hypogammaglobulinemia together with M-protein and to exclude monoclonal gammopathy. All the exams performed did not show any significant results, the patients were re-included in the waiting list and one of them was transplanted. Given our experience and what is reported in the literature, there seems to be enough evidence to consider leukopenia as an extrarenal manifestation of ADPKD. However, the clinical significance of leukopenia in ADPKD patients is not known. It could be interesting to investigate the leucocytes' function and if ADPKD patients with leukopenia are more susceptible to infection, or not. Moreover, it would be very useful to analyze the relationship between such manifestation and genotype/phenotype.

Keywords: ADPKD; chronic kidney disease; kidney transplant; leukopenia; lymphopenia
Front Mol Biosci. 2022 ;9 885592

INPP5E and Coordination of Signaling Networks in Cilia.

Renshuai Zhang, Jianming Tang, Tianliang Li, Jun Zhou, Wei Pan.

  Primary cilia are ubiquitous mechanosensory organelles that specifically coordinate a series of cellular signal transduction pathways to control cellular physiological processes during development and in tissue homeostasis. Defects in the function or structure of primary cilia have been shown to be associated with a large range of diseases called ciliopathies. Inositol polyphosphate-5-phosphatase E (INPP5E) is an inositol polyphosphate 5-phosphatase that is localized on the ciliary membrane by anchorage via its C-terminal prenyl moiety and hydrolyzes both phosphatidylinositol-4, 5-bisphosphate (PtdIns(4,5)P2) and PtdIns(3,4,5)P3, leading to changes in the phosphoinositide metabolism, thereby resulting in a specific phosphoinositide distribution and ensuring proper localization and trafficking of proteins in primary cilia. In addition, INPP5E also works synergistically with cilia membrane-related proteins by playing key roles in the development and maintenance homeostasis of cilia. The mutation of INPP5E will cause deficiency of primary cilia signaling transduction, ciliary instability and ciliopathies. Here, we present an overview of the role of INPP5E and its coordination of signaling networks in primary cilia.

Keywords:  INPP5E; cilia; ciliopathies; membrane-associated proteins; signaling networks

DOI:  https://doi.org/10.3389/fmolb.2022.885592
Am J Physiol Renal Physiol. 2022 Apr 25.

Contribution of Afferent Renal Nerves to Cystogenesis and Arterial Pressure Regulation in a Preclinical Model of Autosomal Recessive Polycystic Kidney Disease.

Madeline M Gauthier, Melissa R Dennis, Mark N Morales, Heddwen L Brooks, Christopher T Banek.

  Polycystic kidney disease (PKD) is the most common inheritable cause of kidney failure, and the underlying mechanisms remain incompletely uncovered. Renal nerves contribute to hypertension and chronic kidney disease - frequent complications of PKD. There is limited evidence that renal nerves may contribute to cardiorenal dysfunction in PKD, and no investigations of the role of sympathetic versus afferent nerves in PKD. Afferent renal nerve activity (ARNA) is elevated in models of renal disease and fibrosis. However, it remains unknown if this is true in PKD. We tested the hypothesis that ARNA is elevated in a preclinical model of autosomal recessive PKD (ARPKD), and that targeted renal nerve ablation would attenuate cystogenesis and cardiorenal dysfunction. We tested this by performing a total (T-RDNx) or afferent (A-RDNx) denervation in 4-week-old male and female PCK rats, then quantifying renal and cardiovascular responses 6 weeks following treatment. Cystogenesis was attenuated with A-RDNx and T-RDNx vs. sham controls, highlighting a crucial role for renal afferent nerves in cystogenesis. In contrast, blood pressure was improved with T-RDNx but not A-RDNx. Importantly, treatments produced similar results in both males and females. Direct renal afferent nerve recordings revealed that ARNA was 2-fold greater in PCK rats vs. non-cystic controls and was directly correlated to cystic severity. To our knowledge, we are the first to demonstrate that PCK rats have greater ARNA than non-cystic, age-matched controls. The findings of these studies support a novel and crucial role for renal afferent innervation in cystogenesis in the PCK rat.

Keywords:  afferent nerve activity; polycystic kidney disease; renal afferent nerves; renal denervation; sex differences

DOI:  https://doi.org/10.1152/ajprenal.00009.2022
Semin Cell Dev Biol. 2022 Apr 21. pii: S1084-9521(22)00135-5. [Epub ahead of print]

Ciliary signaling in stem cells in health and disease: Hedgehog pathway and beyond.

Issei S Shimada, Yoichi Kato.

  The primary cilium is a hair-like sensory compartment that protrudes from the cellular surface. The primary cilium is enriched in a variety of signaling molecules that regulate cellular activities. Stem cells have primary cilia. They reside in a specialized environment, called the stem cell niche. This niche contains a variety of secreted factors, and some of their receptors are localized in the primary cilia of stem cells. Here, we summarize the current understanding of the function of cilia in compartmentalized signaling in stem cells. We describe how ciliary signaling regulates stem cells and progenitor cells during development, tissue homeostasis and tumorigenesis. We summarize our understanding of cilia regulated signaling -primary involving the hedgehog pathway- in stem cells in diverse settings that include neuroepithelial cells, radial glia, cerebellar granule neuron precursors, hematopoietic stem cells, hair follicle stem cells, bone marrow mesenchymal stem cells and mammary gland stem cells. Overall, our review highlights a variety of roles that ciliary signaling plays in regulating stem cells throughout life.

Keywords:  Cilia; Development; Gpr161; Sonic Hedgehog; Stem cells; Tumorigenesis

DOI:  https://doi.org/10.1016/j.semcdb.2022.04.011
Nat Biomed Eng. 2022 Apr;6(4): 463-475

Modelling ciliopathy phenotypes in human tissues derived from pluripotent stem cells with genetically ablated cilia.

Nelly M Cruz, Raghava Reddy, José L McFaline-Figueroa, Christine Tran, Hongxia Fu, Benjamin S Freedman.

The functions of cilia-antenna-like organelles associated with a spectrum of disease states-are poorly understood, particularly in human cells. Here we show that human pluripotent stem cells (hPSCs) edited via CRISPR to knock out the kinesin-2 subunits KIF3A or KIF3B can be used to model ciliopathy phenotypes and to reveal ciliary functions at the tissue scale. KIF3A-/- and KIF3B-/- hPSCs lacked cilia, yet remained robustly self-renewing and pluripotent. Tissues and organoids derived from these hPSCs displayed phenotypes that recapitulated defective neurogenesis and nephrogenesis, polycystic kidney disease (PKD) and other features of the ciliopathy spectrum. We also show that human cilia mediate a critical switch in hedgehog signalling during organoid differentiation, and that they constitutively release extracellular vesicles containing signalling molecules associated with ciliopathy phenotypes. The capacity of KIF3A-/- and KIF3B-/- hPSCs to reveal endogenous mechanisms underlying complex ciliary phenotypes may facilitate the discovery of candidate therapeutics.

DOI: https://doi.org/10.1038/s41551-022-00880-8
Zhonghua Nei Ke Za Zhi. 2022 May 01. 61(5): 559-564

[Interleukin 33 inhibits lipopolysaccharide-induced high permeability of cardiac microvascular endothelial cells].

S S Huang, Z X Yang, D Y Guo, B B Jia, J Yan.

Objective: To investigate the effect of interleukin-33 (IL-33) on lipopolysaccharide (LPS)-induced permeability of rat cardiac microvascular endothelial cells (RCMECs). Methods: RCMECs were cultured in vitro to be divided into control group, LPS group, IL-33 group and LPS+IL-33 group. The effect of IL-33 on the proliferation of RCMECs was detected by cell counting reagent (CCK8). Fluorescein isothiocyanate (FITC)-dextran assay was used to evaluate the permeability of RCMECs. The expression of vascular endothelial calmodulin, ras homologous gene family (Rho) member A (RhoA) and phosphorylated Rho-associated coiled-coil-containing protein kinase (p-ROCK2) proteins were tested by western blot. High-throughput sequencing and gene ontology (GO) were performed for gene expression in LPS and LPS+IL-33 groups. Results: No significant effect of IL-33 at 10-50 ng/ml on the proliferation of RCMECs was observed (P>0.05). Compared with the control group, the permeability of RCMECs (permeability coefficient ratio 1.404±0.029 vs. 1.000±0.200, P<0.05) was significantly increased in LPS group and the expression of vascular endothelial calmodulin (relative gray value 0.429 5±0.012 9 vs. 0.594 9±0.014 2, P<0.05) was down-regulated, while the permeability of monolayers (permeability coefficient ratio, 0.948±0.013, P<0.01) was decreased in LPS+IL-33 group and the expression of vascular endothelial calmodulin (relative grayscale value 0.549 1±0.012 0, P<0.005) was up-regulated compared with the LPS group. High-throughput sequencing data revealed that the differential genes downregulated in the LPS and LPS+IL-33 groups were associated with cytoskeleton and Rho signaling pathway. Compared with the control group, RhoA (relative gray value 0.211 4±0.009 9 vs. 0.135 0±0.007 6, P<0.000 1) and p-ROCK (relative gray value 0.656 3±0.013 2 vs. 0.503 6±0.036 2, P<0.000 1) protein expression was upregulated in the LPS group. When compared with LPS group, RhoA (relative gray value 0.157 7±0.010 7, P=0.000 2), p-ROCK (relative gray value 0.427 7±0.003 8, P<0.000 1) protein expression was decreased in LPS+IL-33 group. Conclusion: IL-33 may improve LPS-induced hyperpermeability of RCMECs by inhibiting RhoA and p-ROCK protein expression in Rho/Rho-associated coiled-coil-containing protein kinase signaling pathway.

DOI: https://doi.org/10.3760/cma.j.cn112138-20210625-00444
Exp Ther Med. 2022 May;23(5): 355

Cadmium exposure enhances VE-cadherin expression in endothelial cells via suppression of ROCK signaling.

Xiaorui Li, Xiao Li, Rong Sun, Mei Gao, Hui Wang.

  Vascular endothelium is a target of cadmium (Cd), which is a global pollutant of the environment. However, the detailed effects and underlying mechanisms remain to be elucidated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with 0.1, 1, 5, 10, 50 µM cadmium chloride (CdCl2) for 12 h. It was found that vascular endothelial (VE)-cadherin mRNA and protein expression was upregulated by Cd in HUVECs in a dose-dependent manner. Higher levels of VE-cadherin were detected at cell-to-cell junctions in HUVECs treated with 10 µM CdCl2 compared with normal condition. The phosphorylation level of myosin-binding subunit of myosin phosphatase, a downstream substrate of Rho-associated protein kinase (ROCK), was reduced by 10 µM CdCl2, suggesting that Cd inhibited the Rho/ROCK pathway. Activation of ROCK by narciclasine reversed the Cd-induced increase of VE-cadherin expression. By contrast, ROCK pathway inhibitor Y27632 increased VE-cadherin expression in HUVECs. Following inhibition of the ROCK pathway, Cd did not significantly alter the level of VE-cadherin. Taken together, the results suggested that Cd exposure enhanced VE-cadherin expression in endothelial cells via suppression of ROCK signaling.

Keywords:  Rho-associated protein kinase; cadmium; endothelial cells; vascular endothelial cadherin

DOI:  https://doi.org/10.3892/etm.2022.11282
Nat Commun. 2022 Apr 28. 13(1): 2317

Kidney epithelial cells are active mechano-biological fluid pumps.

Mohammad Ikbal Choudhury, Yizeng Li, Panagiotis Mistriotis, Ana Carina N Vasconcelos, Eryn E Dixon, Jing Yang, Morgan Benson, Debonil Maity, Rebecca Walker, Leigha Martin, Fatima Koroma, Feng Qian, Konstantinos Konstantopoulos, Owen M Woodward, Sean X Sun.

The role of mechanical forces driving kidney epithelial fluid transport and morphogenesis in kidney diseases is unclear. Here, using a microfluidic platform to recapitulate fluid transport activity of kidney cells, we report that renal epithelial cells can actively generate hydraulic pressure gradients across the epithelium. The fluidic flux declines with increasing hydraulic pressure until a stall pressure, in a manner similar to mechanical fluid pumps. For normal human kidney cells, the fluidic flux is from apical to basal, and the pressure is higher on the basal side. For human Autosomal Dominant Polycystic Kidney Disease cells, the fluidic flux is reversed from basal to apical. Molecular and proteomic studies reveal that renal epithelial cells are sensitive to hydraulic pressure gradients, changing gene expression profiles and spatial arrangements of ion exchangers and the cytoskeleton in different pressure conditions. These results implicate mechanical force and hydraulic pressure as important variables during kidney function and morphological change, and provide insights into pathophysiological mechanisms underlying the development and transduction of hydraulic pressure gradients.

DOI: https://doi.org/10.1038/s41467-022-29988-w
Elife. 2022 Apr 27. pii: e73614. [Epub ahead of print]11

Mechanical stimulation promotes enthesis injury repair by mobilizing Prrx1+ cells via ciliary TGF-β signaling.

Han Xiao, Tao Zhang, Chang Jun Li, Yong Cao, Lin Feng Wang, Hua Bin Chen, Sheng Can Li, Chang Biao Guan, Jian Zhong Hu, Di Chen, Can Chen, Hong Bin Lu.

  Proper mechanical stimulation can improve rotator cuff enthesis injury repair. However, the underlying mechanism of mechanical stimulation promoting injury repair is still unknown. In this study, we found that Prrx1+ cell was essential for murine rotator cuff enthesis development identified by single-cell RNA sequence and involved in the injury repair. Proper mechanical stimulation could promote the migration of Prrx1+ cells to enhance enthesis injury repair. Meantime, TGF-β signaling and primary cilia played an essential role in mediating mechanical stimulation signaling transmission. Proper mechanical stimulation enhanced the release of active TGF-β1 to promote migration of Prrx1+ cells. Inhibition of TGF-β signaling eliminated the stimulatory effect of mechanical stimulation on Prrx1+ cell migration and enthesis injury repair. In addition, knockdown of Pallidin to inhibit TGF-βR2 translocation to the primary cilia or deletion of Ift88 in Prrx1+ cells also restrained the mechanics-induced Prrx1+ cells migration. These findings suggested that mechanical stimulation could increase the release of active TGF-β1 and enhance the mobilization of Prrx1+ cells to promote enthesis injury repair via ciliary TGF-β signaling.

Keywords:  mouse; regenerative medicine; stem cells

DOI:  https://doi.org/10.7554/eLife.73614
Cancer Treat Res Commun. 2022 Apr 21. pii: S2468-2942(22)00056-9. [Epub ahead of print]31 100566

Delineating and sparing functional nephrons for radiotherapy in the case of lymphoma with polycystic kidney disease.

Venkada Manickam Gurusamy, Suparna Halsnad Chandramouli, Muhammad Usman, Saju Raveendran Divakar, Rabih Wafiq Hammoud, Noora Al-Hammadi.

   PURPOSE: It is imperative to spare functioning kidneys from high radiation doses when they are near enough to radiotherapy (RT) target volumes in patients with polycystic kidney disease (PKD). To achieve this intent, we designed the unique approach that we report here.
METHODS AND MATERIALS: The patient who has PKD, presented with B-cell lymphoma involving paraaortic lymph nodes. After completing chemotherapy, RT was planned to the residual nodal disease. The diagnostic positron emission tomography computed tomography (PETCT) scan was fused with the RT planning CT scan. 18F-2-deoxy-2(F)-fluro-d-glucose (FDG) avid active kidneys were contoured separately, and the treatment plan was optimized to avoid these volumes.
RESULTS: The functional volume was 17.52% of the right kidney whereas it was 7.44% of the left. The mean doses were 4.61 Gy and 4.2 Gy, respectively. The baseline estimated glomerular filtration rate (eGFR) was >60 mL/min; at 18 months follow-up, it was 62 mL/min.
CONCLUSIONS: Delineation of functional nephrons was feasible while utilizing the staging FDG-PETCT scan for radiotherapy contouring in our patient, which aided to achieve the optimal dose-volume constraints. Further studies are warranted to analyze and quantify the benefit of this easily accessible method in the future.

Keywords:  Delineation; Functional nephrons; IMRT; PETCT; Radiotherapy; Sparing

DOI:  https://doi.org/10.1016/j.ctarc.2022.100566
Korean J Physiol Pharmacol. 2022 May 01. 26(3): 175-182

Lysophosphatidylcholine induces azurophil granule translocation via Rho/Rho kinase/F-actin polymerization in human neutrophils.

Hwa-Yong Ham, Shin-Hae Kang, Dong-Keun Song.

  Translocation of azurophil granules is pivotal for bactericidal activity of neutrophils, the first-line defense cells against pathogens. Previously, we reported that lysophosphatidylcholine (LPC), an endogenous lipid, enhances bactericidal activity of human neutrophils via increasing translocation of azurophil granules. However, the precise mechanism of LPC-induced azurophil granule translocation was not fully understood. Treatment of neutrophil with LPC significantly increased CD63 (an azurophil granule marker) surface expression. Interestingly, cytochalasin B, an inhibitor of action polymerization, blocked LPC-induced CD63 surface expression. LPC increased F-actin polymerization. LPC-induced CD63 surface expression was inhibited by both a Rho specific inhibitor, Tat-C3 exoenzyme, and a Rho kinase (ROCK) inhibitor, Y27632 which also inhibited LPC-induced F-actin polymerization. LPC induced Rho-GTP activation. NSC23766, a Rac inhibitor, however, did not affect LPC-induced CD63 surface expression. Theses results suggest a novel regulatory mechanism for azurophil granule translocation where LPC induces translocation of azurophil granules via Rho/ROCK/F-actin polymerization pathway.

Keywords:  Azurophil granule; Lysophosphatidylcholine; Neutrophil; Translocation

DOI:  https://doi.org/10.4196/kjpp.2022.26.3.175
Int J Endocrinol. 2022 ;2022 8486965

Pyrogallol-Phloroglucinol-6, 6-Bieckol Restored Primary Cilia Length, Which Was Decreased by High-Fat Diet in Visceral Adipose Tissue, and Decreased Adipogenesis.

Seyeon Oh, Myeongjoo Son, Ji Tae Jang, Chul Hyun Park, Kuk Hui Son, Kyunghee Byun.

Length of primary cilia, which involves cell cycle reentry and disassembly of cilia, promotes cell mitosis. It is known that the cilia length in adipose tissue of the high-fat diet (HFD) animals was shortened and accompanied by increased adipogenesis. Male C57BL/6N mice were randomly divided into groups. The mice group was given the normal fat diet (NFD/saline), HFD mice group for 4 weeks, and then HFD was also treated for the next 4 weeks with saline (HFD/saline), Ecklonia cava extract (HFD/ECE), or pyrogallol-phloroglucinol-6, 6-bieckol, a segment of ECE (HFD/PPB). We evaluated the effect of ECE and PPB on modulating cilia length of visceral adipose tissue and decreasing adipogenesis by decreasing cell cycle reentry using an HFD-fed mouse model. ECE and PPB decreased physiological changes, which increased by HFD, but ECE and PPB decreased the upregulation of the IL-6/STAT3/AURKA signaling pathway, which is involved in cilia disassembly. In addition, ECE or PPB elongated the cilia and decreased cyclin A2 and Cdk2 expression, which promote cell cycle reentry, and decreased the adipogenesis genes. PPB and ECE restored cilia length and decreased adipogenesis through modulating the IL-6/STAT3/AURKA pathway and decreasing cell cycle reentry in the visceral adipose tissue of HFD/saline mice group.

DOI: https://doi.org/10.1155/2022/8486965