bims-bicyki 2022-03-27 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–03–27
fourteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Polycystin-2 (TRPP2): Ion Channel Properties and Regulation.
Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment.
Congenital Heart Disease in Adults with Autosomal Dominant Polycystic Kidney Disease.
Terpinen-4-ol inhibits the proliferation and mobility of pancreatic cancer cells by downregulating Rho-associated coiled-coil containing protein kinase 2.
Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial.
Rapidly Progressing to ESRD in an Individual with Coexisting ADPKD and Masked Klinefelter and Gitelman Syndromes.
Quantification of Abdominal Muscle Mass and Diagnosis of Sarcopenia with Cross-Sectional Imaging in Patients with Polycystic Kidney Disease: Correlation with Total Kidney Volume.
Primary Cilia and Their Role in Acquired Heart Disease.
Spontaneous Polycystic Kidneys with Chronic Renal Failure in an Aged House Musk Shrew (Suncus murinus).
Regulation of Smoothened Trafficking and Abundance in Hedgehog Signaling.
Evolutionary conservation of centriole rotational asymmetry in the human centrosome.
Analysis of the diagnosis of Japanese patients with primary ciliary dyskinesia using a conditional reprogramming culture.
Role of NIMA-related Kinase 2 (NEK2) in lung cancer: Mechanisms and therapeutic prospects.
Polycystic Ovarian Syndrome: A Complex Disease with a Genetics Approach.

Gene. 2022 Mar 18. pii: S0378-1119(22)00132-9. [Epub ahead of print] 146313

Polycystin-2 (TRPP2): Ion Channel Properties and Regulation.

María Del Rocío Cantero, Horacio F Cantiello.

  Polycystin-2 (TRPP2, PKD2, PC2) is the product of the PKD2 gene, whose mutations cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). PC2 belongs to the superfamily of TRP (Transient Receptor Potential) proteins that generally function as Ca2+-permeable nonselective cation channels implicated in Ca2+ signaling. PC2 localizes to various cell domains with distinct functions that likely depend on interactions with specific channel partners. Functions include receptor-operated, nonselective cation channel activity in the plasma membrane, intracellular Ca2+ release channel activity in the endoplasmic reticulum (ER), and mechanosensitive channel activity in the primary cilium of renal epithelial cells. Here we summarize our current understanding of the properties of PC2 and how other transmembrane and cytosolic proteins modulate this activity, providing functional diversity and selective regulatory mechanisms to its role in the control of cellular Ca2+ homeostasis.

Keywords:  ADPKD; PKD2; Polycystin-2; TRP channels; TRPP2

DOI:  https://doi.org/10.1016/j.gene.2022.146313
Int J Mol Sci. 2022 Mar 19. pii: 3317. [Epub ahead of print]23(6):

Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment.

Jana Reiterová, Vladimír Tesař.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, with an estimated prevalence between 1:1000 and 1:2500. It is mostly caused by mutations of the PKD1 and PKD2 genes encoding polycystin 1 (PC1) and polycystin 2 (PC2) that regulate cellular processes such as fluid transport, differentiation, proliferation, apoptosis and cell adhesion. Reduction of calcium ions and induction of cyclic adenosine monophosphate (sAMP) promote cyst enlargement by transepithelial fluid secretion and cell proliferation. Abnormal activation of MAPK/ERK pathway, dysregulated signaling of heterotrimeric G proteins, mTOR, phosphoinositide 3-kinase, AMPK, JAK/STAT activator of transcription and nuclear factor kB (NF-kB) are involved in cystogenesis. Another feature of cystic tissue is increased extracellular production and recruitment of inflammatory cells and abnormal connections among cells. Moreover, metabolic alterations in cystic cells including defective glucose metabolism, impaired beta-oxidation and abnormal mitochondrial activity were shown to be associated with cyst expansion. Although tolvaptan has been recently approved as a drug that slows ADPKD progression, some patients do not tolerate tolvaptan because of frequent aquaretic. The advances in the knowledge of multiple molecular pathways involved in cystogenesis led to the development of animal and cellular studies, followed by the development of several ongoing randomized controlled trials with promising drugs. Our review is aimed at pathophysiological mechanisms in cystogenesis in connection with the most promising drugs in animal and clinical studies.

Keywords:  autosomal dominant polycystic kidney disease; cystogenesis; therapy

DOI:  https://doi.org/10.3390/ijms23063317
Am J Nephrol. 2022 Mar 21. 1-9

Congenital Heart Disease in Adults with Autosomal Dominant Polycystic Kidney Disease.

Maroun Chedid, Christian Hanna, Ghaith Zaatari, Yaman Mkhaimer, Prajwal Reddy, Laureano Rangel, Dalia Zubidat, Daniel-Hasan Nabil Kaidbay, Maria V Irazabal, Heidi M Connolly, Sarah R Senum, Charles D Madsen, Marie C Hogan, Ziad Zoghby, Peter C Harris, Vicente E Torres, Jonathan N Johnson, Fouad T Chebib.

   INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is caused mainly by pathogenic variants in PKD1 or PKD2 encoding the polycystin-1 and -2 proteins. Polycystins have shown to have an essential role in cardiac development and function in animal models. In the current study, we describe the clinical association between ADPKD and congenital heart disease (CHD).
METHODS: Medical records from Mayo Clinic were queried for all patients with confirmed ADPKD and CHD between 1993 and 2020. CHD was categorized into left-to-right shunt, obstructive, and complex lesions. Patent foramen ovale, mitral valve prolapse, and bicuspid aortic valve anomalies were excluded.
RESULTS: Twenty-five out of 1,359 (1.84%) ADPKD patients were identified to have CHD. Of these, 84% were Caucasians and 44% were males. The median (Q1-Q3) age (years) at CHD diagnosis was 12.0 (2.0-43.5). Fourteen patients (56%) had left-to-right shunt lesions, 6 (24%) had obstructive lesions and 5 (20%) complex lesions. Seventeen patients (68%) had their defects surgically corrected at a median age (Q1-Q3) of 5.5 (2.0-24.7). Among 13 patients with available genetic testing, 12 (92.3%) had PKD1 pathogenic variants, and none had PKD2. The median (Q1-Q3) age at last follow-up visit was 47.0 (32.0-62.0) and median (Q1-Q3) eGFR was 35.8 (11.4-79.0) mL/min/1.73 m2. Three patients (12%) died; all of them had left-to-right shunt lesions.
DISCUSSION/CONCLUSION: We observed a higher CHD frequency in ADPKD than the general population (1.84 vs. 0.4%). While only PKD1 pathogenic variants were identified in this cohort, further studies are needed to confirm this novel finding and understand the role of polycystins in the development of the heart and vessels.

Keywords:  Autosomal dominant polycystic kidney disease; Complex heart lesions; Congenital heart disease; Left-to-right shunt lesions; Obstructive lesions; Polycystic kidney disease

DOI:  https://doi.org/10.1159/000522377
Bioengineered. 2022 Apr;13(4): 8643-8656

Terpinen-4-ol inhibits the proliferation and mobility of pancreatic cancer cells by downregulating Rho-associated coiled-coil containing protein kinase 2.

Wenpeng Cao, Ruhua Tian, Runsang Pan, Baofei Sun, Chaolun Xiao, Yunhua Chen, Zhirui Zeng, Shan Lei.

  Terpinen-4-ol (T4O), a compound isolated from the seeds of turmeric, has exhibited anti-malignancy, anti-aging, and anti-inflammatory properties in previous studies. However, the specific effects and molecular mechanisms of T4O on pancreatic cancer (PC) cells remain largely unknown. In this study, we demonstrated that T4O markedly suppressed PC cell proliferation and colony formation in vitro and induced apoptosis. Similarly, T4O significantly inhibited the migration and invasion of PC cells in vitro. Through RNA sequencing, 858 differentially expressed genes (DEGs) were identified, which were enriched in the Rhodopsin (RHO)/ Ras homolog family member A (RHOA) signaling pathway. Rho-associated coiled-coil containing protein kinase 2 (ROCK2), a DEG enriched in the RHO/RHOA signaling pathway, was considered as a key target of T4O in PC cells; it was significantly reduced after T4O treatment, highly expressed in PC tissues, and negatively associated with patient outcome. Overexpression of ROCK2 significantly reduced the inhibitory effects of T4O on PC cell proliferation and mobility. Moreover, T4O inhibited cell proliferation in vivo and decreased the Ki-67, cell nuclear antigen, EMT markers, and ROCK2 expression. In conclusion, we consider that T4O can suppress the malignant biological behavior of PC by reducing the expression of ROCK2, thus contributing to PC therapy.

Keywords:  Pancreatic cancer; ROCK2; mobility; proliferation; terpinen-4-ol

DOI:  https://doi.org/10.1080/21655979.2022.2054205
Clin J Am Soc Nephrol. 2022 Mar 21. pii: CJN.11260821. [Epub ahead of print]

Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial.

Bart J Kramers, Iris W Koorevaar, Maatje D A van Gastel, Harry van Goor, Kenneth R Hallows, Hiddo L Heerspink, Hui Li, Wouter N Leonhard, Dorien J M Peters, Jiedong Qiu, Daan J Touw, Ron T Gansevoort, Esther Meijer.

   BACKGROUND AND OBJECTIVES: The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers.
RESULTS: Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m2) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (P<0.001) with hydrochlorothiazide and to 5.4 L/24 h (P<0.001) on metformin. During hydrochlorothiazide treatment, plasma copeptin (surrogate for vasopressin) decreased, quality of life improved, and several markers of kidney damage and glucose metabolism improved. Metformin did not induce changes in these markers or in quality of life. Given these results, the effect of adding hydrochlorothiazide to tolvaptan was investigated on long-term kidney outcome in an animal experiment. Water intake in tolvaptan-hydrochlorothiazide cotreated mice was 35% lower than in mice treated with tolvaptan only. Combination treatment was superior to "no treatment" on markers of disease progression (kidney weight, P=0.003 and cystic index, P=0.04) and superior or equal to tolvaptan alone.
CONCLUSIONS: Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection.
PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.

Keywords:  ADPKD; clinical trial; diabetes insipidus; diuretics; hydrochlorothiazide; metformin; receptors; vasopressin

DOI:  https://doi.org/10.2215/CJN.11260821
Genes (Basel). 2022 Feb 23. pii: 394. [Epub ahead of print]13(3):

Rapidly Progressing to ESRD in an Individual with Coexisting ADPKD and Masked Klinefelter and Gitelman Syndromes.

Ramón Peces, Carlos Peces, Rocío Mena, Emilio Cuesta, Fe Amalia García-Santiago, Marta Ossorio, Sara Afonso, Pablo Lapunzina, Julián Nevado.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic hereditary renal disease, promoting end-stage renal disease (ESRD). Klinefelter syndrome (KS) is a consequence of an extra copy of the X chromosome in males. Main symptoms in KS include hypogonadism, tall stature, azoospermia, and a risk of cardiovascular diseases, among others. Gitelman syndrome (GS) is an autosomal recessive disorder caused by SLC12A3 variants, and is associated with hypokalemia, hypomagnesemia, hypocalciuria, normal or low blood pressure, and salt loss. The three disorders have distinct and well-delineated clinical, biochemical, and genetic findings. We here report a male patient with ADPKD who developed early chronic renal failure leading to ESRD, presenting with an intracranial aneurysm and infertility. NGS identified two de novo PKD1 variants, one known (likely pathogenic), and a previously unreported variant of uncertain significance, together with two SLC12A3 pathogenic variants. In addition, cytogenetic analysis showed a 47, XXY karyotype. We investigated the putative impact of this rare association by analyzing possible clinical, biochemical, and/or genetic interactions and by comparing the evolution of renal size and function in the proband with three age-matched ADPKD (by variants in PKD1) cohorts. We hypothesize that the coexistence of these three genetic disorders may act as modifiers with possible synergistic actions that could lead, in our patient, to a rapid ADPKD progression.

Keywords:  ADPKD; Gitelman syndrome; Klinefelter syndrome; apoptosis; chronic kidney disease progression; fibrosis; intracranial aneurysm

DOI:  https://doi.org/10.3390/genes13030394
Diagnostics (Basel). 2022 Mar 20. pii: 755. [Epub ahead of print]12(3):

Quantification of Abdominal Muscle Mass and Diagnosis of Sarcopenia with Cross-Sectional Imaging in Patients with Polycystic Kidney Disease: Correlation with Total Kidney Volume.

Chih-Horng Wu, Tai-Shuan Lai, Yung-Ming Chen, Chyi-Mong Chen, Shun-Chung Yang, Po-Chin Liang.

   BACKGROUND: Polycystic kidney disease (PKD) is an inherited disorder characterized by renal cysts that may mask lean body loss. This study quantified and compared muscle mass by using computed tomography (CT) and magnetic resonance imaging (MRI) images between the PKD and control groups and correlated muscle mass with total kidney volume (TKV).
METHODS: We retrospectively enrolled patients who had a new diagnosis of PKD from May 2015 to May 2016. The CT and MRI images at the third lumbar level were processed to measure the total abdominal muscle (TAM) area for the diagnosis of sarcopenia, and TKV was estimated using the ellipsoid formula.
RESULTS: We included 37 women and 25 men (mean age: 50.40 years) in the PKD group. There was no difference in body mass index and albumin levels, but significant differences in creatinine level (p < 0.001), TAM area (p = 0.047), and TKV (p < 0.001), were noted between the two groups. A significantly negative correlation was observed between TKV and TAM area after adjustment for body height (r = -0.217, p = 0.003).
CONCLUSIONS: CT and MRI images can accurately diagnose sarcopenia, which may be masked by cysts in patients with PKD.

Keywords:  computed tomography; magnetic resonance imaging; polycystic kidney disease; sarcopenia

DOI:  https://doi.org/10.3390/diagnostics12030755
Cells. 2022 Mar 11. pii: 960. [Epub ahead of print]11(6):

Primary Cilia and Their Role in Acquired Heart Disease.

Zachariah E Hale, Junichi Sadoshima.

  Primary cilia are non-motile plasma membrane extrusions that display a variety of receptors and mechanosensors. Loss of function results in ciliopathies, which have been strongly linked with congenital heart disease, as well as abnormal development and function of most organ systems. Adults with congenital heart disease have high rates of acquired heart failure, and usually die from a cardiac cause. Here we explore primary cilia's role in acquired heart disease. Intraflagellar Transport 88 knockout results in reduced primary cilia, and knockout from cardiac endothelium produces myxomatous degeneration similar to mitral valve prolapse seen in adult humans. Induced primary cilia inactivation by other mechanisms also produces excess myocardial hypertrophy and altered scar architecture after ischemic injury, as well as hypertension due to a lack of vascular endothelial nitric oxide synthase activation and the resultant left ventricular dysfunction. Finally, primary cilia have cell-to-cell transmission capacity which, when blocked, leads to progressive left ventricular hypertrophy and heart failure, though this mechanism has not been fully established. Further research is still needed to understand primary cilia's role in adult cardiac pathology, especially heart failure.

Keywords:  cardiomyopathy; ciliopathy; congenital heart disease; heart failure; primary cilia

DOI:  https://doi.org/10.3390/cells11060960
Vet Sci. 2022 Mar 08. pii: 123. [Epub ahead of print]9(3):

Spontaneous Polycystic Kidneys with Chronic Renal Failure in an Aged House Musk Shrew (Suncus murinus).

Tohru Kimura.

  Polycystic kidney disease is one of the most common inheritable renal diseases, characterized by the formation of multiple fluid-filled renal cysts. This disease is a progressive and unfortunately incurable condition. A case of polycystic kidney with chronic renal failure in house musk shrew (Suncus murinus) is described. At clinical presentation, a 16-month-old Suncus murinus showed weight loss and coarse fur. Regarding the biochemical profile, total protein concentrations increased, resulting in a declined albumin: globulin ratio. Blood urea nitrogen and creatinine concentrations were markedly elevated, indicating the end stage of chronic renal failure. Serum amyloid A levels increased and revealed inflammatory reaction during the cyst formation. Histopathologically, multiple cysts were lined by a single layer of epithelial cells or low cuboidal epithelium. The contents were homogenous eosinophilic materials (mucopolysaccharides or mucoproteins) and these cysts contained abundant macrophages. There were also regeneration and dilatation of renal tubes and interstitial fibrosis. The atrophic glomeruli and glomerular capsules were thickened and hyalinized by dense amorphous mucopolysaccharides. These histopathological findings suggested that the pathogenesis of polycystic kidney disease shared a common mechanistic feature across species.

Keywords:  dilatation; histopathology; house musk shrew (Suncus murinus); inflammation; interstitial fibrosis; macrophages; polycystic kidneys; renal tubes; serum amyloid A; serum biochemistry

DOI:  https://doi.org/10.3390/vetsci9030123
Front Cell Dev Biol. 2022 ;10 847844

Regulation of Smoothened Trafficking and Abundance in Hedgehog Signaling.

Jianhang Jia, Jin Jiang.

  The GPCR-family protein Smoothened (Smo) is essential for Hedgehog (Hh) signal transduction in both insects and vertebrates. The regulation of subcellular localization and abundance of Smo is a critical step in Hh signaling. Recent studies have demonstrated that Smo is subjected to ubiquitination mediated by multiple E3 ubiquitin ligases, leading to Smo endocytosis and subsequent degradation through the proteasome- and lysosome-mediated pathways in Drosophila. Ubiquitination of Smo also promotes its ciliary exit in mammalian cells. Hh inhibits Smo ubiquitination by blocking E3 ligase recruitment and promoting Smo deubiquitination through the ubiquitin-specific protease 8 (USP8) in Drosophila. Inhibition of Smo ubiquitination by Hh promotes Smo cell surface accumulation in Drosophila and ciliary accumulation in mammalian cells. Interestingly, Hh also induces sumoylation of Smo in both Drosophila and mammalian cells, which promotes Smo cell surface/ciliary accumulation. This review focuses on how ubiquitination and sumoylation regulate Smo intracellular trafficking and abundance and how these processes are regulated by Hh.

Keywords:  GPCR; Smurf; endocytosis; hedgehog; primary cilium; smoothened; sumoylation; ubiquitination

DOI:  https://doi.org/10.3389/fcell.2022.847844
Elife. 2022 Mar 23. pii: e72382. [Epub ahead of print]11

Evolutionary conservation of centriole rotational asymmetry in the human centrosome.

Noémie Gaudin, Paula Martin Gil, Meriem Boumendjel, Dmitry Ershov, Catherine Pioche-Durieu, Manon Bouix, Quentin Delobelle, Lucia Maniscalco, Than Bich Ngan Phan, Vincent Heyer, Bernardo Reina-San-Martin, Juliette Azimzadeh.

  Centrioles are formed by microtubule triplets in a nine-fold symmetric arrangement. In flagellated protists and in animal multiciliated cells, accessory structures tethered to specific triplets render the centrioles rotationally asymmetric, a property that is key to cytoskeletal and cellular organization in these contexts. In contrast, centrioles within the centrosome of animal cells display no conspicuous rotational asymmetry. Here, we uncover rotationally asymmetric molecular features in human centrioles. Using ultrastructure expansion microscopy, we show that LRRCC1, the ortholog of a protein originally characterized in flagellate green algae, associates preferentially to two consecutive triplets in the distal lumen of human centrioles. LRRCC1 partially co-localizes and affects the recruitment of another distal component, C2CD3, which also has an asymmetric localization pattern in the centriole lumen. Together, LRRCC1 and C2CD3 delineate a structure reminiscent of a filamentous density observed by electron microscopy in flagellates, termed the 'acorn'. Functionally, the depletion of LRRCC1 in human cells induced defects in centriole structure, ciliary assembly and ciliary signaling, supporting that LRRCC1 cooperates with C2CD3 to organizing the distal region of centrioles. Since a mutation in the LRRCC1 gene has been identified in Joubert syndrome patients, this finding is relevant in the context of human ciliopathies. Taken together, our results demonstrate that rotational asymmetry is an ancient property of centrioles that is broadly conserved in human cells. Our work also reveals that asymmetrically localized proteins are key for primary ciliogenesis and ciliary signaling in human cells.

Keywords:  cell biology; human

DOI:  https://doi.org/10.7554/eLife.72382
Respir Investig. 2022 Mar 16. pii: S2212-5345(22)00019-3. [Epub ahead of print]

Analysis of the diagnosis of Japanese patients with primary ciliary dyskinesia using a conditional reprogramming culture.

Atsushi Kurokawa, Mitsuko Kondo, Nahoko Honda, Mami Orimo, Azusa Miyoshi, Fumi Kobayashi, Kazuhiro Abe, Tomohiro Akaba, Mayoko Tsuji, Ken Arimura, Kaname Nakatani, Makoto Ikejiri, Osamitsu Yagi, Kiyoshi Takeyama, Hideki Katsura, Kazuhiko Takeuchi, Etsuko Tagaya.

   BACKGROUND: Primary ciliary dyskinesia (PCD) is diagnosed through multiple methods, including transmission electron microscopy (TEM), a high-speed video microscopy analysis (HSVA), immunofluorescence (IF), and genetic testing. A primary cell culture has been recommended to avoid the misdiagnosis of secondary ciliary dyskinesia derived from infection or inflammation and improve diagnostic accuracy. However, primary cells fail to differentiate into ciliated cells through repeated passages. The conditional reprogramming culture (CRC) method, a combination of a Rho-kinase inhibitor and fibroblast feeder cells, has been applied to cystic fibrosis. The goal of this study was to evaluate the value of CRC in diagnosing PCD in Japanese patients.
METHODS: Eleven patients clinically suspected of having PCD were included. Airway epithelial cells were obtained from an endobronchial forceps biopsy and cultured at the air-liquid interface (ALI) combined with CRC. Ciliary movement, ultrastructure, and mutated ciliary protein evaluation were performed using HSVA, TEM, and IF, respectively. Genetic testing was performed on some patients.
RESULTS: CRC yielded dense and well-differentiated ciliated cells with a high success rate (∼90%). In patients with PCD, the ciliary ultrastructure phenotype (outer dynein arm defects or normal ultrastructure) and IF findings (absence of the mutated ciliary protein) were confirmed after CRC. In DNAH11-mutant cases with normal ultrastructure by TEM, the HSVA revealed stiff and hyperfrequent ciliary beating with low bending capacity in CRC-expanded cells, thereby supporting the diagnosis.
CONCLUSIONS: CRC could be a potential tool for improving diagnostic accuracy and contributing to future clinical and basic research in PCD.

Keywords:  Air-liquid interface; Bronchiectasis; Bronchoscopy; Conditional reprogramming culture; Primary ciliary dyskinesia

DOI:  https://doi.org/10.1016/j.resinv.2022.02.003
Fundam Clin Pharmacol. 2022 Mar 26.

Role of NIMA-related Kinase 2 (NEK2) in lung cancer: Mechanisms and therapeutic prospects.

Darshak Shah, Mit Joshi, Bhoomika M Patel.

  The second most common cancer in both males and females is lung cancer. Chemotherapeutic resistance is the main problem associated with the treatment of lung cancer. Radiation therapy and surgery also produce recurrence in lung cancer patients; this shows the need to develop novel agents acting on new targets. A Never in Mitosis (NIMA) Related Kinase 2 (NEK2) is a serine/threonine kinase associated with the family of NIMA-related kinase (NEK). NEK2 plays an important role in the regulating mitotic processes, such as centrosome duplication and separation, kinetochore attachment, spindle assembly checkpoint, and microtubule stabilization. Several in vitro, in vivo, and clinical studies have confirmed the overexpression of NEK2 in various types of cancers including lung cancer. Overexpression of NEK2 in NSCLC cells increased cell proliferation and chromosomal instability. The overexpression of NEK2 results in the activation of its downstream proteins such as β-catenin, MAD2, Hec1, Rootletin, C-Nap1, CDC20, Cep68, and Sgo1. Activation of the Akt, β-catenin, and Wnt pathways could promote growth and metastasis of lung cancer cells. Such confirmation suggests that NEK2 is a novel target for treating many cancers including lung cancer. The current review provides an idea about functions and regulation of NEK2, and emphasizes about the role of NEK2 in lung cancer by discussing in vitro, in vivo and clinical studies pertaining to the same.

Keywords:  NIMA-related Kinase 2 (NEK2); cell cycle; centrosome dysjunction; chromosomal instability; lung cancer; spindle assembly

DOI:  https://doi.org/10.1111/fcp.12777
Biomedicines. 2022 Feb 24. pii: 540. [Epub ahead of print]10(3):

Polycystic Ovarian Syndrome: A Complex Disease with a Genetics Approach.

Himani Nautiyal, Syed Sarim Imam, Sultan Alshehri, Mohammed M Ghoneim, Muhammad Afzal, Sami I Alzarea, Emine Güven, Fahad A Al-Abbasi, Imran Kazmi.

  Polycystic ovarian syndrome (PCOS) is a complex endocrine disorder affecting females in their reproductive age. The early diagnosis of PCOS is complicated and complex due to overlapping symptoms of this disease. The most accepted diagnostic approach today is the Rotterdam Consensus (2003), which supports the positive diagnosis of PCOS when patients present two out of the following three symptoms: biochemical and clinical signs of hyperandrogenism, oligo, and anovulation, also polycystic ovarian morphology on sonography. Genetic variance, epigenetic changes, and disturbed lifestyle lead to the development of pathophysiological disturbances, which include hyperandrogenism, insulin resistance, and chronic inflammation in PCOS females. At the molecular level, different proteins and molecular and signaling pathways are involved in disease progression, which leads to the failure of a single genetic diagnostic approach. The genetic approach to elucidate the mechanism of pathogenesis of PCOS was recently developed, whereby four phenotypic variances of PCOS categorize PCOS patients into classic, ovulatory, and non-hyperandrogenic types. Genetic studies help to identify the root cause for the development of this PCOS. PCOS genetic inheritance is autosomal dominant but the latest investigations revealed it as a multigene origin disease. Different genetic loci and specific genes have been identified so far as being associated with this disease. Genome-wide association studies (GWAS) and related genetic studies have changed the scenario for the diagnosis and treatment of this reproductive and metabolic condition known as PCOS. This review article briefly discusses different genes associated directly or indirectly with disease development and progression.

Keywords:  biochemical; hyperandrogenism; multigene; ovulatory; polycystic

DOI:  https://doi.org/10.3390/biomedicines10030540