Cyst Enlargement Research Articles

Pharmacological effect of pinostrobin on CFTR‐mediated Cl‐ secretion and renal cyst development in in vitro model of polycystic kidney disease

Cystic fibrosis transmembrane conductance regulator (CFTR) plays crucial role in renal cyst expansion via increase in fluid accumulation. Evidence suggests that inhibition of CFTR retard cyst development and enlargement in polycystic kidney disease (PKD). Here we investigated the pharmacological effect of pinostrobin, a bioactive natural flavonoid on CFTR‐mediated Cl‐ secretion and renal cyst expansion in in vitro model; human autosomal dominant polycystic kidney disease (ADPKD) cell line and Type I Mardin Darby Canine Kidney (MDCK) cells. Treatment with pinostrobin (10 and 50 µM) significantly reduces MDCK cyst formation and enlargement in concentration‐dependent manner. Pinostrobin reduces the number of renal cyst colonies corresponding with a decrease in cell proliferation and extracellular signal‐regulated kinases (ERK) signaling. Additionally, pinostrobin retarded cyst expansion via inhibition on CFTR‐mediated chloride secretion. The inhibitory effect of pinostrobin was not due to the decrease in cell viability and activity of Na+‐K+‐ATPase. Our findings define that pinostrobin might be the candidate for further study as the therapeutic agents for PKD treatment.

Percutaneous sclerotherapy using a 4 F pigtail catheter and 40 milliliters of 5% ethanolamine oleate for symptomatic large hepatic cysts.

PURPOSE We retrospectively evaluated the efficacy of percutaneous sclerotherapy using a 4 F catheter and 40 mL of 5% ethanolamine oleate (EO) for symptomatic large hepatic cysts. METHODS Twenty-four patients, including 10 with polycystic liver disease (PLD), were eligible. The mean long- and short-axis diameters of the cyst on computed tomography (CT) were 145.0 ± 35.5 mm (range, 72-216 mm) and 110.5 ± 21.4 mm (range, 63-150 mm), respectively. After aspiration of the fluid contents using a 4 F pigtail catheter, 40 mL of 5% EO was injected into the cyst for 30 min. Then, the catheter was withdrawn after EO removal. Symptomatic relief and complications were evaluated. The percentage reductions at the early (1-3 months later) and late (at the final follow-up) responses were evaluated using an estimated cyst volume calculated by using the following formula: volume = π/6 × long-axis diameter × (short-axis diameter)2 on the maximum cross-section image on CT. Spearman's rank correlation coefficient (ρ) was used to evaluate the correlation between the pretreatment estimated cyst volume and percentage reduction of early and late responses and between the percentage reduction of the late response and length of the follow-up period after sclerotherapy. RESULTS The symptoms disappeared in 23 patients and improved in 1 patient with PLD. The mean aspirated fluid volume was 1337.8 ± 845.4 mL (range, 140-3200 mL). In 1 patient, EO injection was postponed until the second procedure was performed 40 days later due to intraperitoneal leakage of contrast material. In another patient, the EO volume was reduced to 20 mL because of a small cyst size. The mean early and late percentage reductions of the treated cyst were 52.3% ± 23.8% and 87.5% ± 20.4% (mean follow-up period: 48.0 ± 42.4 months), respectively. The symptom recurred in 2 patients with PLD and 1 underwent additional sclerotherapy 14 months later due to re-enlargement of the treated cyst. Another patient underwent transarterial embolization 5 years and 4 months later for other enlarged cysts, although the treated cyst markedly shrank. There were significant negative correlations between the pretreatment estimated cyst volume and percentage reduction of early (P = .027, ρ = - 0.46) and late (P= .007, ρ = - 0.52) responses. However, there were no significant correlations between the percentage reduction and length of the follow-up period (P = .19, ρ = 0.31). Transient pain developed in 1 patient and low-grade fever in 3. CONCLUSION Sclerotherapy using a 4 F catheter and 40 mL of 5% EO is safe and effective for symptomatic large hepatic cysts.

Combined Neuroendoscopic Techniques in the Management of Pediatric Brain and Skull Base Tumors: A Single-Institutional Case Series

Central nervous system tumors encompass the leading cause of cancer-related death in the pediatric population. Neuroendoscopic techniques have been optimized over the years, becoming an important tool for the management of brain tumors. Our study aims to review the indications for neuroendoscopic procedures and the feasibility of combined interventions. This is a single-center, self-adjudicated, retrospective experience. Inclusion criteria consisted of pediatric patients (≤18years old) who underwent management of brain tumor or related diseases with the employment of neuroendoscopy. A total of 47 patients undergoing 51 procedures met inclusion criteria. The mean age was 9.8±4.6 years, and the majority were female (55.3%). Common indications for endoscopic intervention were hydrocephalus management (n= 24; 16 endoscopic third ventriculostomies and 9 septostomies), tumor biopsy (n= 19), cyst fenestration (n= 16), and tumor resection (n= 9). In one third of the cases, combined interventions occurred during a single operative session. Hydrocephalus was successfully managed in 74.4% of cases; tumor biopsy confirmed the diagnosis in 95.8% of cases, and gross total resection was achieved in 88.9% of cases. Cyst fenestration required reintervention in 3 cases: one case associated with initial cyst enlargement and 2 cases with the development of new tumor cysts separated from the originally fenestrated cyst. The overall complication rate was 6.3%, with only one major safety event, which was successfully managed. Neuroendoscopy is an important minimally invasive tool for diagnosing and treating pediatric patients with brain tumors, permitting to address multiple problems in a single surgery.

Pharmacological Effects of Panduratin A on Renal Cyst Development in In Vitro and In Vivo Models of Polycystic Kidney Disease.

Renal cyst expansion in polycystic kidney disease (PKD) involves abnormalities in both cyst-lining-cell proliferation and fluid accumulation. Suppression of these processes may retard the progression of PKD. Evidence suggests that the activation of 5′ AMP-activated protein kinase (AMPK) inhibits cystic fibrosis transmembrane conductance regulator (CFTR)–mediated chloride secretion, leading to reduced progression of PKD. Here we investigated the pharmacological effects of panduratin A, a bioactive compound known as an AMPK activator, on CFTR-mediated chloride secretion and renal cyst development using in vitro and animal models of PKD. We demonstrated that AMPK was activated in immortalized normal renal cells and autosomal dominant polycystic kidney disease (ADPKD) cells following treatment with panduratin A. Treatment with panduratin A reduced the number of renal cyst colonies corresponding with a decrease in cell proliferation and phosphorylated p70/S6K, a downstream target of mTOR signaling. Additionally, panduratin A slowed cyst expansion via inhibition of the protein expression and transport function of CFTR. In heterozygous Han:Sprague–Dawley (Cy/+) rats, an animal model of PKD, intraperitoneal administration of panduratin A (25 mg/kg BW) for 5 weeks significantly decreased the kidney weight per body weight ratios and the cystic index. Panduratin A also reduced collagen deposition in renal tissue. Intraperitoneal administration of panduratin A caused abdominal bleeding and reduced body weight. However, 25 mg/kg BW of panduratin A via oral administration in the PCK rats, another non-orthologous PKD model, showed a significant decrease in the cystic index without severe adverse effects, indicating that the route of administration is critical in preventing adverse effects while still slowing disease progression. These findings reveal that panduratin A might hold therapeutic properties for the treatment of PKD.

Primary intraosseous squamous cell carcinoma arising in odontogenic cysts: A report of five cases and a review of the literature

Primary intraosseous carcinoma (PIOC) is rare entity with an estimated incidence of 0.01-0.02% of all oral cancer. To date, 133 PIOC cases have been reported with most occurring in the setting of periapical/residual cysts. Distinc- tion from carcinomas arising from the oral or antral mucosa may be difficult, especially when the cortical plates have been destroyed. Therefore, signs of oral ulceration preclude the diagnosis of PIOC. Identification of a benign cystic structure exhibiting transition to a squamous cell carcinoma may be of help in establishing the diagnosis and etiology of the tumor. The aim of our study was to evaluate the cases of only primary intraosseous squamous cell carcinomas arising in odontogenic cysts diagnosed in the Oral Pathology Laboratory at New York Presbyterian Queens between 1995-2019 with the goal of adding valuable information to the literature for this uncommon en- tity. Five cases of PIOC were identified. For each case the histology, demographics, radiographic descriptions and radiographs when possible were reviewed. In all cases, transition from a cystic structure to infiltrating carcinoma was identified. In no case did the overlying surface mucosa exhibit dysplastic changes or transition to carcinoma. Four cases occurred in the maxilla and one in the mandible. The average age of patients in this study was 67.6 years with a range of 37 to 81. Three patients were males and two were female. Three cases presented as ill-defined radiolucencies and one was described as a cystic expansion. Two PIOCs arose in the setting of a periapical cyst, one in the setting of a residual cyst and one in the setting of a dentigerous cyst. Two cases had associated bone loss. While uncommon, the possibility of carcinoma arising in what appears clinically to be a cyst, supports the need to submit all tissue for microscopic examination.

Automatic cyst and kidney segmentation in autosomal dominant polycystic kidney disease: Comparison of U-Net based methods

Autosomal Dominant Polycystic Kidney Disease is a genetic disease that causes uncontrolled growth of fluid-filled cysts in the kidney. Kidney enlargement resulting from the expansion of cysts is continuous and often associated with decreased renal function and kidney failure. Mouse and rat models are necessary to discover new drugs able to halt the progression of the disease. The analysis of the effects of pharmacological interventions in these models is based on renal morphology and quantification of changes in total renal volume and cyst volume. This requires a proper, reproducible and fast segmentation of the kidney images. We propose a set of fully convolutional networks for kidney and cyst segmentation in micro-CT images, based on the U-Net architecture, to compare them and analyze which ones perform better on contrast-enhanced micro-CT images from normal rats and rats with Autosomal Dominant Polycystic Kidney Disease. Networks have been tested on a series images, and the performance has been evaluated in terms of Intersection over Union and Dice coefficients. Results showed that the best performing networks are the U-Net in which a batch normalization layer is applied after each pair of 3 × 3 convolutions, and the U-Net in which convolutional layers are replaced by inception blocks. Results also showed accurate cyst-to-kidney volume ratios obtained from the segmented images, which is one of main metrics of interest. Finally, segmentation performance has been found to be stable as the images in the training set vary. Therefore, the proposed automatic methodology is suitable and immediately applicable to segment cysts and kidney from micro-CT images, and directly provides the cyst-to-kidney volume ratio.

Astroblastoma with Rapid Cyst Expansion and Hemorrhage in an Adult: A Case Report

Astroblastoma is an extremely rare primary brain tumor accounting for 0.45 to 2.8% of all neuroglial tumors and usually occurs in pediatrics and young adults. The natural history of astroblastoma still remains unknown. In the World Health Organization (WHO) classification of tumors of the central nervous system, astroblastoma is classified as other neuroepithelial tumors and standard treatment other than surgery has not been established. As molecular and genetic diagnosis becomes more important in the latest WHO classification of brain tumors, the development of therapeutic options based on the information of molecular genetics are expected. Here we report a case of astroblastoma in a 49-year-old male. Small tumor was discovered by coincidence during his check-up following traffic accident, but three months later, tumor bleeding with cystic enlargement resulted in disturbance of consciousness. Initial diagnosis of low grade astroblastoma with BRAFV600E mutation was made. After 1 year, local tumor recurrence was observed. The histological diagnosis at recurrence was high grade astroblastoma. We here, discuss about diagnosis, treatment and the possibility of usefulness of molecular genetic analysis for astroblastoma with some literature review. (Received 10 August, 2021; Accepted 15 December, 2021; Published 1 April, 2022).

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

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.

Pinostrobin inhibits renal CFTR-mediated Cl− secretion and retards cyst growth in cell-derived cyst and polycystic kidney disease rats

Cystic fibrosis transmembrane conductance regulator (CFTR) plays crucial role in renal cyst expansion via increase in fluid accumulation. Inhibition of CFTR has been proposed to retard cyst development and enlargement in polycystic kidney disease (PKD). Pinostrobin, a bioactive natural flavonoid, possesses several pharmacological effects. The present study investigated pharmacological effects of pinostrobin on CFTR-mediated Cl− secretion and renal cyst expansion in in vitro and in vivo models. Pinostrobin (10 and 50 μM) reduced number of MDCK cell-derived cyst colonies and inhibited cyst expansion via inhibition of cell proliferation and CFTR-mediated Cl− secretion. The inhibitory effect of pinostrobin was not due to the decrease in cell viability and activity of Na+-K+-ATPase. We also investigated the natural analogue pinocembrin as well as the synthetic analogue pinostrobin oxime. Both pinocembrin and pinostrobin oxime did not reduce CFTR-mediated Cl− secretion. In PKD rats, oral administration of pinostrobin (40 mg/kg/day) exhibited a decreasing in cystic area compared to vehicle-treated rats. Pinostrobin treatment inhibited renal expression of CFTR protein in PKD rats. Our findings highlighted the potential therapeutic application of pinostrobin in PKD.

Clinicopathological features of very well-differentiated adenocarcinoma of the stomach

Objective: To investigate the clinicopathological features of very well-differentiated adenocarcinoma (VWDA) of the stomach. Methods: The clinicopathological data of 12 cases of VWDA of the stomach were collected retrospectively at the People's Liberation Army Joint Logistics Support Force 989 Hospital (formerly 152 Hospital), Pingdingshan, China, from January 2013 to May 2021. The histological characteristics and immunophenotypes were observed and analyzed with review of current literature. Results: There were 8 males and 4 females with a median age of 63 years (range 47 to 80 years). The tumor involved in the upper part of the stomach in 6 cases, the middle part in 2 cases, and the lower part in 4 cases. The median diameter of the tumors was 17 mm (range 5-65 mm). The tumor cells were similar to absorbent cells, Paneth cells, foveolar epithelial cells, and goblet cells. The cells were arranged in a single layer, and the nuclei were slightly enlarged and located at the base. The nuclei were fusiform to slightly irregular, with loss of nuclear polarity. Early tubular VWDA was found in 9 cases, and the tumor glands were similar to intestinal metaplasia. In two cases the tumors infiltrated into the submucosa. The lesions in the mucosa and submucosa showed the glands with cystic expansion, bending, branching, spiky and abortive growth pattern. One case of early papillary tubular VWDA was confined to the mucosal layer and composed of foveolar-type epithelial cells. There were two cases of advanced papillary tubular VWDA, which consisted of foveolar-type epithelial, pyloric glands, or mucinous neck cells and were associated with intra-lymphatic cancer embolus and lymph node metastases. Background mucosal atrophy and intestinal metaplasia were observed in all cases. Immunohistochemical staining showed intestinal type VWDA in 1 case, mixed gastrointestinal type VWDA in 9 cases, and gastric type VWDA in 2 cases. The Ki-67 proliferation index of 8 cases limited to the mucosa was 40%-70%, 2 cases of infiltration into the submucosa and 2 cases of advanced carcinoma was 10%-25%. All the tumors showed a wild type of p53 protein expression pattern and negative HER2. Adenocarcinoma or high-grade dysplasia was diagnosed on preoperative biopsy in 5 cases, and chronic atrophic gastritis with intestinal metaplasia in 7 cases. The median follow-up time was 28 months (range 12-72 months). No recurrence was found in the 10 patients with early cancer. Of the two patients with advanced carcinoma, one patient had lung metastases and the other died. Conclusions: Gastric VWDA is a rare low-grade malignancy with structural features of highly differentiated adenocarcinoma and extremely low cytological atypia. The diagnostic value of structural abnormality is significantly greater than cytological atypia. The invasive growth of irregular glands in the deep mucosa and submucosa is reliable evidence for diagnosis. The diagnosis of intramucosal VWDA is challenging and very difficult in some biopsy specimens.

Secreted Neutrophil Gelatinase-Associated Lipocalin Shows Stronger Ability to Inhibit Cyst Enlargement of ADPKD Cells Compared with Nonsecreted Form.

Polycystic kidney disease (PKD) is one of the most common inherited diseases and is characterized by the development of fluid-filled cysts along multiple segments of the nephron. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of PKD, which is caused by mutations in either PKD1 or PKD2 genes that encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. As ADPKD progresses, cysts enlarge and disrupt normal kidney architecture, eventually leading to kidney failure. Our previous study showed that overexpression of exogenous kidney-specific neutrophil gelatinase-associated lipocalin (NGAL) reduced cyst progression and prolonged the lifespan of ADPKD mice (Pkd1L3/L3, 2L3 for short). In this study, we attempted to explore the underlying mechanism of reduced cyst progression in the presence of NGAL using immortalized 2L3 cells. The results of MTT and BrdU incorporation assays showed that recombinant mouse NGAL (mNGAL) protein significantly decreased the viability and proliferation of 2L3 cells. Flow cytometry and western blot analyses showed that mNGAL inhibited activation of the ERK and AKT pathways and induced apoptosis and autophagy in 2L3 cells. In addition, a 3D cell culture platform was established to identify cyst progression in 2L3 cells and showed that mNGAL significantly inhibited cyst enlargement in 2L3 cells. Overexpression of secreted mNGAL (pN + LS) and nonsecreted mNGAL (pN − LS) repressed cell proliferation and cyst enlargement in 2L3 cells and had effects on markers involved in proliferation, apoptosis, and autophagy. However, secreted mNGAL had a more pronounced and consistent effect than that of nonsecreted form. These results reveal that secreted mNGAL has stronger ability to inhibit cyst enlargement of ADPKD cells than that of nonsecreted form. These findings could help to identify strategies for the future clinical treatment of ADPKD.

Biomarkers involved in the proliferation of the odontogenic keratocyst, glandular odontogenic cyst and botryoid odontogenic cyst.

Odontogenic cysts are a heterogeneous group of lesions with varied clinical behavior. To analyze the expression of the epidermal growth factor receptor (EGFR), Cyclin D1, and transcription factor SOX2 in the odontogenic epithelium evaluating the cell cycle control and cystic expansion. This was a cross-sectional study including 40 cases, 20 odontogenic keratocysts (OKC), 10 botryoid odontogenic cysts (BOC), and 10 glandular odontogenic cysts (GOC). All cases of OKC, BOC, and GOC were positive for EGFR in all layers of the cyst lining. The highest expression of nuclear Cyclin D1 was observed in the suprabasal layer of OKCs and in the basal and suprabasal layers of GOC and BOC (p < 0.001). In addition, SOX2 was only expressed in the suprabasal layer of OKCs. The high expression of EGFR in the cyst membrane suggests that EGF stimulates epithelial proliferation in BOCs, and the high expression of SOX2 in OKCs may be related to the presence of stem cells in the lesion. Cyclin D1 is related to cell cycle disruption in G1-S contributing to stimulates epithelial proliferation of OKCs and GOCs and BOCs.

Lessons From the Clinic: ADPKD Genetic Test Unraveling Severe Phenotype, Intrafamilial Variability, and New, Rare Causing Genotype

Autosomal dominant polycystic kidney disease (ADPKD) is the prevalent inherited renal disease worldwide. Cystogenesis originates focally in the tubule and usually starts in utero although ADPKD symptoms usually develop in the fourth decade. The progressive cystic enlargement leads to end-stage renal disease in approximately 70% of patients with a median age of 58 years. Family history is present in >85% of cases; in 10% to 15% of cases, a family history may be absent because of de novo mutation, mosaicism, or mild disease.

Release of Matrix Metalloproteinases by Macrophages in Radicular Cysts and Residual Radicular Cysts.

Radicular cysts (RCs) and residual radicular cysts (RRCs) are the sequelae of dental caries and that leads to proliferation of epithelial rests of Malassez in periapical tissues. The aim was to evaluate the relationship between Langerhans cells, macrophages, matrix metalloproteinases (MMP-9, MMP-13), and tumor necrosis factor-alpha (TNF-α) in the capsule and lining epithelium of cystic lesions. Twenty RCs and 20 RRCs were submitted to immunohistochemical analysis with anti-CD68, anti-CD1a, anti-MMP-9, anti-MMP-13, and anti-TNF-α antibodies. The Mann-Whitney test and the Spearman correlation test were used for analysis of the data (P<0.05). The immunoexpression of MMP-13 and CD68 was significantly higher in RCs when compared with RRCs (P=0.011 and 0.012, respectively). The presence of an intense inflammatory infiltrate was significantly correlated with the immunoexpression of CD68 in RCs (P=0.025). Expression of CD68 showed a significant positive correlation with MMP-13 (P=0.015). A moderate correlation was observed between MMP-9 and MMP-13 (P=0.010). TNF-α expression was more common in RCs (P=0.001). CD1a was more frequently expressed in atrophic epithelium (P=0.041) and was significantly correlated with TNF-α (P=0.014). Langerhans cells induce a greater release of TNF-α which, in turn, is responsible for the stimulation of M1 macrophages. Higher immunoexpression of MMP-13 and MMP-9 is observed in the early stages of RCs compared with RRCs. Therefore, the toxins of microorganisms present in highly inflamed RCs are the main factors triggering a proinflammatory immune response and greater cystic expansion in the early stages of these lesions.

The role of neutrophils and platelets on the development and enlargement of jaw cysts

The role of neutrophils and platelets on the development and enlargement of jaw cysts

Dandy–Walker Malformation

Dandy–Walker Malformation (DWM) is a condition affecting the cerebellum. It consists of hypoplastic vermis, cystic enlargement of the fourth ventricle, and cystic formation near the posterior fossa. Ultrasound and magnetic resonance imaging scan are beneficial in inspecting these complications for both fetal and infantile cases. In this case series, fetal manifestations of DWM are explored through discussing maternal vitals, gestational age, clinical findings, and diagnostic imaging features (e.g., areas of encephalic enlargement and presentations of cystic dilation). It was observed that this condition is often mistaken for an arachnoid cyst, Blake’s pouch cyst, Joubert anomaly, or Arnold–Chiari malformation. It is, therefore, essential to develop a framework with sufficiently conspicuous DWM imaging features and clinical manifestations to improve diagnostic accuracy.

THE EFFECT OF ALLOXAN-INDUCED HYPERGLYCEMIA ON THE RENAL CORTEX

About 422 million people in the world suffer from diabetes mellitus. Among diseases, diabetes ranks third, and among endocrine disorders, it ranks first. Some issues concerning the pathogenesis of this disease are unclear. The main reason for diabetes damage is high blood glucose levels. Hyperglycaemia has a toxic effect on the vessels of the kidneys. The present study aims to investigate the impact of alloxan-induced diabetes mellitus on the remodeling of the renal cortex. Materials and methods. We divided twenty-four mature white male rats into the control and experimental groups. We administered alloxan to experimental animals intraperitoneally at a single dose of 40 mg/kg. Blood glucose levels were measured 2, 12, and 24 hours after injection of alloxan and then weekly. The average glucose level remained 11.0 ± 2.0 mmol/l. Animals were sacrificed on days 14, 21, and 45. We stained histological preparations of kidneys with hematoxylin and eosin. The selected dose of alloxan and the method of its administration caused persistent hyperglycemia in rats and did not lead to their death. Results. On the 14th day, the diseased kidney had a thickening of the glomerular capillary walls. Nephrons had a spherical shape with a slightly uneven surface. On the 21st day of the observation, it was more difficult to distinguish the cortex from the medulla. On the 45th day, the distal tubules lost their usual shape, became thinner, and were difficult to distinguish from other tubules by histological preparation. The cortex became spongy due to cystic dilation of the tubules. Conclusions. All components of the renal cortex underwent daily changes. At the early stages of the experiment, it looked much denser compared to the cortical layer of the kidneys of animals in the control group. The number of subcapsular nephrons visually increased, and the renal capsule thickened. In the later period of the experiment, dilatation and blood fullness of glomerular capillary with their leukocyte infiltration were observed. In addition, there was a cystic expansion of the tubules, due to which the cortical layer of the kidney looked like a sponge.

Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The purpose of this study was to discover an effective therapeutic drug for ADPKD. With virtual screening, Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney-specific Pkd1 knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library. In vitro experiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner. In vivo, obacunone treatment significantly reduced the renal cyst development in PKD mice. Western blot and morphological analysis revealed that obacunone served as a NRF2 activator in ADPKD, which suppressed lipid peroxidation by up-regulating GPX4 and finally restrained excessive cell proliferation by down-regulating mTOR and MAPK signaling pathways. Experimental data demonstrated obacunone as an effective renal cyst inhibitor for ADPKD, indicating that obacunone might be developed into a therapeutic drug for ADPKD treatment.

Examining the Role of HIPPO/YAP and AMOT Dysregulation and Imbalance in Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder, most commonly caused by mutations in Polycystin-1 and Polycystin-2 (PC1 and PC2), in which many large lumenal cysts develop in the kidney epithelium. The disease is progressive and ultimately leads to renal dialysis and/or kidney transplant given the lack of efficacious therapeutic intervention. Current research has implicated HIPPO/YAP pathway dysregulation and AMOT imbalance following defects in cell-cell adhesion and contact inhibition as the molecular basis for ADPKD. To test this hypothesis as to the minimum cellular changes necessary to produce cystogenesis, the Bacallao lab microinjected normal human kidney epithelial (HK2) cells in order to drive ectopic expression of Cadherin-8 (CAD-8). Our Imaging with confocal microscopy and subsequent image analysis indicates CAD-8, a cadherin abnormally expressed in renal epithelial cells of ADPKD patients, is sufficient to cause formation of cysts albeit with uncharacteristically small lumens compared to typical ADPKD cysts. However, these cells exhibit significantly larger cyst expansion when they are transduced for coexpression of CAD-8 and constitutively active YAP5SA. Cells modified for heterozygosity with respect to a defective PC1 gene (PKD) also exhibited significantly larger lumen cysts when transduced with YAP5SA reinforcing the role of Yap in lumen size control. Finally, PKD cells transduced with AMOTL1 exhibited significantly smaller lumen sizes. AMOTL1 belongs to a family of adapter proteins which bind and inhibit Yap activity thus showing conclusively that positive and negative modulation of Yap activity correlates with cyst lumen size expansion and reduction respectively.&#x0D; “This project was funded, in part, with support from the O’Brien Center for Advanced Renal Microscopic Analysis funded, in part by P30 DK079312 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.”

GESTATIONAL TROPHOBLASTIC DISEASE

Gestational trophoblastic disease (GTD) is a group of tumors defined by abnormal trophoblastic proliferation. GTD is divided into hydatidiform moles (contain villi) and other trophoblastic neoplasms (lack villi).1 The malignant forms of the disease are also collectively known as gestational trophoblastic tumors or neoplasia (GTN).GTN includes the invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Southeast Asia and Japan have the highest reported incidence estimated to be two in 1000 pregnancies. In high-income countries, the incidence of a complete mole is approximately 1–3 per 1000 pregnancies, and the incidence of a partial mole is about 3 per 1000 pregnancies. Approximately 15–20% of patients will be treated for gestational trophoblastic neoplasia after the evacuation of complete hydatidiform mole. GTD develop from abnormal proliferation of trophoblastic tissue and form botryoid arranged vesicles. Risk factors include extremes of age, ethnicity, and a prior history of an HM, suggesting a genetic basis for its etiology. GTD causes a broad spectrum of different symptoms. The most frequent clinical symptom is abnormal vaginal bleeding. Other signs include uterine enlargement more significant than expected for gestational age, absent fetal heart tones, cystic ovary enlargement, hyperemesis gravidarum, and abnormally high level of β-hCG for gestational age. Ultrasound is the gold standard in non-invasive techniques, but histological examination is necessary to reach the final diagnosis. Different treatment modalities are available for gestational trophoblastic neoplasm depending on the type and stage; these include D&amp;C (dilation and curettage), chemotherapy, hysterectomy, or a combination of these.2 The prognostic score for GTN reported by FIGO is a score of 0–6 is the low-risk group and 7 is the high-risk group. All patients who have hydatidiform mole should be up for β-hCG surveillance and monitoring. Most relapses occur within the first year after completion of chemotherapy. A generally approved schedule of β-hCG surveillance indicates monitoring weekly for six weeks after chemotherapy followed by biweekly measurements until six months after chemotherapy. Afterward, a biannual measurement of β-hCG for five years is sufficient.1 Seeing this, the determination of the diagnosis of GTD becomes very important. With the proper diagnosis, the management of the patient will also improve.