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.

Is Chlamydia to Blame for Koala Reproductive Cysts?

A significant threat to koala populations is infection from Chlamydia, which results in disease and death. Wild koalas with Chlamydia infections are admitted to wildlife hospitals and treated with antibiotics; however, up to 50% of koalas that present to wildlife hospitals do not survive. A major contributor to high mortality is the development of reproductive cysts, resulting in female infertility and euthanasia. However, the diagnosis of reproductive disease is limited to ultrasound with no further investigations. This communication highlights reports of histological and microbiological findings, the accuracy of ultrasound to necropsy reports and other possible causes for reproductive cyst development previously reported in other hosts. Our conclusions identify a significant knowledge gap in the aetiology of koala reproductive cysts and highlight the urgent need for future investigations.

mTOR inhibitors and risk of ovarian cysts: a systematic review and meta-analysis

ObjectiveTo summarise the available evidence on frequency of ovarian cyst development during mammalian target of rapamycin inhibitors (mTORi) treatment.MethodsPubMed/Medline and EMBASE databases were searched, from 1990 up to March 2020, using the following keywords: ‘tacrolimus’, ‘sirolimus’, ‘temsirolimus’, ‘everolimus’, ‘deforolimus’, ‘mTOR’ and ‘ovarian cysts’ (Limit: Human, English, full article). Studies were selected for the review if they met the following criteria: clinical studies, studies reporting original data, studies reporting the number of patients using mTORi, studies reporting the number of patients with ovarian cysts.We selected 7 of 20 retrieved studies. Study design, population, sample size, criteria for diagnosis of ovarian cysts, drug doses and follow-up length were extracted. Pooled estimate of incidence was calculated for ovarian cysts as a percentage, with 95% CI.ResultsFour hundred-six women were included in the selected studies. The pooled incidence was 37.0% (95% CI 16.0% to 58.1%) for all ovarian cysts, and 17.3% (95% CI 5.6% to 29.1%) for clinically significant ovarian cysts. Based on two articles, comparing mTORi and non-mTORi for immunosuppression, pooled OR for ovarian cyst incidence was 4.62 (95% CI 2.58 to 8.28).ConclusionOvarian cyst development is a common adverse event during immunosuppression treatment with mTORi. These cysts are benign conditions, but they require pelvic ultrasound follow-up and in some cases hospital admission and surgery.

Inhibiting Focal Adhesion Kinase Ameliorates Cyst Development in Polycystin-1–Deficient Polycystic Kidney Disease in Animal Model

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous cysts originating from renal tubules and is associated with significant tubular epithelial cell proliferation. Focal adhesion kinase (FAK) promotes tumor growth by regulating multiple proliferative pathways.MethodsWe established the forskolin (FSK)-induced three-dimensional (3D) Madin–Darby Canine Kidney cystogenesis model and 8-bromoadenosine-3`,5`-cyclic monophosphate–stimulated cyst formation in ex vivo embryonic kidney culture. Cultured human renal cyst–lining cells (OX-161) and normal tubular epithelial cells were treated with FAK inhibitors or transfected with green fluorescent protein–tagged FAK mutant plasmids for proliferation study. Furthermore, we examined the role of FAK in two transgenic ADPKD animal models, the kidney-specific Pkd1 knockout and the collecting duct–specific Pkd1 knockout mouse models.ResultsFAK activity was significantly elevated in OX-161 cells and in two ADPKD mouse models. Inhibiting FAK activity reduced cell proliferation in OX-161 cells and prevented cyst growth in ex vivo and 3D cyst models. In tissue-specific Pkd1 knockout mouse models, FAK inhibitors retarded cyst development and mitigated renal function decline. Mechanically, FSK stimulated FAK activation in tubular epithelial cells, which was blocked by a protein kinase A (PKA) inhibitor. Inhibition of FAK activation by inhibitors or transfected cells with mutant FAK constructs interrupted FSK-mediated Src activation and upregulation of ERK and mTOR pathways.ConclusionsOur study demonstrates the critical involvement of FAK in renal cyst development, suggests that FAK is a potential therapeutic target in treating patients with ADPKD, and highlights the role of FAK in cAMP-PKA–regulated proliferation.

A RARE PRESENTATION OF CHOLEDOCHAL CYST IN ADULT.

Choledochal cyst (CC) is a relative rare condition in adult population. Only 20% of CC presents in adult population, of these 80% presents with additional hepatobiliary pathology (1,2). With widespread usage of cross sectional imaging, more cysts are likely being identified incidentally in asymptomatic individuals. The development of cancer arising from cysts increases from <0.7% in first decade of life to >11.4% after 2nd decade of life. Anatomic abnormality pancreaticbiliary maljunction (PBM) is a noted etiologic factor for cyst development and even for development of cancer in cysts. We report a rare adult presentation of choledochal cyst with underlying abnormal pancreaticobiliary maljunction with gall bladder carcinoma.

A comprehensive scoping review of tibial cysts after anterior cruciate ligament reconstruction

Purpose The purpose of this study was to perform a scoping review of published literature reporting on surgical management of tibial cysts which developed after ACLR. Methods A scoping review was conducted following the Arksey and O’Malley framework for scoping studies and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension for scoping reviews (PRISMA-ScR) guidelines. A search strategy using the terms [“Tibial Cyst” AND “ACL”], [“Pretibial Cyst” AND “ACL”] was applied to the PUBMED database. Results Thirty-seven studies published between 1990 and 2019 were a part of this scoping review. Non-absorbable implants for tibial graft fixation were used in 10 studies (comprising a total 21 patients), while bio-absorbable implants were used in 27 studies (comprising a total 115 patients). Incidence of tibial cyst was reported in 3 studies (434 primary ACLRs) from whom 3.9% (n = 17) developed tibial cyst. Tibial cyst development in relation to use of bio-absorbable screws for tibial ACL graft fixation was reported in 16 studies (42.1%). Use of bio-absorbable screws with another factor was found to be related to tibial cyst development in another 1 study (2.6%). Most common symptoms were presence of mass or swelling, pain, tenderness, drainage, instability and effusion. Conclusion This scoping review demonstrated that tibial cysts is more frequently related to bioabsorbable screws, however it can also occur due to other causes. Current literature on tibial cyst after ACLR is of low-quality evidence. Future research is required to better understand aetiology, risk factors for cyst formation and the best possible mode of management. Level of evidence IV

A Family of Toxoplasma gondii Genes Related to GRA12 Regulate Cyst Burdens and Cyst Reactivation

ABSTRACT Toxoplasma gondii causes a chronic infection that renders the immunocompromised human host susceptible to toxoplasmic encephalitis triggered by cyst reactivation in the central nervous system. The dense granule protein GRA12 is a major parasite virulence factor required for parasite survival during acute infection. Here, we characterized the role of four GRA12-related genes in acute and chronic stages of infection. While GRA12A, GRA12B, and GRA12D were highly expressed in asexual stage tachyzoites and bradyzoites, expression of GRA12C appeared to be restricted to the sexual stages. In contrast to deletion of GRA12 (Δgra12), no major defects in acute virulence were observed in Δgra12A, Δgra12B, or Δgra12D parasites, though Δgra12B parasites exhibited an increased tachyzoite replication rate. Bradyzoites secreted GRA12A, GRA12B, and GRA12D and incorporated these molecules into the developing cyst wall, as well as the cyst matrix in distinct patterns. Similar to GRA12, GRA12A, GRA12B, and GRA12D colocalized with the dense granules in extracellular tachyzoites, with GRA2 and the intravacuolar network in the tachyzoite stage parasitophorous vacuole and with GRA2 in the cyst matrix and cyst wall. Chronic stage cyst burdens were decreased in mice infected with Δgra12A parasites and were increased in mice infected with Δgra12B parasites. However, Δgra12B cysts were not efficiently maintained in vivo. Δgra12A, Δgra12B, and Δgra12D in vitro cysts displayed a reduced reactivation efficiency, and reactivation of Δgra12A cysts was delayed. Collectively, our results suggest that a family of genes related to GRA12 play significant roles in the formation, maintenance, and reactivation of chronic stage cysts. IMPORTANCE If host immunity weakens, Toxoplasma gondii cysts recrudesce in the central nervous system and cause a severe toxoplasmic encephalitis. Current therapies target acute stage infection but do not eliminate chronic cysts. Parasite molecules that mediate the development and persistence of chronic infection are poorly characterized. Dense granule (GRA) proteins such as GRA12 are key virulence factors during acute infection. Here, we investigated four GRA12-related genes. GRA12-related genes were not major virulence factors during acute infection. Instead, GRA12-related proteins localized at the cyst wall and cyst matrix and played significant roles in cyst development, persistence, and reactivation during chronic infection. Similar to GRA12, the GRA12-related proteins selectively associated with the intravacuolar network of membranes inside the vacuole. Collectively, our results support the hypothesis that GRA12 proteins associated with the intravacuolar membrane system support parasite virulence during acute infection and cyst development, persistence, and reactivation during chronic infection.

β-importins Tnpo-SR and Cadmus and the small GTPase Ran promote ovarian cyst formation in Drosophila

ABSTRACTGerm cells undergo mitotic expansion via incomplete cytokinesis, forming cysts of undifferentiated cells that remain interconnected prior to meiotic initiation, through mechanisms that are not well-defined. In somatic cells, Ras-related nuclear protein (Ran) spatiotemporally regulates mitotic spindle assembly, cleavage furrow formation and abscission. Here, we identify Ran and β-importins as critical regulators of cyst development in the Drosophila ovary. Depletion of Ran or the β-importins Tnpo-SR and cadmus disrupts oocyte selection and results in egg chambers with variable numbers of germ cells, suggesting abnormal cyst development and cyst fragmentation. We demonstrate that Ran, Tnpo-SR, and Cadmus regulate key cellular processes during cyst formation, including cell cycle dynamics, fusome biogenesis, and ring canal stability, yet do so independently of mitotic spindle assembly. Further, Tnpo-SR and Cadmus control cyclin accumulation and suppress cytokinesis independent of Ran-GTP, suggesting that β-importins sequester protein cargos that normally promote the mitotic-to-meiotic transition. Our data demonstrates that Ran and β-importins are critical for germ cell cyst formation, a role that is likely conserved in other organisms.SUMMARY STATEMENTRan and two β-importins function coordinately to promote oocyte selection and cyst development in the Drosophila ovary.