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Kenney, M. C.

Publications and source records attributed to Kenney, M. C..

5 recordsLinked to original sources
bioRxiv2023

Pulsed ultrasound modulates the cytotoxic effect of cisplatin and doxorubicin on cultured human retinal pigment epithelium cells (ARPE-19)

ObjectivePulsed ultrasound has been proposed as a tool to enhance ocular drug delivery, but its effects on drug potency are not well understood. Doxorubicin-HCl and cisplatin are two drugs commonly used to treat ocular melanoma. We report the effects of pulsed ultrasound on the cytotoxicity of doxorubicin-HCl and cisplatin in vitro. MethodsCultured human retinal pigment epithelium cells (ARPE-19) cells were treated with doxorubicin-HCl or cisplatin in the presence or absence of ultrasound. MTT and Trypan blue assays were performed at 24 and 48 hours post-treatment to assess cell metabolism and death. ResultsCells treated with ultrasound plus doxorubicin-HCl demonstrated a significant decrease in metabolism compared to cells treated with doxorubicin-HCl alone. In contrast, cells treated with ultrasound plus cisplatin exhibited a significant increase in metabolism compared to cells treated with cisplatin alone at 48-hours. Cells treated with cisplatin pre-treated with ultrasound (US-Cis) exhibited a significant decrease in metabolism. Cell death was similar in doxorubicin- and cisplatin-treated cells with and without ultrasound. ConclusionPulsed ultrasound enhances the cytotoxicity of doxorubicin-HCl at 24- and 48-hours post-treatment but abrogates cisplatin toxicity 48-hours post-treatment. This suggests ultrasound modulates cell-drug interactions in a drug-specific manner. These findings may influence the future development of ultrasound-assisted ocular drug delivery systems.

cell biology↗
bioRxiv2021

Transcription Factor Gene Pea3 Regulates Erectile Function in Mice

BackgroundMale mice with homozygous loss of function mutations of the ETS transcription factor gene Pea3 (Pea3 null) are infertile due to their inability to deposit semen plugs, however the specific deficits in male sexual behaviors that drive this phenotype are unknown. AimTo investigate the regulatory role of the Pea3 gene in organizing gross sexual behaviors and erectile functioning during active copulation. MethodsThe copulatory behavior of male mice (Pea3 null and control) with hormonally primed ovariectomized females was monitored via high-speed and high-resolution digital videography to assess for differences in female-directed social behaviors, gross sexual behaviors (mounting, thrusting), and erectile and ejaculatory function. OutcomesPea3 null male mice have dramatically reduced erectile function during sexual intercourse, however other aspects of male sexual behaviors are largely intact. ResultsPea3 null male mice exhibit greatly reduced erectile function, with 44% of males displaying no visible erections during mounting behaviors, and none achieving sustained erections. As such, Pea3 null males are incapable of intromission, and semen plug deposition, despite displaying largely normal female-directed social behaviors, mounting behaviors, and ejaculatory grasping behavior. Additionally, the coordination of the timing of thrusting trains is impaired in Pea3 null males. Clinical ImplicationsThe identification of the transcription factor Pea3 in regulating erectile function in mice may provide a useful target for understanding the genetics of male sexual dysfunction in human patients. Strengths and LimitationsHigh-speed and high-resolution videography allows for a detailed analysis of male sexual behaviors and erectile functioning in Pea3 null and control mice. How disruption of the Pea3 gene translates to erectile dysfunction is still unknown. ConclusionThe transcription factor gene Pea3 regulates the ability to achieve and maintain erections in male mice.

animal behavior and cognition↗
bioRxiv2020

Quantifying Color Vision Changes Associated with Cataracts Using Cone Contrast Thresholds

PurposeThe cone contrast threshold (CCT) test quantified color vision changes in subjects of all ages and those undergoing cataract surgery. MethodsTwenty-four healthy volunteers from two cohort studies performed CCT using best corrected visual acuity, filters, mydriasis, and pinhole correction. Retrospective cross-sectional study of patients seen in eye clinics evaluated the relationship between age and color vision, and age and lens status in 355 eyes. Lastly, 25 subjects performed CCT before and after cataract surgery. ResultsCCT scores were most reliable in the non-mydriatic condition without pinhole correction. Progressively dense brown filters produced small but significant reductions in S-cone sensitivity. Linear regression analysis of phakic subjects showed a decline for all cone classes with age. Rate of decline was greater for S-cones (slope (95% CI) = -1.09 (-1.23, 0.94)) than M-cones (slope (95% CI) = -0.80 (-0.95, -0.66)) and L-cones (slope (95% CI) = -0.66 (-0.81, - 0.52)). CCT scores increased for S-cones but reduced for L- and M-cones in pseudophakic subjects compared to phakic patients. CCT scores after cataract surgery increased for S-cones, M-cones, and L-cones by 33.0 (p<0.001), 24.9 (p=0.001), and 22.0 (p=0.008). ConclusionsCCT assessment allows for clinically practical quantitation of color and contrast vision improvement after cataract surgery and aging patients who note poor vision despite good visual acuity. Translational RelevanceCCT testing, historically used in research, is now a clinically practical tool to evaluate age and cataract related changes in color and contrast vision and routinely quantify vision beyond black and white visual acuity testing.

pathology↗
bioRxiv2018

Role of STING complex in differential retrograde signaling in cybrids with K versus H haplogroup mtDNA

Mitochondrial (mt) DNA haplogroups, defined by specific single nucleotide polymorphism (SNPs) patterns, represent populations of diverse geographic origins and may play a role in disparate disease susceptibilities found in different ethnic/racial populations. The most common European haplogroup is H, while the K haplogroup is highly associated with Ashkenazi Jewish populations. Studies using transmitochondrial cybrids (cell lines with identical nuclei but mitochondria from either H or K haplogroup subjects) demonstrated significant molecular and biological differences but mechanisms for these disparities are unclear. In this study, we hypothesized that there is differential retrograde signaling occurring between the Stimulator of Interferon Genes (STING) pathway and H versus K mtDNA haplogroups. Results showed that K cybrids exhibit increased levels of cytoplasmic mtDNA fragments. After STING Knock-Down, H cybrids had lower expression levels for EGFR, BRCA1, DNMT3A, DNMT3B, HDAC1, and IFN genes, but upregulated DNMT3A compared to control H cybrids. The STING-KD K cybrids showed downregulation of EGFR, DNMT3A, HDAC1, HCAD9, CFH, and CHI, along with upregulation of DNMT1 and IL-6 compared to control K cybrids. Since all cybrids have identical nuclei, the STING DNA sensor system interacts differently with K haplogroup mtDNA compared to H mtDNA for genes related to cancer (EGFR, BRCA1), methylation (DNMT1, DNMT3A, DNMT3B), acetylation (HDAC1, HDCA9), complement (CFH, CHI) and inflammation (IFN, IL-6). In summary, in non-pathologic conditions, (a) STING is an important retrograde signaling mechanism(s) and (b) cybrids possessing Ashkenazi Jewish mtDNA (K haplogroup) interact with the STING complex differently compared to H cybrids which affects various disease-related pathways.

cell biology↗