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Reactive oxygen species (ROS) are a heterogeneous group of highly reactive ions and molecules derived from molecular oxygen (O2), which can cause DNA damage and lead to skin cancer. NADPH oxidase 1 (Nox1) is a major producer of ROS in the skin upon exposure to ultraviolet light. Functionally, Nox1 forms a holoenzyme complex that generates two superoxide molecules and reduces NADPH. The signaling activation occurs when the organizer subunit Noxo1 translocates to the plasma membrane bringing a cytochrome p450 through interaction with Cyba. We propose to design inhibitors that prevent Cyba-Noxo1 binding as a topical application to reduce UV-generated ROS in human skin cells. 

Inhibitor design started from an apocynin backbone structure to generate a small molecule to serve as an anchor point, inhibitor 1, followed by adding a polyethylene glycol linked biotin in inhibitor 2. Further in vitro experiments using isothermal calorimetric (ITC) were used to quantify the binding affinity (KD). ITC and MALDI (TOF) MS was also used to show if binding of a Cyba peptide to Noxo1 was blocked. In vivo experiments were performed using donated skin explants with topical application of the two inhibitors while exposing the samples to UV. 

Inhibitors 1 and 2 were nontoxic in human cells, and successfully increased cell viability after UV exposure. Biophysical using ITC and MALDI revealed biotin as not necessary for inhibition while confirming affinity between inhibitor 2 and Noxo1. Further in vitro experiments using isothermal calorimetric binding quantification showed that inhibitor 2 bound a Noxo1 peptide with a KD of 2nM. Both using isothermal calorimetric binding and MALDI (TOF) MS showed that the binding of a Cyba peptide to Noxo1 was blocked. Experiments show that in primary skin explant models with ultraviolet light exposure, inhibitor 2 reduced the amount of cyclobutene pyrimidine dimers in DNA, a molecule known to lead to carcinogenesis. 

These findings demonstrate a novel inhibition of Nox1, which serves as a basis for further research to determine if this inhibitor can be added to topical sunscreens for public use in hopes of decreasing UVR-induced DNA damage and subsequent carcinogenesis. In addition, this novel sunscreen formulation could be a non-toxic alternative to chemical based barrier sunscreens that are currently on the market. 


AMA Research Challenge 2023

Serendipitous Identification of a NOXO1 Inhibitor By Addition of a Polyethylene Glycol Chain

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Background
Ceramides play an essential role in the formation of the stratum corneum, and include a long-chain sphingoid base in an amide linkage with one or more fatty acids (FAs). Skin contains many unique FAs, particularly esterified omega (EO)-hydroxy(OH)ceramides with ultra-long FA chains, which are critical to the CLE.
Atopic Dermatitis, a common pediatric skin disorder with cutaneous inflammation and barrier impairment, is recognized to have a deficiency of ceramides, including EO-OH ceramides, based on targeted lipidomic analyses. Untargeted lipidomics (Q Exactive HF OrbiTrap) is a new technology that, as RNA-Seq or proteomics, allows comprehensive comparison of diseased vs healthy tissues but has yet to be described for skin.

Methods
We extracted lipids from tape strips of lesional atopic dermatitis (AD-L) and nonlesional (NL) skin from 31 AD patients (0.2-17.3 yrs old, mean 7 yrs; 51% female; 58% White) and 14 age- and site-matched healthy controls (C) for untargeted lipidomic analysis.

Results
PCA plots showed distinct separation between AD-L and C skin, regardless of sex or age. 637 distinct ceramide species were detected in AD and 616 in C skin, with 291 decreased in AD-L vs. C and 242 reduced in AD-L vs NL skin. Total normalized signal response of ceramides decreased 84% in AD-L and 51% in NL skin vs C (p < 0.001). Most ceramide classes decreased by >80% in AD-L vs C skin (EO by 88-93%; ODS/ADS 91%; NP 90%; NH 87%; NSD 83%; OH/AH 83%; and OSD/ASD 82%).
We found a new ceramide class (m), overall decreased in AD-L by 81%. A few species were increased in EOSD, OH/AH, OSD/ASD, NDS, NH, NP, and NS classes. Ceramide changes in NL skin were all in AD-L. Decreased AD-L ceramides correlated with eczema severity indices: SCORAD and EASI scores (Spearman r= –0.4 to -0.57, p < 0.001); m-ceramides with EASI and Pruritus ADQ scores (r= -0.43 and r= -0.44, p < 0.01). Increases of NDS in AD-L correlated with EASI (r=0.48, p < 0.01); and NH, NP, and NS with Itch VAS (r= 0.73 to 0.93, all p < 0.05).

Conclusion
The discovery of a new ceramide class (m), which is found to be decreased in AD-L highlights the value of untargeted lipidomic analyses for understanding skin disorders and in clinical trials that can target specific ceramides in the metabolic pathway.

Untargeted Lipidomic Analysis from Atopic Dermatitis Stratum Corneum Reveals Novel Ceramide Defects

INTRODUCTION: Snail, also known as the “land helix,” has been used in traditional and contemporary medicine to treat various ailments and has provided dermatological benefits in human history. Snail secretions have been shown to improve wound healing, relieve pain, and prevent associated complications due to their antimicrobial, anti-inflammatory, and anti-aging properties. We performed a literature review on topical snail derivatives and their potential to treat different dermatological conditions and the limitations of each publication. 

METHODS: A literature search was performed using 324 search terms with combinations using Boolean operators. Inclusion and Exclusion criteria were used to review the relevance of each paper. Literature analysis included two randomized controlled trials that fit both inclusion and exclusion criteria. 

RESULTS: Two studies illustrated the use of snail derivatives on dermatological conditions in humans and mice, respectively. A double-blinded randomized controlled trial showed significant improvement in periocular and perioral rhytides when using topical combination serum of Cryptomphalus aspersa after 12 weeks of treatment. Similarly, another randomized controlled trial showed significant improvement in wound healing when using topical snail secretion from Helix aspersa after 14 days of treatment. 

DISCUSSION: Literature has shown that snail mucus has properties that allow improvement of skin appearance thanks to its use as emollient with moisturizing and lubricating properties. Growth factors present in snail mucus have can reduce the presence of wrinkles, leading to anti-aging properties. Additionally, snail mucus aids in collagen production, a key factor in wound healing, and decreases inflammatory cells and cytokine release, which are usually seen in chronic inflammation. 

CONCLUSION: Results from this literature review show that topical application of snail mucus can have beneficial dermatological outcomes, such as anti-aging properties and improved wound healing. More research is needed to investigate additional therapeutics and cosmetic effects of snail secretion on the skin.


A Systematic Review of the Dermatological Benefits of Topical Snail Derivatives

• Silicone and other Polymers are used to create simulated skin for task trainers and other products in health care simulations.
• Silicones are created and sold in varying firmness termed durometer.
• Platinum cured Silicones are fixed after cure and cannot be melted or
reformed after they are cut or punctured.
• A newer Polymer that is thermoplastic (able to be reshaped and formed by melting) - is called synthetic ballistics gelatin or Styrene ethylene butylene styrene (SEBS).

Adjusting durometer to create more realistic soft- tissue in synthetic ballistics gelatin

Pathologic white adipose tissue (WAT) expansion is known to occur under conditions of metabolically “unhealthy” obesity. Such obesity is marked by physiologic abnormalities and depends on the location of WAT depots, as well as an individual’s comorbidities. Hypoxic conditions, in particular, can shift the direction of metabolic pathways, with the signaling molecule HIF1α playing a large role in driving a cascade resulting in adipose tissue expansion. This study aimed to identify the specific mitochondrial metabolic changes that arise in WAT precursor cells in response to HIF1α induction. WAT was extracted from mice inguinal fat depots and the stromal vascular fraction, containing adipose precursor cells, was isolated and plated. They were treated with either of two HIF1α inducers, COCl2 or DMOG, or left without treatment as controls. Targeted metabolomics through gas chromatography-mass spectroscopy (GC-MS) was utilized to assess levels of both glycolysis-related metabolites and tricarboxylic acid (TCA) cycle intermediates produced within the cells. Compared to the control group, COCl2 significantly increased lactate levels (t(10) = 5.93, p < .001) and α-ketoglutarate levels (t(10) = 6.75, p < .001) while significantly decreasing malate levels (t(10) = -5.03, p < .001). Both COCl2 (t(10) = -8.12, p < .001) and DMOG (t(10) = -2.69, p < .05) significantly decreased citrate levels compared to the control group. All other metabolites assessed showed no significant difference between treatment and control groups. The metabolomics data revealed dysfunctions of glycolysis and the TCA cycle upon treatment of adipose precursor cells with inducers of HIF1α. A potential cause of this may have been a reliance on reductive glutamine metabolism to drive α-ketoglutarate into fatty acids as an alternate energy source under hypoxic conditions. Understanding the molecular controls at play in this process is critical to preventing the adverse effects of metabolically unhealthy obesity, such as fibrosis and organ damage. Previous literature has shown that there is the potential to modify the fate of adipose precursor cells to prevent them from committing to a fibrotic phenotype. By incorporating metabolic data similar to that produced in this study on HIF1α with findings on modifying adipose precursor cell fate, it may be possible to prevent or treat unhealthy obesity from a clinical standpoint.

HIF1α Signaling to Target Mitochondrial Metabolism for Regulation of Adipose Precursor Cell Fate

Introduction 
Pre-eclampsia is one of the leading causes of maternal, fetal, and neonatal morbidity and mortality, complicating about 4% of pregnancies. Recent work has identified PERIOD3 (PER3), a gene regulating 24-hour circadian rhythms, to be downregulated in the preeclamptic placenta. The role of circadian rhythms in the placenta largely remains unknown. Our goal is to establish an organotypic placental preparation to allow screening of drugs that regulate circadian rhythms. These studies are a first step towards understanding how circadian rhythm changes are caused in the placenta and will be the basis for future studies to understand how circadian rhythm disruption in the placenta cause pregnancy complications, such as preeclampsia.

Methods 
We established a novel organotypic placenta preparation allowing to study circadian rhythms in a LumiCycle using gestation day (GD) 14 and GD18 placental explants from the validated circadian reporter mouse Per2::Luciferase. Using H&E we validated the explants to be >80% enriched in either decidua (DC) which is strictly of maternal origin, labyrinth (LB) which is strictly of fetal origin, and the junctional zone (JZ) which consists of binucleated cells fused of maternal and fetal cells.

Results 
Through H&E staining, we validated by distinct morphology that the DC is enriched with neutrophils; the JZ contains spongiotrophoblasts and glycogen trophoblasts; whereas the LB has anucleated red blood cells. We next established a protocol to record Per2::Luciferase circadian rhythms for <6 days. We found that the Per2::Luciferase circadian rhythm shortens with increased gestational age, where the period in DC, LZ and LB in the GD14 placenta is ~4h longer than in the GD18 placenta, showing an unexpected plasticity in circadian timekeeping in the placenta. Because PER3 is downregulated in the pre-eclamptic placenta, we asked if the explants would be useful for pharmacologically screenings. We applied PF670462 (1μM), which stabilizes PER1/2/3, or epidermal growth factor (EGF, 30ng/mL), a growth factor important in placental function and a PER2 enhancer. PF670462 lengthened Per2::Luciferase period in the DC and JZ, confirming the expected circadian rhythm stabilizing effect of PF670462. Surprisingly, EGF only modulated circadian rhythms in the GD14 placental, where EGF shortened Per2::Luciferase period in DC, and lengthen the period in the JZ and LB zones in the GD14 placenta. This data suggests EGF has gestational age and placenta zone specific effects.

Conclusion 
We validated a novel ex vivo placental preparation to study circadian rhythms at GD14 and GD18. We identified a placenta zone and gestation age specific effect of EGF, an effect future studies will further expand on. This model will be useful to complete pharmacological screenings of drugs that can restore circadian rhythms in the preeclamptic placenta.

Validation of a Novel Placenta Explant Protocol Allowing
Screening of Drugs Modulating Circadian Rhythms in the Mouse Placenta

Objective / Hypothesis: Cell replacement therapy is rapidly emerging as a viable cure for Type 1 Diabetes Mellitus; however, the supply of insulin-producing cells for transplantation is severely limited due to a shortage of pancreatic islet donors. Current strategies include generating stem-cell derived pancreatic islets (SC-islets) for eventual implantation, but current methods generate functionally immature cells (mostly due to lack of vascularization and the importance of endothelial cell proximity), which complicates clinical translation. Our goal with this project is to create functionally competent insulin-secreting cells with a built-in vascular network. We hypothesize that the orthogonal differentiation of human induced pluripotent stem cells (h-iPSCs) into beta cells and vascular cells will enable the development of SC-islets with a built-in vasculature.

Approach: We developed an orthogonal differentiation strategy using doxycycline-inducible transgenes encoding key transcription factors to induce differentiation of h-iPSCs into endothelial cells (iECs) and mural cells (iMCs). We are using our differentiation protocol that generates SC-islets from human embryonic stem cells (hESCs) through a multi-stage procedure reminiscent of pancreatic development to generate islet endocrine cells. In the initial phases of the experiment, we used INS1 insulin-secreting rat insulinoma cells in place of SC-islet cells due to their ease of use (no need for >31-day differentiation protocol) and direct translatability to the behavior of SC-islet cells in vitro. These cells were co-cultured and studied by functional assays, imaging, and flow cytometry.

Results: Both transcription factor-based differentiation methods enabled highly efficient differentiation of human iPSCs into competent vascular cells (iECs and iMCs) – h-iPSCs were rapidly and robustly differentiated by simple exposure to doxycycline (4-day process, >95% efficiency). These cells were phenotypically and functionally validated, with the iECs staining positive for CD31, CD144, and VE-Cadherin, and iMCs staining positive for Calponin1, Vimentin, and SM22. These results were confirmed with flow cytometry. Using the INS1 cell line, co-culture of these cells in different ratios of INS1:iEC:iMC did show integrated tube formation reminiscent of vasculature at day 8 (80:18:2 and 91:9:1). In contrast, other ratios (such as 50:50 and 66:33 INS1 to iEC) did not show tube formation, and instead formed segregated cell clusters in which iECs, iMCs, and INS1 cells did not integrate.

Summary / Conclusions: This data shows promising results and suggests an in vitro model for creating an intra-islet vasculature may be achievable, as we did see endothelial/mural cell tube formation in our experiments when using INS1 cells, iECs, and iMCs. Future studies may include additional functional testing and analysis, such as using GSIS to quantify insulin secretion and sc-RNA-seq to study maturation markers pre- and post-differentiation. Once the orthogonal differentiation protocol shows significant success, transplantation studies into animal models could demonstrate how these islets function in vivo.


Generation of stem-cell derived, vascularized islets for transplantation in Type 1 Diabetes Mellitus therapy.

Introduction: While the harmful effects of exogenous glucocorticoids (GC) on the skeleton are well understood, the role of endogenous GC and their glucocorticoid receptor (GR)-mediated signaling in bone are not as clear. Although we originally predicted that GR knockout would be beneficial to the skeleton, both constitutive and adult-onset conditional knockout (CKO) of the GR in osteoprogenitors promoted low bone mass in young female mice that was further exacerbated with age. The goal of this study was to explore the role of the GR in the male skeleton.

Methods: The GR-CKO male mice and wildtype (WT) littermates were created by crossing GRfl/fl and Osx1-Cre+ mice. Constitutive [RD] GR-CKOosx mice were maintained on regular chow until six months of age. Adult onset [Doxy] GR-CKOosx mice were maintained on doxycycline chow until three months of age to negate developmental defects during rapid skeletal growth. Orchidectomy (ORX) or sham procedures were performed aseptically on six-month-old male GR-CKOosx mice and wildtype littermates. In the fourth week post-surgery, the mice underwent DXA scans to assess bone density and body composition. After sacrifice, femurs were harvested and microarchitectural parameters were determined using microCT.

Results: GR-CKO [RD] mice that underwent ORX surgery had a significant loss of body mass, comprised mainly of lean mass, compared to WT-ORX mice. This effect was not seen in GR-CKO ORX [Doxy] mice. Femur microCT analysis revealed that bone mass in male GR-CKOosx was not different from WT mice under sham conditions, but CKO mice had less trabecular bone mass than WT after ORX in both RD and Doxy models.

Conclusion: Male GR-CKOosx mice did not present with a skeletal phenotype until after ORX surgery. ORX induced the same low bone mass phenotype vs. WT mice, as seen in female GR-CKOosx animals. This suggests an important role of sex hormones in mediating bone GR signaling.

The Role of Sex Steroids in Mediating the Effects of Osteoblast-Lineage Glucocorticoid Receptor Signaling in Skeletal Health

Background:
Hypoglycemia poses a significant risk of irreversible neurological damage and mortality, particularly among elderly with diabetes. It is also the most preventable cause of morbidity and mortality in this patient population. The urgent need for heightened awareness and proactive management of hypoglycemia by deprescribing is crucial in order to reduce hospitalization rates and prevent poor outcomes.

Case Presentation:
An elderly male with a history of diabetes and recent hospitalization for acute chronic obstructive pulmonary disease exacerbation arrived at the emergency department (ED) complaining of generalized weakness and urinary retention upon evaluation, he was diagnosed with a urinary tract infection (UTI) and acute kidney injury. His blood glucose level was 100 mg/dL. Intravenous fluids were administered, and a Foley catheter was inserted. The patient's condition improved and was discharged home. However, three days later, the patient returned to the ED in an unresponsive state. His glucose levels were undetectable, and he required intubation for airway protection. A thorough review revealed that he had been on long-acting sulfonylurea and biguanide for the past 30 years and his recent Hemoglobin A1C was 5.8. Despite extensive evaluations, no alternative cause was identified and he was diagnosed with hypoglycemic coma. A week later, with no improvement in his mental status, the patient's family made the difficult decision to pursue a do-not-resuscitate order. The patient was extubated and subsequently passed away.

Discussion:
Hypoglycemic coma is a serious adverse event that can lead to irreversible brain damage and death. It is also the most preventable complication across all healthcare settings including ambulatory, ED, hospital, skilled or long-term care, and assisted living facilities. Providers in these care settings should 1) carefully monitor risk factors like advancing age, new illness, new poor oral intake, and kidney injury that can decrease the clearance of diabetic medications. 2) Closely monitor glucose checks, and provide timely diabetic and diuretic medication dose reductions in acute illness or deprescribe to prevent adverse events or death from hypoglycemia in older diabetic patients.


Hypoglycaemic Coma Manifested by Urinary Tract Infection - A Case report and Comprehensive Review

Background
This study aimed to investigate the impact of COVID-19 on perioperative adverse outcomes in patients undergoing Per Oral Endoscopic Myotomy (POEM) procedures. As the COVID-19 pandemic has presented unique challenges in healthcare, understanding its association with adverse outcomes during POEM is crucial for optimizing patient care and management. 

Methods
The study utilized data from the Nationwide Inpatient Sample (NIS) 2020, a comprehensive and nationally representative database. 464% (p<0.001) more likely to experience pulmonary embolism during POEM.
Results
The cohort included 5,776 adults who underwent POEM, with 118 individuals diagnosed with COVID-19. Demographic variables, comorbidities, and perioperative adverse outcomes were examined. Univariable and multivariable logistic regression analyses were conducted to assess the relationship between COVID-19 and adverse outcomes, while controlling for potential confounding factors. Among the cohort, individuals with COVID-19 had higher rates of complications, including pneumonia, DVT or other thromboembolism, pulmonary collapse or atelectasis, pulmonary embolism, and portal vein thrombosis, compared to those without COVID-19 (p<0.001). In the univariable analysis, individuals with COVID-19 254% (p<0.001) more likely to develop pneumonia and 515% (p<0.001) more likely to develop pulmonary embolism during POEM. In the multivariable analysis, after adjusting for age, gender, race, hospital characteristics, region of the country, insurance, and comorbidities, individuals with COVID-19 were 230% (p<0.001) more likely to develop pneumonia and 464% (p<0.001) more likely to experience pulmonary embolism during POEM. 
Conclusion
This study reveals a significant association between COVID-19 and increased risk of perioperative adverse outcomes, particularly pneumonia and pulmonary embolism, in patients undergoing POEM. These findings emphasize the importance of considering COVID-19 status when evaluating perioperative risks and implementing appropriate preventive measures to improve patient outcomes. The results underscore the need for tailored approaches to mitigate the impact of COVID-19 in the perioperative period and enhance patient safety.

Perioperative Outcomes in Patients Undergoing Per Oral Endoscopic Myotomy (POEM) During the COVID 19 pandemic, a Nationally Representative Study

Background: Intraductal Papillary Mucinous Neoplasms (IPMNs) are the most common subset of cystic neoplasms and are currently only managed by surgery and surveillance; however, because pancreatic surgery proves to be an unnecessary risk in benign cases, an alternative treatment plan is crucial. Previous experimentation showed that IPMNs exhibited higher levels of MAP kinase, a signaling cascade that regulates cell proliferation and differentiation, than pancreatic ductal adenocarcinoma (PDAC). We hypothesized that IPMNs would be more susceptible to MEK (upstream regulator in the MAP kinase pathway) inhibition than conventional PDAC cells due to the significant increase of MAPK phosphorylation in IPMNs.

Methods: 4619 cells were obtained from a mouse PDAC tumor carrying mutations in Kras and Trp53; 4838 cells were obtained from a mouse IPMN tumor carrying mutations in Kras and Gnas (doxycycline-inducible). Cells were treated with 1 ug/ml doxycycline for 24hr prior to treatment. Gene expression was determined by RT-qPCR at 24hr of 100nM Trametinib or vehicle (DMSO) normalizing to Pmm1 levels. Western blotting for phospho-ERK 1/2, total ERK1/2, and GAPDH was used to control for trametinib efficiency. Growth was determined by MT Viability Assay, following indicated concentrations of Trametinib at the indicated timepoints.

Results: Trametinib significantly inhibited expression of Aqp5 in both PDAC and IPMN cells. Mki67 fold change showed a significant decrease in both lines with Trametinib whereas Pcna fold change was significant between PDAC Trametinib vs. vehicle but not in the IPMN line. No significance was noted for Gnas, Spdef, Cdkn2a, and Cdkn1a. Growth and proliferation curves showed the highest concentration of Trametinib (100 nM) prohibiting growth the most in both cell lines.

Conclusion: MEK inhibition had similar effects on PDAC and IPMN cells. Trametinib decreased expression of proliferation markers similarly in both cell lines, consistent with a similar inhibition of growth. Expression of growth arrest markers was unaffected by trametinib. The role of MEK in regulating Aqp5 is novel and will be pursued in future experiments. These experiments were performed in 10% fetal bovine serum which is highly growth stimulatory. Future experiments could treat cells in low or no serum to determine if Trametinib has more of an effect under nutrient-limited conditions. Overall, IPMNs need to be studied more regarding their differences from PDAC and the MAP Kinase pathway.

Next from AMA Research Challenge 2023

Untargeted Lipidomic Analysis from Atopic Dermatitis Stratum Corneum Reveals Novel Ceramide Defects