23 results on '"Poklis, Justin L"'
Search Results
2. Systematic Structure–Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments
- Author
-
St. Onge, Celsey M., Pagare, Piyusha P., Zheng, Yi, Arriaga, Michelle, Stevens, David L., Mendez, Rolando E., Poklis, Justin L., Halquist, Matthew S., Selley, Dana E., Dewey, William L., Banks, Matthew L., and Zhang, Yan
- Abstract
Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure–activity relationship (SAR) systematically studied through design, syntheses, and in vivocharacterization of 24 analogues. Two analogues, 21and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivoeffects primarily mediated by KOR and DOR, penetrated the blood–brain barrier, and did not function as reinforcers. Additionally, 21produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.
- Published
- 2024
- Full Text
- View/download PDF
3. Polycaprolactone microparticles for the subcutaneous administration of cannabidiol: in vitro and in vivo release
- Author
-
Fraguas-Sánchez, Ana Isabel, Hernán, Dolores, Montejo, Consuelo, Poklis, Justin L., Lichtman, Aron H., and Torres-Suárez, Ana Isabel
- Abstract
Graphical abstract:
- Published
- 2023
- Full Text
- View/download PDF
4. Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice
- Author
-
Chen, Chaoling, Wang, Weili, Raymond, Marissa, Ahmadinejad, Fereshteh, Poklis, Justin L., Em, Brandon, Gewirtz, David A., Lichtman, Aron H., and Li, Ningjun
- Abstract
Cisplatin is a potent first-line therapy for many solid malignancies, such as breast, ovarian, lung, testicular, and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits anti-inflammatory effects; however, little is known about its role in cisplatin nephrotoxicity. The current study tested the hypothesis that genetic deletion of Faahmitigates cisplatin-induced AKI. Male wild-type C57BL6 (WT) and Faah−/−mice were administered a single dose of intraperitoneal injection of cisplatin (30 mg/kg) and euthanatized 72 hours later. Faah−/−mice showed a reduction of cisplatin-induced blood urea nitrogen, plasma creatinine levels, kidney injury markers, and tubular damage in comparison with WT mice. The renal protection from Faahdeletion was associated with enhanced tone of AEA-related N-acylethanolamines (palmitoylethanolamide and oleoylethanolamide), attenuated nuclear factor-κB/p65 activity, DNA damage markers p53 and p21, and decreased expression of the inflammatory cytokine interleukin-1β,as well as infiltration of macrophages and leukocytes in the kidneys. Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Our work highlights that FAAH inactivation prevents cisplatin-induced nephrotoxicity in mice and that targeting FAAH could provide a novel strategy to mitigate cisplatin-induced nephrotoxicity.SIGNIFICANCE STATEMENTMice lacking the Faahgene are protected from cisplatin-induced inflammation, DNA damage response, tubular damage, and kidney dysfunction. Inactivation of FAAH could be a potential strategy to mitigate cisplatin-induced nephrotoxicity.
- Published
- 2023
- Full Text
- View/download PDF
5. Design, Synthesis, and Biological Evaluation of NAP Isosteres: A Switch from Peripheral to Central Nervous System Acting Mu-Opioid Receptor Antagonists.
- Author
-
Pagare, Piyusha P., Mengchu Li, Yi Zheng, Kulkarni, Abhishek S., Obeng, Samuel, Boshi Huang, Ruiz, Christian, Gillespie, James C., Mendez, Rolando E., Stevens, David L., Poklis, Justin L., Halquist, Matthew S., Dewey, William L., Selley, Dana E., and Yan Zhang
- Published
- 2022
- Full Text
- View/download PDF
6. Design, Synthesis, and Biological Evaluation of NAP Isosteres: A Switch from Peripheral to Central Nervous System Acting Mu-Opioid Receptor Antagonists
- Author
-
Pagare, Piyusha P., Li, Mengchu, Zheng, Yi, Kulkarni, Abhishek S., Obeng, Samuel, Huang, Boshi, Ruiz, Christian, Gillespie, James C., Mendez, Rolando E., Stevens, David L., Poklis, Justin L., Halquist, Matthew S., Dewey, William L., Selley, Dana E., and Zhang, Yan
- Abstract
The μ opioid receptor (MOR) has been an intrinsic target to develop treatment of opioid use disorders (OUD). Herein, we report our efforts on developing centrally acting MOR antagonists by structural modifications of 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl) carboxamido] morphinan (NAP), a peripherally acting MOR-selective antagonist. An isosteric replacement concept was applied and incorporated with physiochemical property predictions in the molecular design. Three analogs, namely, 25, 26, and 31, were identified as potent MOR antagonists in vivowith significantly fewer withdrawal symptoms than naloxone observed at similar doses. Furthermore, brain and plasma drug distribution studies supported the outcomes of our design strategy on these compounds. Taken together, our isosteric replacement of pyridine with pyrrole, furan, and thiophene provided insights into the structure–activity relationships of NAP and aided the understanding of physicochemical requirements of potential CNS acting opioids. These efforts resulted in potent, centrally efficacious MOR antagonists that may be pursued as leads to treat OUD.
- Published
- 2022
- Full Text
- View/download PDF
7. Pharmacological validation of a translational model of cocaine use disorder: Effects of d-amphetamine maintenance on choice between intravenous cocaine and a nondrug alternative in humans and rhesus monkeys.
- Author
-
Lile, Joshua A, Johnson, Amy R, Banks, Matthew L, Hatton, Kevin W, Hays, Lon R, Nicholson, Katherine L, Poklis, Justin L, Rayapati, Abner O, Rush, Craig R, Stoops, William W, and Negus, S Stevens
- Published
- 2020
- Full Text
- View/download PDF
8. Evaluation of extraction methods for pharmacologically active compounds from anticonvulsant traditional Chinese medicines: Gou Teng, Tian Ma, Jiang Can using DART-TOF-MS
- Author
-
Karin, Kimberly N., Poklis, Justin L., and Peace, Michelle R.
- Abstract
Chinese herbal medicines (CHMs) are classified as dietary supplements. Interactions with western medications, the presence of contaminants or adulterants, or a mis-labeled or mis-used CHM may lead to toxicological emergencies that can be undetected in death investigations. Laboratories must be able to efficiently analyze cases in which CHMs are suspected. Five extractions were evaluated for their ability to extract pharmacologically active compounds from herbal matrices: water, ethanol, microwave-assisted (MAE), ethanol : chloroform, and acid-wash. Anticonvulsive and other pharmacologically active compounds in Gou Teng, Tian Ma, and Jiang Can purchased from Beijing, China and New York were compared in the powder and the extracts using Direct Analysis in Real Time-Mass Spectrometry (DART-MS). Approximately 0.25 g of macerated herb was used per extraction. The water and ethanol extractions were simple liquid extractions. For the MAE, powdered herb was soaked in 65% ethanol, microwaved, and concentrated. The ethanol : chloroform extraction involved soaking in 1 : 1 ethanol : chloroform, sonication, and concentration. In the acid-wash extraction, powdered herb was soaked in acetic acid, followed by addition of sodium hydroxide, hexane extraction, and reconstitution in ethyl acetate. The powdered herbs and extracts were analyzed using a Jeol JMS T100LC AccuTOF DART-MS in positive and negative mode. Of the evaluated methods, no single extraction worked for all active compounds from the three CHMs. The MAE extract contained the most pharmacologically active compounds, while the acid-wash contained the least for the three products. Gou Teng purchased from different sources did exhibit a difference in pharmacologically active compounds, potentially from different species.
- Published
- 2021
- Full Text
- View/download PDF
9. Correction to: Polycaprolactone microparticles for the subcutaneous administration of cannabidiol: in vitro and in vivo release
- Author
-
Fraguas-Sánchez, Ana Isabel, Hernán Pérez de la Ossa, Dolores, Montejo, Consuelo, Poklis, Justin L., Lichtman, Aron H., and Torres-Suárez, Ana Isabel
- Published
- 2023
- Full Text
- View/download PDF
10. Modulation of mean arterial pressure and diuresis by renomedullary infusion of a selective inhibitor of fatty acid amide hydrolase
- Author
-
Ahmad, Ashfaq, Dempsey, Sara K., Daneva, Zdravka, Li, Ningjun, Poklis, Justin L., Li, Pin-Lan, and Ritter, Joseph K.
- Abstract
The kidneys contribute to the control of body fluid and electrolytes and the long-term regulation of blood pressure through various systems, including the endocannabinoid system. Previously, we showed that inhibition of the two major endocannabinoid-hydrolyzing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, in the renal medulla increased the rate of urine excretion (UV) and salt excretion without affecting mean arterial pressure (MAP). The present study evaluated the effects of a selective FAAH inhibitor, N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidine carboxamide (PF-3845) on MAP and renal functions. Infusion of PF-3845 into the renal medulla of C57BL/6J mice reduced MAP during the posttreatment phases and increased UV at 15 and 30 nmol/min per gram kidney weight (g kwt), relative to the pretreatment control phase. Intravenous PF-3845 administration reduced MAP at the 7.5, 15, and 30 doses and increased UV at the 15 and 30 nmol⋅min−1⋅g−1kwt doses. PF-3845 treatment elevated sodium and potassium urinary excretion and medullary blood flow. Homozygous FAAH knockout mice were refractory to intramedullary PF-3845-induced changes in MAP, but UV was increased. Both MAP and UV responses to intramedullary PF-3845 in C57BL/6J mice were diminished by pretreatment with the cannabinoid type 1 receptor-selective antagonist, rimonabant (3 mg/kg, ip) but not the cyclooxygenase 2-selective inhibitor, celecoxib (15 mg/kg, iv). Liquid chromatography-tandem mass spectrometry analyses showed increased anandamide in kidney tissue and 2-arachidonoyl glycerol in plasma after intramedullary PF-3845. These data suggest that inhibition of FAAH in the renal medulla leads to both a diuretic and blood pressure-lowering response mediated by elevated anandamide in kidney tissue or 2-arachidonoyl glycerol in plasma.
- Published
- 2018
- Full Text
- View/download PDF
11. Dietary Omega‐3 Fatty Acids Differentially Impact Acute Ethanol‐Responsive Behaviors and Ethanol Consumption in DBA/2J Versus C57BL/6J Mice
- Author
-
Wolstenholme, Jennifer T., Bowers, M. Scott, Pais, Alexander B., Pais, A. Christian, Poland, Ryan S., Poklis, Justin L., Davies, Andrew G., and Bettinger, Jill C.
- Abstract
Complex interactions between environmental and genetic factors influence the risk of developing alcohol use disorder (AUD) in humans. To date, studies of the impact of environment on AUDrisk have primarily focused on psychological characteristics or on the effects of developmental exposure to ethanol (EtOH). We recently observed that modifying levels of the long‐chain ω‐3 (LCω‐3) fatty acid, eicosapentaenoic acid (EPA), alters acute physiological responses to EtOH in Caenorhabditis elegans. Because mammals derive ω‐3 fatty acids from their diet, here we asked if manipulating dietary levels of LCω‐3 fatty acids can affect EtOH‐responsive behaviors in mice. We used 2 well‐characterized inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), which differ in their responses to EtOH. Age‐matched young adult male mice were maintained on isocaloric diets that differed only by being enriched or depleted in LCω‐3 fatty acids. Animals were subsequently tested for acute EtOH sensitivity (locomotor activation and sedation), voluntary consumption, and metabolism. Fat deposition was also determined. We found that dietary levels of LCω‐3s altered EtOH sensitivity and consumption in a genotype‐specific manner. Both B6 and D2 animals fed high LCω‐3 diets demonstrated lower EtOH‐induced locomotor stimulation than those fed low LCω‐3 diets. EtOH sedation and EtOH metabolism were greater in D2, but not B6 mice on the high LCω‐3 diet. Conversely, LCω‐3 dietary manipulation altered EtOH consumption in B6, but not in D2 mice. B6 mice on a high LCω‐3 diet consumed more EtOH in a 2‐bottle choice intermittent access model than B6 mice on a low LCω‐3 diet. Because EtOH sensitivity is predictive of risk of developing AUDin humans, our data indicate that dietary LCω‐3 levels should be evaluated for their impact on AUDrisk in humans. Further, these studies indicate that genetic background can interact with fatty acids in the diet to significantly alter EtOH‐responsive behaviors. ω‐3 levels are strongly modulated by diet, and there is wide variation in ω‐3 levels in humans. We fed C57BL/6J (B6) and DBA/2J (D2) mice diets that differed in their levels of ω‐3 fatty acids. Dietary ω‐3 fatty acids modified acute ethanol sensitivity of both strains and modulated ethanol drinking in B6. The genetic background could interact with diet to modify these effects. These data point to the importance of diet as an environmental influence on physiological responses to ethanol.
- Published
- 2018
- Full Text
- View/download PDF
12. Stimulation of diuresis and natriuresis by renomedullary infusion of a dual inhibitor of fatty acid amide hydrolase and monoacylglycerol lipase
- Author
-
Ahmad, Ashfaq, Daneva, Zdravka, Li, Guangbi, Dempsey, Sara K., Li, Ningjun, Poklis, Justin L., Lichtman, Aron, Li, Pin-Lan, and Ritter, Joseph K.
- Abstract
The renal medulla, considered critical for the regulation of salt and water balance and long-term blood pressure control, is enriched in anandamide and two of its major metabolizing enzymes, cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH). Infusion of anandamide (15, 30, and 60 nmol·min−1·kg−1) into the renal medulla of C57BL/6J mice stimulated diuresis and salt excretion in a COX-2- but not COX-1-dependent manner. To determine whether endogenous endocannabinoids in the renal medulla can elicit similar effects, the effects of intramedullary isopropyl dodecyl fluorophosphate (IDFP), which inhibits the two major endocannabinoid hydrolases, were studied. IDFP treatment increased the urine formation rate and sodium excretion in a COX-2- but not COX-1-dependent manner. Neither anandamide nor IDFP affected the glomerular filtration rate. Neither systemic (0.625 mg·kg−1·30 min−1iv) nor intramedullary (15 nmol·min−1·kg−1·30 min−1) IDFP pretreatment before intramedullary anandamide (15–30 nmol·min−1·kg−1) strictly blocked effects of anandamide, suggesting that hydrolysis of anandamide was not necessary for its diuretic effect. Intramedullary IDFP had no effect on renal blood flow but stimulated renal medullary blood flow. The effects of IDFP on urine flow rate and medullary blood flow were FAAH-dependent as demonstrated using FAAH knockout mice. Analysis of mouse urinary PGE2concentrations by HPLC-electrospray ionization tandem mass spectrometry showed that IDFP treatment decreased urinary PGE2. These data are consistent with a role of FAAH and endogenous anandamide acting through a COX-2-dependent metabolite to regulate diuresis and salt excretion in the mouse kidney.
- Published
- 2017
- Full Text
- View/download PDF
13. Effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in male rhesus monkeys.
- Author
-
Schwienteck, Kathryn L, Negus, S Stevens, Poklis, Justin L, and Banks, Matthew L
- Published
- 2015
- Full Text
- View/download PDF
14. A determination of the aerosolization efficiency of drugs of abuse in a eutectic mixture with nicotine in electronic cigarettes
- Author
-
Reveil, Laerissa, Pearcy, Adam C., Povlick, Jazmine, Poklis, Justin L., Halquist, Matthew S., and Peace, Michelle R.
- Abstract
Characterize the effects of drug interactions with nicotine in the electronic cigarette (e-cigarette).
- Published
- 2022
- Full Text
- View/download PDF
15. Toxicities Associated With NBOMe Ingestion—A Novel Class of Potent Hallucinogens: A Review of the Literature
- Author
-
Suzuki, Joji, Dekker, Michael A., Valenti, Erin S., Arbelo Cruz, Fabiola A., Correa, Ady M., Poklis, Justin L., and Poklis, Alphonse
- Abstract
A new class of synthetic hallucinogens called NBOMe has emerged as drugs of abuse.
- Published
- 2015
- Full Text
- View/download PDF
16. Cannabinoid Receptor–Interacting Protein 1a Modulates CB1Receptor Signaling and Regulation
- Author
-
Smith, Tricia H., Blume, Lawrence C., Straiker, Alex, Cox, Jordan O., David, Bethany G., McVoy, Julie R. Secor, Sayers, Katherine W., Poklis, Justin L., Abdullah, Rehab A., Egertová, Michaela, Chen, Ching-Kang, Mackie, Ken, Elphick, Maurice R., Howlett, Allyn C., and Selley, Dana E.
- Abstract
Cannabinoid CB1receptors (CB1Rs) mediate the presynaptic effects of endocannabinoids in the central nervous system (CNS) and most behavioral effects of exogenous cannabinoids. Cannabinoid receptor–interacting protein 1a (CRIP1a) binds to the CB1R C-terminus and can attenuate constitutive CB1R-mediated inhibition of Ca2+channel activity. We now demonstrate cellular colocalization of CRIP1aat neuronal elements in the CNS and show that CRIP1ainhibits both constitutive and agonist-stimulated CB1R-mediated guanine nucleotide–binding regulatory protein (G-protein) activity. Stable overexpression of CRIP1ain human embryonic kidney (HEK)-293 cells stably expressing CB1Rs (CB1-HEK), or in N18TG2 cells endogenously expressing CB1Rs, decreased CB1R-mediated G-protein activation (measured by agonist-stimulated [35S]GTPγS (guanylyl-5′-[O-thio]-triphosphate) binding) in both cell lines and attenuated inverse agonism by rimonabant in CB1-HEK cells. Conversely, small-interfering RNA–mediated knockdown of CRIP1ain N18TG2 cells enhanced CB1R-mediated G-protein activation. These effects were not attributable to differences in CB1R expression or endocannabinoid tone because CB1R levels did not differ between cell lines varying in CRIP1aexpression, and endocannabinoid levels were undetectable (CB1-HEK) or unchanged (N18TG2) by CRIP1aoverexpression. In CB1-HEK cells, 4-hour pretreatment with cannabinoid agonists downregulated CB1Rs and desensitized agonist-stimulated [35S]GTPγS binding. CRIP1aoverexpression attenuated CB1R downregulation without altering CB1R desensitization. Finally, in cultured autaptic hippocampal neurons, CRIP1aoverexpression attenuated both depolarization-induced suppression of excitation and inhibition of excitatory synaptic activity induced by exogenous application of cannabinoid but not by adenosine A1 agonists. These results confirm that CRIP1ainhibits constitutive CB1R activity and demonstrate that CRIP1acan also inhibit agonist-stimulated CB1R signaling and downregulation of CB1Rs. Thus, CRIP1aappears to act as a broad negative regulator of CB1R function.
- Published
- 2015
- Full Text
- View/download PDF
17. Effects of the fatty acid amide hydrolase inhibitor URB597 on pain-stimulated and pain-depressed behavior in rats
- Author
-
Kwilasz, Andrew J., Abdullah, Rehab A., Poklis, Justin L., Lichtman, Aron H., and Negus, Sidney S.
- Abstract
Cannabinoid receptor (CBR) agonists produce antinociception in conventional preclinical assays of pain-stimulated behavior but are not effective in preclinical assays of pain-depressed behavior. Fatty acid amide hydrolase (FAAH) inhibitors increase physiological levels of the endocannabinoid anandamide, which may confer improved efficacy and safety relative to direct CBR agonists. To further evaluate FAAH inhibitors as candidate analgesics, this study assessed the effects of the FAAH inhibitor URB597 in assays of acute pain-stimulated and pain-depressed behavior in male Sprague–Dawley rats. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response or depress positively reinforced operant behavior (intracranial self-stimulation), and URB597 was tested 1 and 4 h after administration. Consistent with FAAH inhibitor effects in other assays of pain-stimulated behavior, URB597 (1–10 mgkg intraperitoneally) produced dose-related and CB1R-mediated decreases in acid-stimulated stretching. Conversely, in the assay of acid-depressed intracranial self-stimulation, URB597 produced a delayed, partial and non-CBR-mediated antinociceptive effect. The antinociceptive dose of URB597 (10 mgkg) increased plasma and brain anandamide levels. These results suggest that URB597 produces antinociception in these models of ‘pain stimulated’ and ‘pain depressed’ behavior, but with different rates of onset and differential involvement of CBRs.
- Published
- 2014
- Full Text
- View/download PDF
18. Production and actions of the anandamide metabolite prostamide E2 in the renal medulla.
- Author
-
Ritter, Joseph K, Li, Cao, Xia, Min, Poklis, Justin L, Lichtman, Aron H, Abdullah, Rehab A, Dewey, William L, and Li, Pin-Lan
- Abstract
Medullipin has been proposed to be an antihypertensive lipid hormone released from the renal medulla in response to increased arterial pressure and renal medullary blood flow. Because anandamide (AEA) possesses characteristics of this purported hormone, the present study tested the hypothesis that AEA or one of its metabolites represents medullipin. AEA was demonstrated to be enriched in the kidney medulla compared with cortex. Western blotting and enzymatic analyses of renal cortical and medullary microsomes revealed opposite patterns of enrichment of two AEA-metabolizing enzymes, with fatty acid amide hydrolase higher in the renal cortex and cyclooxygenase-2 (COX-2) higher in the renal medulla. In COX-2 reactions with renal medullary microsomes, prostamide E2, the ethanolamide of prostaglandin E₂, was the major product detected. Intramedullarily infused AEA dose-dependently increased urine volume and sodium and potassium excretion (15-60 nmol/kg/min) but had little effect on mean arterial pressure (MAP). The renal excretory effects of AEA were blocked by intravenous infusion of celecoxib (0.1 μg/kg/min), a selective COX-2 inhibitor, suggesting the involvement of a prostamide intermediate. Plasma kinetic analysis revealed longer elimination half-lives for AEA and prostamide E2 compared with prostaglandin E₂. Intravenous prostamide E2 reduced MAP and increased renal blood flow (RBF), actions opposite to those of angiotensin II. Coinfusion of prostamide E2 inhibited angiotensin II effects on MAP and RBF. These results suggest that AEA and/or its prostamide metabolites in the renal medulla may represent medullipin and function as a regulator of body fluid and MAP.
- Published
- 2012
- Full Text
- View/download PDF
19. Acid Sphingomyelinase Gene Deficiency Ameliorates the Hyperhomocysteinemia-Induced Glomerular Injury in Mice
- Author
-
Boini, Krishna M., Xia, Min, Li, Caixia, Zhang, Chun, Payne, Lori P., Abais, Justine M., Poklis, Justin L., Hylemon, Philip B., and Li, Pin-Lan
- Abstract
Hyperhomocysteinemia (hHcys) enhances ceramide production, leading to the activation of NADPH oxidase and consequent glomerular oxidative stress and sclerosis. The present study was performed to determine whether acid sphingomyelinase (Asm), a ceramide-producing enzyme, is implicated in the development of hHcys-induced glomerular oxidative stress and injury. Uninephrectomized Asm-knockout (Asm−/−) and wild-type (Asm+/+) mice, with or without Asm short hairpin RNA (shRNA) transfection, were fed a folate-free (FF) diet for 8 weeks, which significantly elevated the plasma Hcys level compared with mice fed normal chow. By using in vivomolecular imaging, we found that transfected shRNAs were expressed in the renal cortex starting on day 3 and continued for 24 days. The FF diet significantly increased renal ceramide production, Asm mRNA and activity, urinary total protein and albumin excretion, glomerular damage index, and NADPH-dependent superoxide production in the renal cortex from Asm+/+mice compared with that from Asm−/−or Asm shRNA-transfected wild-type mice. Immunofluorescence analysis showed that the FF diet decreased the expression of podocin but increased desmin and ceramide levels in glomeruli from Asm+/+mice but not in those from Asm−/−and Asm shRNA-transfected wild-type mice. In conclusion, our observations reveal that Asm plays a pivotal role in mediating podocyte injury and glomerular sclerosis associated with NADPH oxidase–associated local oxidative stress during hHcys.
- Published
- 2011
- Full Text
- View/download PDF
20. Role of sphingolipid mediator ceramide in obesity and renal injury in mice fed a high-fat diet.
- Author
-
Boini, Krishna M, Zhang, Chun, Xia, Min, Poklis, Justin L, and Li, Pin-Lan
- Abstract
The present study tested a hypothesis that excess accumulation of sphingolipid, ceramide, its metabolites, or a combination contributes to the development of obesity and associated kidney damage. Liquid chromatography/mass spectrometry analysis demonstrated that C57BL/6J mice on the high-fat diet (HFD) had significantly increased plasma total ceramide levels compared with animals fed a low-fat diet (LFD). Treatment of mice with the acid sphingomyelinase (ASMase) inhibitor amitriptyline significantly attenuated the HFD-induced plasma ceramide levels. Corresponding to increase in plasma ceramide, the HFD significantly increased the body weight gain, plasma leptin concentration, urinary total protein and albumin excretion, glomerular damage index, and adipose tissue ASMase activity compared with the LFD-fed mice. These HFD-induced changes were also significantly attenuated by treatment of mice with amitriptyline. In addition, the decline of plasma glucose concentration after an intraperitoneal injection of insulin (0.15 U/kg b.wt.) was more sustained in mice on the HFD with amitriptyline than on the HFD alone. Intraperitoneal injection of glucose (3 g/kg b.wt.) resulted in a slow increase followed by a rapid decrease in the plasma glucose concentration in LFD and HFD plus amitriptyline-treated mice, but such blood glucose response was not observed in HFD-fed mice. Immunofluorescence analysis demonstrated a decrease in the podocin and an increase in the desmin in the glomeruli of HFD-fed mice compared with the LFD and HFD plus amitriptyline-treated mice. In conclusion, our results reveal a pivotal role for ceramide biosynthesis in obesity, metabolic syndrome, and associated kidney damage.
- Published
- 2010
- Full Text
- View/download PDF
21. High performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for detection and quantification of select NLRP3 inhibitors from brain tissue
- Author
-
Boice, Ashley G., Poklis, Justin L., Guo, Chunqing, Wang, Xiang-Yang, Zhang, Shijun, and Halquist, Matt S.
- Abstract
The NLRP3 inflammasome is an essential component of the innate immune system and has been implicated in neurodegenerative and inflammatory disorders. Therefore, there is increasing interest to develop inhibitors of the NLRP3 inflammasome to achieve disease intervention. Recently, we have developed a series of sulfonamide-based NLRP3 inhibitors as potential treatments for neurodegenerative diseases. One of the challenges for CNS therapeutics is blood-brain barrier penetration. Therefore, a method to detect and compare the blood-brain barrier penetration of these inhibitors is required but has not yet been established. In this study, we established a method to evaluate and quantify the blood-brain barrier penetration of JC-171, one of our lead NLRP3 inhibitors in comparison with MCC950, another known urea-based NLRP3 inhibitor using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method. The results suggest that this methodology has the ability to provide reliable measurements for brain exposure.
- Published
- 2021
- Full Text
- View/download PDF
22. Beware of blotting paper hallucinogens: severe toxicity with NBOMes.
- Author
-
Isbister, Geoffrey K., Poklis, Alphonse, Poklis, Justin L., and Grice, Jeffrey
- Abstract
The article presents a case study of the toxicity of dimethoxyphenyl-N-[(2-methoxyphenyl)methyl] ethanamine derivatives (NBOMes), a novel class of potent synthetic hallucinogens, which became available as recreational drugs. It cites the case of a 16-year-old male presented to the emergency department after ingesting what he believed to be LSD (lysergic acid diethylamide) on red blotting paper. It reminds clinicians to be aware of NBOMes, which can cause prolonged agitation and hallucinations.
- Published
- 2015
- Full Text
- View/download PDF
23. Disposition of Valproic Acid in a Case of Fatal Intoxication
- Author
-
Poklis, Alphonse, Poklis, Justin L., Trautman, Donna, Treece, Chad, Backer, Ronald, and Harvey, Charles M.
- Abstract
The case history and toxicological findings of a fatal suicidal valproic acid overdose are presented. Valproic acid concentrations were determined in body tissues and fluids by gas-liquid chromatography (GLC) following both direct extraction and the method of standards addition and quantitative fluorescence polarization immunoassay. The quantitative results obtained by the three procedures were in good agreement. Qualitative identification of valproic acid as its methylated derivative was by ion-trap gas chromatography-mass spectrometry. Toxicological analysis by direct extraction GLC yielded the following valproate concentrations (mg/mL or mg/kg): blood, 1050; bile, 713; brain, 510; heart, 670; kidney, 1580; liver, 985; and vitreous, 516. A total of 15.1 g of valproate was recovered in the stomach contents. These findings far exceed those associated with valproate therapy and are similar to the limited valproate disposition data reported in prior fatal overdoses.
- Published
- 1998
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.