Rxivist logo

Rxivist combines biology preprints from bioRxiv and medRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 128,741 papers from 551,614 authors.

Most downloaded biology preprints, all time

in category pharmacology and toxicology

1,135 results found. For more information, click each entry to expand.

1021: Improved bioavailability of montelukast through a novel oral mucoadhesive film in humans and mice
more details view paper

Posted 08 Nov 2020

Improved bioavailability of montelukast through a novel oral mucoadhesive film in humans and mice
95 downloads bioRxiv pharmacology and toxicology

Johanna Michael, Diana Marisa de Sousa, Justin Conway, Erick Gonzalez-Labrada, Rodolphe Obeid, Julia Tevini, Thomas Felder, Birgt Hutter-Paier, Horst Zerbe, Nadine Paiement, Ludwig Aigner

The leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low and non-responders in the population. Besides that, tablets are suboptimal formulations for patients suffering of dysphagia, for example seen in COVID19 patients or in patients with neurodegenerative diseases such as Alzheimers Disease. The increasing interest in repurposing of MTK for the treatment of such patients and the need for an improved bioavailability triggered us to reformulate MTK. The aim was to develop a mucoadhesive MTK film with a good safety and improved pharmacological, i.e. improved bioavailability, profile in humans as well as in a mouse model of Alzheimers Disease. We tested dissolution of the mucoadhesive film containing MTK in saliva buffer and assessed pharmacoexposure and kinetics after acute and chronic oral application in mice. Furthermore, we performed a Phase I safety / bioavailability / pharmacokinetic analysis in healthy volunteers. The latter included a comparison with the marketed tablet form as well as a quantitative analysis of the MTK levels in the cerebrospinal fluid. The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical phase 1a study in healthy humans. Furthermore, there were measurable amounts of MTK present in the cerebrospinal fluid (CSF) at the 3.0 and 7.0 hour time points post drug administration in humans. In mice, MTK was detected in serum and CSF after acute and chronic exposure in a dose dependent manner. The developed mucoadhesive film of MTK represents a promising alternative for the tablet delivery. The oral film might lower the non-responder rate in patients with asthma and might be an interesting product for repurposing of MTK in other diseases. As we demonstrate BBB penetrance in a preclinical model as well as in a clinical study, the oral film of MTK might find its use as a therapeutic for acute and chronic neurodegenerative diseases such as dementias and stroke. ### Competing Interest Statement Justin Conway, Erick Gonzales-Labrada, Rodolphe Obeid, Horst Zerbe, Nadine Paiement are from IntelgenX, who has filed patent applications on the MTK film and its use. Ludwig Aigner is consultant at IntelgenX.

1022: ExHuMId: A curated resource and analysis of Exposome of Human Milk across India
more details view paper

Posted 08 Nov 2020

ExHuMId: A curated resource and analysis of Exposome of Human Milk across India
94 downloads bioRxiv pharmacology and toxicology

Bagavathy Shanmugam Karthikeyan, Janani Ravichandran, S.R. Aparna, Areejit Samal

Human milk is a vital source of nourishment for infants, containing nutrients, immunoprotective components, and bioactive substances. However, several environmental contaminants find their way into human milk. Although lactation physiology has been well documented, the effect of human milk contaminants on maternal and infant health remains unclear. Human milk is the major route of contaminant exposure to infants; these contaminants and their effects can themselves be considered an exposome. While there are chemical regulations in India and scientific literature on environmental contaminants is available, yet there is a lack of systematic compilation, monitoring, and risk management of human milk contaminants. We have harnessed the potential of this large body of literature to develop the Exposome of Human Milk across India (ExHuMId) containing detailed information on 101 environmental contaminants detected in human milk samples, studied across 13 Indian states, compiled from 36 research articles. ExHuMId also compiles the detected concentrations of the contaminants, structural and physicochemical properties, and factors associated with the donor of the sample. Here, we also present findings from a three-pronged analysis of ExHuMId and two other resources on human milk contaminants, with a focus on the Indian scenario. Through a comparative analysis with global chemical regulations and guidelines, we identify human milk contaminants of high concern, such as potential carcinogens, endocrine disruptors and neurotoxins. We then study the physicochemical properties of the contaminants to gain insights on their propensity to transfer into human milk. Further, we employ a systems biology approach to shed light on potential effects of human milk contaminants on maternal and infant health, by identifying contaminant-gene interactions associated with lactation, cytokine signalling and production, and protein-mediated transport. ExHuMId is accessible online at: https://cb.imsc.res.in/exhumid/. ### Competing Interest Statement The authors have declared no competing interest.

1023: Hexarelin exerts neuroprotective and antioxidant effects against hydrogen peroxide-induced toxicity through the modulation of MAPK and PI3K/Akt patways in Neuro-2A cells.
more details view paper

Posted 16 Nov 2020

Hexarelin exerts neuroprotective and antioxidant effects against hydrogen peroxide-induced toxicity through the modulation of MAPK and PI3K/Akt patways in Neuro-2A cells.
94 downloads bioRxiv pharmacology and toxicology

Ramona Meanti, Laura Rizzi, Elena Bresciani, Laura Molteni, Vittorio Locatelli, Silvia Coco, Robert John Omeljaniuk, Antonio Torsello

Hexarelin, a synthetic hexapeptide, protects cardiac and skeletal muscles by inhibiting apoptosis, both in vitro and in vivo . Moreover, evidence suggests that hexarelin could have important neuroprotective bioactivity. Oxidative stress and the generation of free radicals has been implicated in the etiologies of several neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and multiple sclerosis. In addition to direct oxidative stress, exogenous hydrogen peroxide (H 2 O 2 ) can penetrate biological membranes and enhance the formation of other reactive oxygen species. The aim of this study was to examine the inhibitory influence of hexarelin on H 2 O 2 ?induced apoptosis in Neuro-2A cells, a mouse neuroblastoma cell line. Our results indicate that H 2 O 2 reduced the viability of Neuro-2A cells in a dose-related fashion. Furthermore, H 2 O 2 induced significant changes in the morphology of Neuro-2A cells, reflected in the formation of apoptotic cell bodies, and an increase of nitric oxide (NO) production. Hexarelin effectively antagonized H 2 O 2 oxidative damage to Neuro-2A cells as indicated by improved cell viability, normal morphology and reduced nitrite (NO 2 - ) release. Hexarelin treatment of Neuro-2A cells also reduced mRNA levels of caspases-3 and -7 and those of the pro-apoptotic molecule Bax; by contrast, hexarelin treatment increased anti-apoptotic Bcl-2 mRNA levels. Hexarelin also reduced MAPKs phosphorylation induced by H 2 O 2 and concurrently increased p-Akt protein expression. In conclusion, our results identify several neuroprotective and anti-apoptotic effects of hexarelin. These properties suggest that further investigation of hexarelin as a neuroprotective agent in an investigational and therapeutic context are merited.

1024: Acetylation of L-leucine switches its carrier from the L-amino acid transporter (LAT) to organic anion transporters (OAT)
more details view paper

Posted 13 Nov 2020

Acetylation of L-leucine switches its carrier from the L-amino acid transporter (LAT) to organic anion transporters (OAT)
94 downloads bioRxiv pharmacology and toxicology

G.C. Churchill, Michael Strupp, Tatiana Bremova-Ertl, Mallory Factor, M. Patterson, F.M. Platt, A. Galione

N-acetyl-DL-leucine is an analogue of the alpha amino acid leucine with a chiral stereocenter. The active L-enantiomer of the racemate is currently under development for rare neurological disorders. Here we present evidence that a selective recognition of N-acetyl-L-leucine versus L-leucine by different uptake transporters significantly contributes to the therapeutic effects of N-acetyl-L-leucine. A previous study of the pharmacokinetics of racemic N-acetyl-DL-leucine and N-acetyl-L-leucine revealed D-L enantiomer competition and saturation kinetics, best explained by carrier-mediated uptake. The strategy we used was to first analyze the physicochemical properties associated with good oral bioavailable drugs and how these are alerted by N-acetylation by comparing N-acetyl-L-leucine with L-leucine. Using in silico computational chemistry we found that N-acetylation has a profound impact on certain physicochemical properties that can rationalize why N-acetyl-L-leucine is drug-like compared to L-leucine. Our calculations show that at physiological pH, L-leucine is a zwitterion, whereas N-acetyl-L-leucine is present as mainly an anion. Specifically, N-acetylation removes a charge from the nitrogen at physiological pH and N-acetyl-L-leucine is an anion that is then a substrate for the organic anion transporters. We examined N-acetyl-L-leucine uptake in human embryonic kidney cells overexpression candidate organic anion transporters (OAT) and pharmacological inhibitors. We found that N-acetyl-L-leucine is a translocated substrate for OAT1 and OAT3 with low affinity (Km ~10 mM). In contrast, L-leucine is known to be transported by the L-type Amino Acid Transporter (LAT) with high affinity (Km ~0.2 mM) and low capacity. The clinical consequence is that L-leucine uptake becomes saturated at 50-fold lower concentration than N-acetyl-L-leucine. These results demonstrate a mechanism of action that explains why N-acetyl-L-leucine is effective as a drug and L-leucine itself is not. ### Competing Interest Statement GCC is a cofounder, shareholder and consultant to IntraBio. MS is a shareholder to IntraBio, and consultant for Abbott, Actelion, AurisMedical, Heel, IntraBio and Sensorion; he has received speaker's honoraria from Abbott, Actelion, Auris Medical, Biogen, Eisai, Grunenthal, GSK, Henning Pharma, Interacoustics, Johnson & Johnson, MSD, Otometrics, Pierre-Fabre, TEVA, UCB. TBE received honoraria for lecturing from Actelion and Sanofi Genzyme. MF is a co-founder, shareholder, and Chairman of IntraBio. MCP is a shareholder of IntraBio, and has received consulting fees, honoraria and research grants from Actelion Pharmaceuticals Ltd. and Biomarin. FMP is a cofounder, shareholder, and consultant to IntraBio and consultant to Actelion and Orphazyme. AG is a cofounder, shareholder and consultant to IntraBio. IntraBio owns patents EP3359146 and EP3416631 (related to treatment of lysosomal storage disorders and neurodegenerative diseases with acetyl-Leucine and its analogues). IntraBio has pending patent applications EP19174007.5, EP3482754, PCT/US2018/056420, PCT/US2018/018420, PCT/IB2018/054676, PCT/IB2019/051214, PCT/IB2017/054928, PCT/GB2017/051090, PCT/IB2017/054929, USPTO 62/812,987, USPTO 62/842,296, USPTO 62/888,894, USPTO 62/895,144, USPTO 62/868,383, USPTO 62/931,003, USPTO 62/960,637, and PCT/IB2019/060525 relating to treatment of lysosomal storage disorders, neurodegenerative diseases and neurodegeneration with acetyl-leucine and its analogues.

1025: Modulation of Recombinant Human T-type calcium Channels by Δ9-tetrahydrocannabinolic acid in vitro
more details view paper

Posted 11 Oct 2020

Modulation of Recombinant Human T-type calcium Channels by Δ9-tetrahydrocannabinolic acid in vitro
94 downloads bioRxiv pharmacology and toxicology

Somayeh Mirlohi, Chris Bladen, Marina Santiago, Mark Connor

Introduction: Low voltage-activated T-type calcium channels (T-type I Ca), CaV3.1, CaV3.2, and CaV3.3 are opened by small depolarizations from the resting membrane potential in many cells and have been associated with neurological disorders including absence epilepsy and pain. Δ9-tetrahydrocannabinol (THC) is the principal psychoactive compound in Cannabis and also directly modulates T-type I Ca , however, there is no information about functional activity of most phytocannabinoids on T-type I Ca, including Δ9-tetrahydrocannabinol acid (THCA), the natural non-psychoactive precursor of THC. The aim of this work was to characterize THCA effects on T-type I Ca . Materials and Methods: We used HEK293 Flp-In-TREx cells stably expressing CaV3.1, 3.2 or 3.3. Whole-cell patch clamp recordings were made to investigate cannabinoid modulation of I Ca . Results: THCA and THC inhibited the peak current amplitude CaV3.1 with a pEC50s of 6.0 ± 0.7 and 5.6 ± 0.4, respectively. 1 μM THCA or THC produced a significant negative shift in half activation and inactivation of CaV3.1 and both drugs prolonged CaV3.1 deactivation kinetics. THCA (10 μM) inhibited CaV3.2 by 53% ± 4 and both THCA and THC produced a substantial negative shift in the voltage for half inactivation and modest negative shift in half activation of CaV3.2. THC prolonged the deactivation time of CaV3.2 while THCA did not. THCA inhibited the peak current of CaV3.3 by 43% ± 2 (10μM) but did not notably affect CaV3.3 channel activation or inactivation, however, THC caused significant hyperpolarizing shift in CaV3.3 steady state inactivation. Discussion: THCA modulated T-type I Ca currents in vitro, with significant modulation of kinetics and voltage dependence at low μM concentrations. This study suggests that THCA may have potential for therapeutic use in pain and epilepsy via T-type channel modulation without the unwanted psychoactive effects associated with THC ### Competing Interest Statement The authors have declared no competing interest.

1026: Estimating daily intakes of manganese due to breast milk, infant formulas, or young child nutritional beverages in the United States and France: Comparison to sufficiency and toxicity thresholds
more details view paper

Posted 11 Jun 2020

Estimating daily intakes of manganese due to breast milk, infant formulas, or young child nutritional beverages in the United States and France: Comparison to sufficiency and toxicity thresholds
94 downloads bioRxiv pharmacology and toxicology

Erika J. Mitchell, Seth H. Frisbie, Stéphane Roudeau, Asuncion Carmona, Richard Ortega

Background: Although manganese (Mn) is an essential nutrient, recent research has revealed that excess Mn in early childhood may have adverse effects on neurodevelopment. Methods: We estimated daily total Mn intake due to breast milk at average body weights by reviewing reported concentrations of breast milk Mn and measurements of body weight and breast milk intake at 3 weeks, 4.25 months, 7 months, and 18 months. We compared these figures to the Mn content measured in 44 infant, follow-up, and toddler formulas purchased in the United States and France. We calculated Mn content of formula products made with ultra-trace elemental analysis grade water (0 μg Mn/L) and with water containing 250 μg Mn/L, a concentration which is relatively high but less than the World Health Organization Health-based value of 400 μg Mn/L or the United States Environmental Protection Agency Health Advisory of 350 μg Mn/L. Results: Estimated mean daily Mn intake from breast milk ranged from 1.2 μg Mn/kg/day (3 weeks) to 0.16 μg Mn/kg/day (18 months), with the highest intakes at the youngest age stage we considered, 3 weeks. Estimated daily Mn intake from formula products reconstituted with 0 μg Mn/L water ranged from 130 μg Mn/kg/day (3 weeks) to 4.8 μg Mn/kg/day (18 months) with the highest intakes at 3 weeks. Formula products provided 28 to 520 times greater than the mean daily intake of Mn from breast milk for the 4 age stages that we considered. Estimated daily Mn intake from formula products reconstituted with water containing 250 μg Mn/L ranged from 12 μg Mn/kg/day to 170 μg Mn/kg/day, which exceeds the United States Environmental Protection Agency Reference Dose of 140 μg Mn/kg/day for adults. Conclusions: Mn deficiency is highly unlikely with exclusive breast milk or infant formula feeding, but established tolerable daily intake levels for Mn may be surpassed by some of these products when following labeled instructions. ### Competing Interest Statement The authors have declared no competing interest.

1027: Neuroprotective mechanisms of red clover and soy isoflavones in Parkinson's disease models
more details view paper

Posted 02 Dec 2020

Neuroprotective mechanisms of red clover and soy isoflavones in Parkinson's disease models
94 downloads bioRxiv pharmacology and toxicology

Aurélie de Rus Jacquet, Abeje Ambaw, Mitali Arun Tambe, Sin Ying Ma, Michael Timmers, Qing-Li Wu, James E Simon, George P McCabe, Mary Ann Lila, Riyi Shi, Jean-Christophe Rochet

Parkinsons disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration and the spreading of aggregated forms of the presynaptic protein -synuclein (aSyn) throughout the brain. PD patients are currently only treated with symptomatic therapies, and strategies to slow or stop the progressive neurodegeneration underlying the diseases motor and cognitive symptoms are greatly needed. The time between the first neurobiochemical alterations and the initial presentation of symptoms is thought to span several years, and early neuroprotective dietary interventions could delay the disease onset or slow PD progression. This study aimed at characterizing the neuroprotective effects of isoflavones, a class of dietary polyphenols found in soy products and in the medicinal plant red clover (Trifolium pratense). We found that isoflavone-rich extracts and individual isoflavones rescued the loss of dopaminergic neurons and the shortening of neurites in primary mesencephalic cultures exposed to two PD-related insults, the environmental toxin rotenone and an adenovirus encoding the A53T aSyn mutant. The extracts and individual isoflavones also activated the Nrf2-mediated antioxidant response in astrocytes via a mechanism involving inhibition of the ubiquitin-proteasome system, and they alleviated deficits in mitochondrial respiration. Furthermore, an isoflavone-enriched soy extract reduced motor dysfunction exhibited by rats lesioned with the PD-related neurotoxin 6-OHDA. These findings suggest that plant-derived isoflavones could serve as dietary supplements to delay PD onset in at-risk individuals and mitigate neurodegeneration in the brains of patients.

1028: Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib isdriven by off-target Ferrochelatase inhibition
more details view paper

Posted 31 Jan 2021

Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib isdriven by off-target Ferrochelatase inhibition
94 downloads bioRxiv pharmacology and toxicology

Yuntao Bai, Ji Young Kim, Laura A Jayne, Megha Gandhi, Kevin M Huang, Josie A Silvaroli, Veronika Sander, Jason Prosek, Kenar D Jhaveri, Sharyn D Baker, Alex Sparreboom, Amandeep Bajwa, Navjot Singh Pabla

A multitude of disease and therapy related factors drive the frequent development of renal disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause renal dysfunction through on and off-target mechanisms. Interestingly, among the small molecule inhibitors approved for the treatment of cancers that harbor BRAF-kinase activating mutations, vemurafenib can trigger tubular damage and acute kidney injury (AKI). To investigate the underlying mechanisms, here, we have developed cell culture and mouse models of vemurafenib nephrotoxicity. Our studies show that at clinically relevant concentrations vemurafenib induces cell-death in transformed and primary murine and human renal tubular epithelial cells (RTEC). In mice, two weeks of daily vemurafenib treatment causes moderate AKI with histopathological characteristics of RTEC injury. Importantly, RTEC-specific BRAF gene deletion did not influence renal function under normal conditions or alter the severity of vemurafenib-associated renal impairment. Instead, we found that inhibition of ferrochelatase (FECH), an enzyme involved in heme biosynthesis contributes to vemurafenib nephrotoxicity. FECH overexpression protected RTECs and conversely FECH knockdown increased the sensitivity to vemurafenib nephrotoxicity. Collectively, these studies suggest that vemurafenibassociated RTEC dysfunction and nephrotoxicity is BRAF-independent and caused in part by offtarget FECH inhibition.

1029: Protective Effects of Edaravone Against Hypoxia-Induced Lethality in Mice
more details view paper

Posted 26 May 2020

Protective Effects of Edaravone Against Hypoxia-Induced Lethality in Mice
93 downloads bioRxiv pharmacology and toxicology

Fatemeh Shaki, Mina Mokhtaran, Amir Shamshirian, Shahram Eslami, Danial Shamshirian, Mohammad Ali Ebrahimzadeh

Edaravone is used for the treatment of acute cerebral infarction in Japan. However, nothing is known about the protective effects of this drug against hypoxia-induced lethality. In this study, the protective effects of edaravone against hypoxia-induced lethality and oxidative stress in mice were evaluated by three experimental models of hypoxia, which are asphyctic, haemic, and circulatory. Statistically significant protective activities were established in all tested models of hypoxia. Antihypoxic activities were especially pronounced in asphytic and circulatory hypoxia. The effect was dose-dependent. Edaravone, at 5 mg kg-1, showed statistically significant activities respect to the control groups. It significantly prolonged the latency for death. At 2.5 mg kg-1, it also prolonged survival time (26.08 +/- 5.26 min), but this effect was not statistically significant from the control (P>0.05). On the other hand, edaravone significantly inhibited hypoxia-induced oxidative stress (lipid peroxidation and glutathione oxidation) in three models of hypoxia. In conclusion, the results obtained in this study showed that Edaravone has very good protective effects against the hypoxia in all tested models. ### Competing Interest Statement The authors have declared no competing interest.

1030: Immunosuppressive effect of the Fusarium secondary metabolite butenolide in human colon epithelial cells.
more details view paper

Posted 18 Apr 2020

Immunosuppressive effect of the Fusarium secondary metabolite butenolide in human colon epithelial cells.
93 downloads bioRxiv pharmacology and toxicology

Lydia Woelflingseder, Gerhard Adam, Doris Marko

Butenolide (BUT, 4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is a secondary metabolite produced by several Fusarium species and is co-produced with the major trichothecene mycotoxin deoxynivalenol (DON) on cereal grains throughout the world. BUT has low acute toxicity and only very limited occurrence and exposure data are available. The intestinal epithelium represents the first physiological barrier against food contaminants. We aimed to elucidate the intestinal inflammatory response of the human, non cancer epithelial HCEC-1CT cells to BUT and to characterize potential combinatory interactions with co-occurring trichothecenes, such as DON and NX-3. Using a reporter gene approach, BUT (≥5 μM, 20 h) was found to decrease lipopolysaccharide (LPS; 10 ng/mL) induced nuclear factor kappa B (NF-κB) activation in a dose-dependent manner, and in combinatory treatments represses trichothecene-induced enhancement of this important inflammatory pathway. Analyzing transcription and secretion levels of NF-κB-dependent, pro-inflammatory cytokines, revealed a significant down-regulation of IL-1β, IL-6 and TNF-α in IL-1β-stimulated (25 ng/mL) HCEC-1CT cells after BUT exposure (10 μM). Trichothecene-induced expression of pro-inflammatory cytokines by the presence of 1 μM DON or NX-3 was substantially suppressed in the presence of 10 μM BUT. The emerging mycotoxin BUT has the ability to suppress NF-κB-induced intestinal inflammatory response mechanisms and to modulate substantially the immune responsiveness of HCEC-1CT cells after trichothecene treatment. Our results suggest that BUT, present in naturally occurring mixtures of Fusarium fungal metabolites, should be increasingly monitored, and the mechanism of inhibition of NF-κB that might affect the pathogenesis or progression of intestinal inflammatory disorders, should be further investigated. ### Competing Interest Statement The authors have declared no competing interest.

1031: Liquid foam therapy (LiFT) for homogenous distribution of exogenous pulmonary surfactant in ARDS
more details view paper

Posted 01 Dec 2020

Liquid foam therapy (LiFT) for homogenous distribution of exogenous pulmonary surfactant in ARDS
93 downloads bioRxiv pharmacology and toxicology

Rami Fishler, Yan Ostrovski, Avital Frenkel, Simon Dorfman, Vera Brod, Tali Haas, Dan Waisman, Josué Sznitman

Lung surfactant dysfunction has a critical role in the pathophysiology of acute respiratory distress syndrome (ARDS). Yet, efforts to treat ARDS patients with liquid instillations of exogenous surfactant have so far failed. One of the ongoing challenges in surfactant therapy is obtaining a homogeneous distribution of surfactant within the lungs despite an inherent tendency to non-uniform spreading, owing amongst others to the influence of gravity. Here, we show that liquid foam therapy (LiFT), where surfactant is foamed prior to intratracheal administration, may improve notably surfactant distribution while maintaining safety and efficacy. We first show quantitatively that a foamed surrogate surfactant solution distributes more uniformly in ex vivo pig lungs compared to endotracheal instillations of the liquid solution, while maintaining pulmonary airway pressures within a safe range. Next, we demonstrate that a foamed commercial surfactant preparation (Infasurf) is effective in an established in vivo rat lung lavage model of ARDS. Our results suggest that LiFT may be more effective than liquid instillations for treating ARDS and serve as a proof-of-principle towards large animal and clinical trials.

1032: Red-beet betalain pigments inhibit amyloid-beta aggregation and prevent the progression of Alzheimer's disease in a Caenorhabditis elegans model
more details view paper

Posted 24 Dec 2020

Red-beet betalain pigments inhibit amyloid-beta aggregation and prevent the progression of Alzheimer's disease in a Caenorhabditis elegans model
93 downloads bioRxiv pharmacology and toxicology

Tomohiro Imamura, Hironori Koga, Yasuki Higashimura, Kenji Matsumoto, Masashi Mori

Betalain pigments are mainly produced by plants in the order Caryophyllales. The biological functions of betalain pigments have gained recent interest; antioxidant, anti-inflammatory, and anticancer activities have been reported. To explore the biological effects of betalain pigments, we investigated the effects of betalain pigments derived from red-beet on amyloid-{beta} (A{beta}) aggregation, which is one of the causes of Alzheimers disease (AD). We conducted a ThT fluorescence assay, which revealed that red-beet betalain extract significantly suppressed the increase in fluorescence derived from A{beta} aggregation compared the control. Observations using transmission electron microscopy confirmed that A{beta} fibers and amorphous aggregation were reduced in the betalain pigment treatment. Furthermore, we performed a trait investigation using a nematode model of AD and found that the progression of symptoms was significantly suppressed in the group that ingested betalain pigment. These results suggest that betalain pigment may suppress the progression of AD.

1033: Super-dosed butyrate induces a revisable metabolic paralysis through transient mitochondrial reprogramming in the gut-brain axis
more details view paper

Posted 26 Dec 2020

Super-dosed butyrate induces a revisable metabolic paralysis through transient mitochondrial reprogramming in the gut-brain axis
92 downloads bioRxiv pharmacology and toxicology

Yanhong Xu, Shiqiao Peng, Xinyu Cao, Shengnan Qian, Shuang Shen, Juntao Luo, Xiaoying Zhang, Hongbin Sun, Wei L. Shen, Weiping Jia, Jianping Ye

Background and purposeSodium butyrate (SB) is a major product of gut microbiota with signaling activity in the human body. However, the toxic effect of SB remains largely unknown. This issue is addressed in current study. Experimental approachSB (0.3 - 2.5 g/kg) was administrated through a single peritoneal injection in mice. The core body temperature and mitochondrial function in the brain hypothalamus were monitored. Pharmacodynamics, targeted metabolomics, electron microscope, oxygen consumption rate and gene knockdown were employed to dissect the mechanism for the toxic effect. Key resultsThe temperature was reduced by SB (1.2 -2.5 g/kg) in a dose-dependent manner in mice for 2-4 hr. In the brain, the effect was associated with SB elevation and neurotransmitter (Glutamate and GABA) reduction. The mitochondria exhibited a transient volume expansion and crista loss in the hypothalamic neurons. ADP/ATP ratio was increased with accumulation of intermediate metabolites in the glycolysis, TCA cycle and pentose phosphate pathways. The mitochondrial protein, adenine nucleotide transporter (ANT), was activated for proton transportation leading to a transient potential collapse by proton leak. The SB activity was attenuated by ANT inhibition from gene knockdown or pharmacological blocker. The temperature drop was attenuated by i.p. injection of norepinephrine. The HDAC inhibitors, such as SAHA and pyruvate, did not exhibit the same effect. Conclusion and implicationsSuper-dosed SB generated an immediate and reversible toxic effect for inhibition of body temperature through transient mitochondrial reprogramming in the brain. The mechanism was quick activation of ANT proteins for the proton leak in mitochondria.

1034: Large-Scale Transcriptional Profiling of Molecular Perturbations Reveals Cell Type Specific Responses and Implications for Environmental Screening
more details view paper

Posted 27 Aug 2020

Large-Scale Transcriptional Profiling of Molecular Perturbations Reveals Cell Type Specific Responses and Implications for Environmental Screening
92 downloads bioRxiv pharmacology and toxicology

Kun Zhang, Yanbin Zhao

Cell-based assays represent nearly half of all high-throughput screens currently conducted for risk assessment of environmental chemicals. However, the sensitivity and heterogeneity among cell lines has long been concerned but explored only in a limited manner. Here, we address this question by conducting a large scale transcriptomic analysis of the responses of discrete cell lines to specific small molecules. Our results illustrate heterogeneity of the extent and timing of responses among cell lines. Interestingly, high sensitivity and/or heterogeneity was found to be cell type-specific or universal depending on the different mechanism of actions of the compounds. Our data provide a novel insight into the understanding of cell-small molecule interactions and have substantial implications for the design, execution and interpretation of high-throughput screening assays. ### Competing Interest Statement The authors have declared no competing interest.

1035: Predicting the Disposition of the Antimalarial Drug Artesunate and its Active Metabolite Dihydroartemisinin Using Physiologically-Based Pharmacokinetic Modeling
more details view paper

Posted 29 Oct 2020

Predicting the Disposition of the Antimalarial Drug Artesunate and its Active Metabolite Dihydroartemisinin Using Physiologically-Based Pharmacokinetic Modeling
91 downloads bioRxiv pharmacology and toxicology

Ryan Arey, Brad Reisfeld

Artemisinin-based combination therapies (ACTs) have proven to be effective in helping to combat the global malaria epidemic. To optimally apply these drugs, information about their tissue-specific disposition is required. Physiologically-based pharmacokinetic (PBPK) modeling is a useful technique for predicting these pharmacokinetic behaviors. In this study, a whole-body PBPK model was developed to simulate the time-dependent tissue concentrations of artesunate (AS) and its active metabolite, dihydroartemisinin (DHA). The model was developed for both rats and humans and incorporated drug metabolism of the parent compound and major metabolite. Model calibration was conducted using data from the literature in a Bayesian framework and model verification was assessed using separate sets of data. Results showed good agreement between model predictions and the validation data, demonstrating the capability of the model in predicting the blood, plasma, and tissue pharmacokinetics of AS and DHA. It is expected that such a tool will be useful in characterizing the disposition of these chemicals and ultimately improve dosing regimens by enabling a quantitative assessment of the tissue-specific drug levels critical in the evaluation of efficacy and toxicity.

1036: Morphological plasticity in Chlamydomonas reinhardtii and acclimation to micropollutant stress
more details view paper

Posted 31 Aug 2020

Morphological plasticity in Chlamydomonas reinhardtii and acclimation to micropollutant stress
91 downloads bioRxiv pharmacology and toxicology

Giulia Cheloni, Vera I. Slaveykova

Phytoplankton are characterized by a great phenotypic plasticity and amazing morphological variability, both playing a primary role in the acclimation to changing environments. However, there is a knowledge gap concerning the role of algal morphological plasticity in stress responses and acclimation to micropollutants. The present study aims examining the palmelloid colony formation of the green alga Chlamydomonas reinhardtii upon micropollutants exposure. Cells were exposed to four micropollutants (MPs) with different modes of action (copper, cadmium, PFOS and paraquat) for a duration of 72h. Effects of MPs on palmelloid formation, growth and physiological traits (chlorophyll fluorescence, membrane integrity and oxidative stress) were monitored via flow cytometry and fluorescence microscopy. Palmelloid formation was observed upon treatment with the four micropollutants. Number of palmelloid colonies and their size were dependent on MP concentration and exposure duration. Cells reverted to their unicellular lifestyle when colonies were harvested and inoculated in fresh medium indicating that palmelloid formation is a plastic response to micropollutants. No physiological effects of these compounds were observed in cells forming palmelloids and palmelloid colonies accumulated lower Cd concentration than unicellular C. reinhardtii suggesting that colony formation protects the cells form MPs exposure. The results show that colony formation in Chlamydomonas reinhardtii is a stress response strategy activated to face sub-lethal micropollutant concentrations. HIGHLIGHTS ### Competing Interest Statement The authors have declared no competing interest. * FCM : flow cytometry MP : micropollutant PFOS : Perfluorooctanesulfonic acid

1037: Ripasudil in a model of pigmentary glaucoma
more details view paper

Posted 05 May 2020

Ripasudil in a model of pigmentary glaucoma
90 downloads bioRxiv pharmacology and toxicology

C. Wang, Y Dang, Susannah Waxman, Y Hong, P Shah, RT Loewen, X Xia, N. A. Loewen

Purpose: To investigate the effects of Ripasudil (K-115), a Rho-kinase inhibitor, in a porcine model of pigmentary glaucoma. Methods: Hallmark features of trabecular meshwork (TM), the principle structure of the outflow system affected in this model, were analyzed. In vitro TM cells and ex vivo perfused eyes were subjected to pigment dispersion followed by K-115 treatment (PK115). PK115 was compared to sham-treated controls (C) and pigment (P). Cytoskeletal alterations were assessed by F-actin labeling. TM cell phagocytosis of fluorescent targets was evaluated by flow cytometry. Cell migration was studied with a wound-healing assay. Intraocular pressure was continuously monitored and compared to after the establishment of the pigmentary glaucoma model and after treatment with K-115. Results: In vitro, the percentage of cells with stress fibers increased in response to pigment but declined sharply after treatment with K-115 (P: 32.8 +/- 2.9%; PK115: 11.6 +/- 3.3%, P < 0.001). Phagocytosis first declined but recovered after K-115 (P: 25.7+/-2.1%, PK115: 33.4+/-0.8%, P <0.01). Migration recuperated at 12h with K-115 treatment (P: 19.1+/-4.6 cells/high-power field, PK115: 42.5+/-1.6 cells/high-power field, P <0.001). Ex vivo, eyes became hypertensive from pigment dispersion but were normotensive after treatment with K-115 (P: 20.3 +/- 1.2 mmHg, PK115: 8.9 +/- 1.7 mmHg; P< 0.005). Conclusion: In vitro, K-115 reduced TM stress fibers, restored phagocytosis, and restored migration of TM cells. Ex vivo, K-115 normalized intraocular pressure. ### Competing Interest Statement The authors have declared no competing interest.

1038: Chemotherapeutic cardiotoxicity is associated with elevated β1-adrenergic receptor density
more details view paper

Posted 18 Sep 2020

Chemotherapeutic cardiotoxicity is associated with elevated β1-adrenergic receptor density
90 downloads bioRxiv pharmacology and toxicology

Manveen K Gupta, Elizabeth E. Martelli, Kate T. Stenson, Sathyamangla V. Naga Prasad

Objective To understand the underlying pathways that promote cardiotoxicity following chemotherapy. Background Anthracyclines are associated with cardiotoxicity which could be potentiated with use of complementary agents (like anti-ERBB2 inhibitors) which together afford robust anti-neoplastic effects. Anthracyclines lead to oxidative stress and thought to induce cardiotoxicity. However, interventions reducing oxidative stress in patients have been unsuccessful suggesting mechanisms beyond oxidative stress. Despite β-adrenergic receptors (βARs) being key regulators of cardiac function, nothing is known about their role in chemotherapy-mediated cardiotoxicity. Methods β1 and/or β2-AR density was assessed in end-stage human heart failure patient samples either due to anthracycline cardiotoxicity or non-anthracycline dilated cardiomyopathy (DCM). Since ERBB2 inhibition is integral to overall chemotherapeutic arsenal, we assessed β1- and/or β2-AR density, cardiac function by echocardiography and immunohistochemistry in mice following ERBB2-specific inhibitor AG825. Results Selective increase in cardiac β1AR density is observed in end-stage human heart failure patient samples due to anthracycline cardiotoxicity as well as in ERBB2 inhibitor-treated mice. Conclusions Elevated β1AR density may be the key common underlying mechanism which is altered in response to chemotherapy promoting cardiac dilation of otherwise healthy hearts. Highlights In contrast to downregulation of β1-adrenergic receptors (β1AR) in end-stage human heart failure, anthracycline cardiotoxicity-mediated failure is associated with selective increase in β1AR density. ERBB2 inhibitor (AG825) treatment in mice results in cardiac dilation and selective rise in β1AR density showing that increased β1AR density in the heart could be a common mechanism underlying cardiotoxicity. ### Competing Interest Statement The authors have declared no competing interest. * EGFR : Epidermal growth factor receptor ERBB2 : Erythroblastic oncogene B DCM : Dilated Cardiomyopathy βAR : beta-adrenergic receptor

1039: Effects of gypenosides on enteroendocrine L-cell function and GLP-1 secretion
more details view paper

Posted 07 Sep 2020

Effects of gypenosides on enteroendocrine L-cell function and GLP-1 secretion
89 downloads bioRxiv pharmacology and toxicology

Chinmai Patibandla, Erin Campbell, Xinhua Shu, Angus M Shaw, Sharron Dolan, Steven Patterson

Glucagon-like peptide 1 (GLP-1) is an incretin hormone produced in gut L-cells, which regulates postprandial glucose-dependent insulin secretion, also known as the incretin effect. GLP-1 secretion may be reduced in type 2 diabetes mellitus, impacting on glycaemic regulation. Thus, methods to enhance endogenous GLP-1 secretion by use of natural GLP-1 secretagogues may improve glucose control in diabetes. Gypenosides (GYP) extracted from the plant Gynostemma Pentaphyllum (Jiaogulan) are known for their glucose-lowering effects both in vitro and in vivo , although their effect on GLP-1 secretion is unknown. Our results showed that GYP enhanced cell viability and significantly upregulated antioxidant gene Nrf2, Cat and Ho-1 expression. GYP did not affect glucokinase expression but downregulated proglucagon gene expression over 24h, although, cellular GLP-1 content was unchanged. Prohormone convertase 1 (Pcsk1) gene expression was unchanged by GYP over 24h, although protein levels were significantly downregulated, while prohormone convertase 2 (Pcsk2) mRNA and protein levels were significantly upregulated. Acute exposure to gypenosides enhanced calcium uptake and GLP-1 release from GLUTag cells both at low and high glucose concentrations. These results suggest that anti-diabetic properties of gypenosides are partly linked to their ability to stimulate GLP-1 secretion. Gypenosides enhance antioxidant gene expression and may protect L-cells from excess oxidative stress. ### Competing Interest Statement The authors have declared no competing interest. * GLP-1 : Glucagon-like peptide-1 GYP : Gypenosides T2DM : Type 2 diabetes mellitus Ncx : Sodium/Calcium exchange channel Sglt1 : Sodium/glucose cotransporter 1 Gcg : Glucagon Gck : Glucokinase Pc1 : Prohormone convertase-1 Pc2 : Prohormone convertase-2 Nrf2 : Nuclear factor erythroid 2-related factor 2 NFkb1 : Nuclear factor Kappa b1 Cat : Catalase Ho-1 : Heme oxygenase-1 MTT : 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

1040: Discovery of a Novel, Selective and Short-Acting Skeletal Myosin II Inhibitor
more details view paper

Posted 29 Jul 2020

Discovery of a Novel, Selective and Short-Acting Skeletal Myosin II Inhibitor
89 downloads bioRxiv pharmacology and toxicology

Laszlo Radnai, Matthew Surman, Madalyn Hafenbreidel, Erica J Young, Rebecca F Stremel, Li Lin, Paolo Pasetto, Xiaomin Jin, Mackenzie Geedy, Joni-Rae Partridge, Aagam Patel, Michael Conlon, James R. Sellers, Michael D Cameron, Gavin Rumbaugh, Patrick Griffin, Theodore M. Kamenecka, Courtney A. Miller

Myosin IIs, actin-based motors that utilize the chemical energy of ATP to generate force, have potential as therapeutic targets. Their heavy chains differentiate the family into muscle (skeletal [SkMII], cardiac, smooth) and nonmuscle myosin IIs. Despite therapeutic potential for muscle disorders, no SkMII-specific inhibitor has been reported and characterized. Here we present the discovery, synthesis and characterization of 'skeletostatins', novel derivatives of the pan-myosin II inhibitor blebbistatin, with selectivity within the myosin IIs for SkMII. In addition, the skeletostatins bear improved potency, solubility and photostability, without cytotoxicity. Based on its optimal in vitro profile, Skeletostatin 1's in vivo tolerability, efficacy and pharmacokinetics were determined. Skeletostatin 1 was well-tolerated in mice, impaired motor performance, and had an excellent muscle to plasma ratio. Skeletostatins are useful probes for basic research and a strong starting point for drug development. ### Competing Interest Statement The authors have declared no competing interest.

Previous page 1 . . . 50 51 52 53 54 55 56 Next page

PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News