Background & AimsThe lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development.MethodsA stable isogenic cross between C57BL/6J (B6) and 129S1/SvImJ (S129) mice were fed a high fat diet with ad libitum consumption of glucose and fructose in physiologically relevant concentrations and compared to mice fed a chow diet and also to both parent strains.ResultsFollowing initiation of the obesogenic diet, B6/129 mice developed obesity, insulin resistance, hypertriglyceridemia and increased LDL-cholesterol. They sequentially also developed steatosis (4–8 weeks), steatohepatitis (16–24 weeks), progressive fibrosis (16 weeks onwards) and spontaneous hepatocellular cancer (HCC). There was a strong concordance between the pattern of pathway activation at a transcriptomic level between humans and mice with similar histological phenotypes (FDR 0.02 for early and 0.08 for late time points). Lipogenic, inflammatory and apoptotic signaling pathways activated in human NASH were also activated in these mice. The HCC gene signature resembled the S1 and S2 human subclasses of HCC (FDR 0.01 for both). Only the B6/129 mouse but not the parent strains recapitulated all of these aspects of human NAFLD.ConclusionsWe here describe a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) that recapitulates the key physiological, metabolic, histologic, transcriptomic and cell-signaling changes seen in humans with progressive NASH.Lay summaryWe have developed a diet-induced mouse model of non-alcoholic steatohepatitis (NASH) and hepatic cancers in a cross between two mouse strains (129S1/SvImJ and C57Bl/6J). This model mimics all the physiological, metabolic, histological, transcriptomic gene signature and clinical endpoints of human NASH and can facilitate preclinical development of therapeutic targets for NASH.
Peripheral neuropathies (PN) can be triggered after metabolic diseases, traumatic peripheral nerve injury, genetic mutations, toxic substances, and/or inflammation. PN is a major clinical problem, affecting many patients and with few effective therapeutics. Recently, interest in natural dietary compounds, such as polyphenols, in human health has led to a great deal of research, especially in PN. Curcumin is a polyphenol extracted from the root of Curcuma longa. This molecule has long been used in Asian medicine for its anti-inflammatory, antibacterial, and antioxidant properties. However, like numerous polyphenols, curcumin has a very low bioavailability and a very fast metabolism. This review addresses multiple aspects of curcumin in PN, including bioavailability issues, new formulations, observations in animal behavioral tests, electrophysiological, histological, and molecular aspects, and clinical trials published to date. The, review covers in vitro and in vivo studies, with a special focus on the molecular mechanisms of curcumin (anti-inflammatory, antioxidant, anti-endoplasmic reticulum stress (anti-ER-stress), neuroprotection, and glial protection). This review provides for the first time an overview of curcumin in the treatment of PN. Finally, because PN are associated with numerous pathologies (e.g., cancers, diabetes, addiction, inflammatory disease...), this review is likely to interest a large audience.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose limiting, and long-lasting side effect of chemotherapy treatment. Unfortunately, no treatment has proven efficacious for this side effect. Rodent models play a crucial role in the discovery of new mechanisms underlying the initiation, progression, and recovery of CIPN and the potential discovery of new therapeutics. However, there is limited consistency in the dose, the sex, age, and genetic background of the animal used in these studies and the outcome measures used in evaluation of CIPN rely primarily on noxious and reflexive measures. The main objective of this study was to provide a comprehensive and systematic characterization of oxaliplatin-induced peripheral neuropathy in mice by using a battery of behavioral, sensory, electrophysiological, and morphometric measures in both sexes of the two widely used strains of mice, C57BL/6J and BALB/cJ. Mice received intraperitoneal injections of 3 or 30 mg/kg cumulative doses of oxaliplatin over the course of 2 weeks. Both doses induced long-term and time-dependent mechanical and cold hypersensitivity. Our results show that 30 mg/kg oxaliplatin reduced the locomotor activity in C57BL/6J mice, and C57BL/6J females showed anxiety-like behavior one-week post completion of treatment. In the same dose group, BALB/cJ males and females sustained a larger decrease in sucrose preference than either male or female C57BL/6J mice. Both strains failed to show significant changes in burrowing and nesting behaviors. Two clinically relevant assessments of changes to the peripheral nerve fibers, nerve conduction and intraepidermal nerve fiber density (IENFD) were evaluated. Only BALB/cJ females showed significant reduction in the nerve conduction amplitude 1 week after 30 mg/kg oxaliplatin regimen. Moreover, this dose of the chemo agent reduced the IENF density in both sexes and strains. Our findings suggest that mouse strain, sex, and assay type should be carefully considered when assessing the effects of oxaliplatin and potential therapeutic interventions.
Trauma is a major problem in the United States. Mortality from trauma is the number one cause of death under the age of 45 in the United States and is the third leading cause of death for all age groups. There are approximately 200,000 deaths per year due to trauma in the United States at a cost of over $671 billion in combined healthcare costs and lost productivity. Unsurprisingly, trauma accounts for approximately 30% of all life-years lost in the United States. Due to immense development of trauma systems, a large majority of trauma patients survive the injury, but then go on to die from complications arising from the injury. These complications are marked by early and significant metabolic changes accompanied by inflammatory responses that lead to progressive organ failure and, ultimately, death. Early resuscitative and surgical interventions followed by close monitoring to identify and rescue treatment failures are key to successful outcomes. Currently, the adequacy of resuscitation is measured using vital signs, noninvasive methods such as bedside echocardiography or stroke volume variation, and other laboratory endpoints of resuscitation, such as lactate and base deficit. However, these methods may be too crude to understand cellular and subcellular changes that may be occurring in trauma patients. Better diagnostic and therapeutic markers are needed to assess the adequacy of interventions and monitor responses at a cellular and subcellular level and inform clinical decision-making before complications are clinically apparent. The developing field of metabolomics holds great promise in the identification and application of biochemical markers toward the clinical decision-making process.
Patients treated with cancer chemotherapeutics frequently report chemotherapy-induced peripheral neuropathy (CIPN), changes in mood (depression and anxiety) and functional impairments. Rodent models of CIPN elicit limited alterations in functional behaviors, which pose challenges in developing preclinical models of chemotherapy-induced behavioral depression. The study examined the consequences of chemotherapy-induced mechanical hypersensitivity (paclitaxel: 32 or 64 mg/kg, cumulative; oxaliplatin: 30 mg/kg, cumulative) on behavioral depression, as measured with operant responding for palatable food during periods of food restriction and ad libitum chow, consumption of noncontingently available palatable food in the presence of ad libitum chow, and voluntary wheel running. The study employed two inbred mouse strains (C57BL/6J and Balb/cJ) and examined potential sex differences. All chemotherapeutic regimens caused profound mechanical hypersensitivity for the duration of the observation periods (up to 7 months), but no treatments changed voluntary wheel running or consumption of noncontingent palatable food. The high dose of paclitaxel temporarily reduced operant responding for palatable food in male C57BL/6J mice undergoing food restriction or maintained on ad libitum chow. However, paclitaxel failed to decrease operant responding for palatable food in free-feeding female C57BL/6J mice or Balb/cJ mice of either sex. Moreover, oxaliplatin did not significantly alter operant responding for palatable food in male or female C57BL/6J mice maintained on ad libitum chow. These findings demonstrate a dissociation between chemotherapy-induced mechanical hypersensitivity and behavioral depression. The transient effects of paclitaxel on operant responding in male C57BL/6J mice may represent a fleeting behavioral correlate of chemotherapy-associated pain-like behaviors.
AIMTo examine the effect of high doses of vitamin C (VitC) on ex vivo human platelets (PLTs).METHODSPlatelet concentrates collected for therapeutic or prophylactic transfusions were exposed to: (1) normal saline (control); (2) 0.3 mmol/L VitC (Lo VitC); or (3) 3 mmol/L VitC (Hi VitC, final concentrations) and stored appropriately. The VitC additive was preservative-free buffered ascorbic acid in water, pH 5.5 to 7.0, adjusted with sodium bicarbonate and sodium hydroxide. The doses of VitC used here correspond to plasma VitC levels reported in recently completed clinical trials. Prior to supplementation, a baseline sample was collected for analysis. PLTs were sampled again on days 2, 5 and 8 and assayed for changes in PLT function by: Thromboelastography (TEG), for changes in viscoelastic properties; aggregometry, for PLT aggregation and adenosine triphosphate (ATP) secretion in response to collagen or adenosine diphosphate (ADP); and flow cytometry, for changes in expression of CD-31, CD41a, CD62p and CD63. In addition, PLT intracellular VitC content was measured using a fluorimetric assay for ascorbic acid and PLT poor plasma was used for plasma coagulation tests [prothrombin time (PT), partial thrombplastin time (PTT), functional fibrinogen] and Lipidomics analysis (UPLC ESI-MS/MS).RESULTSVitC supplementation significantly increased PLTs intracellular ascorbic acid levels from 1.2 mmol/L at baseline to 3.2 mmol/L (Lo VitC) and 15.7 mmol/L (Hi VitC, P < 0.05). VitC supplementation did not significantly change PT and PTT values, or functional fibrinogen levels over the 8 d exposure period (P > 0.05). PLT function assayed by TEG, aggregometry and flow cytometry was not significantly altered by Lo or Hi VitC for up to 5 d. However, PLTs exposed to 3 mmol/L VitC for 8 d demonstrated significantly increased R and K times by TEG and a decrease in the α-angle (P < 0.05). There was also a fall of 20 mm in maximum amplitude associated with the Hi VitC compared to both baseline and day 8 saline controls. Platelet aggregation studies, showed uniform declines in collagen and ADP-induced platelet aggregations over the 8-d study period in all three groups (P > 0.05). Collagen and ADP-induced ATP secretion was also not different between the three groups (P > 0.05). Finally, VitC at the higher dose (3 mmol/L) also induced the release of several eicosanoids including thromboxane B2 and prostaglandin E2, as well as products of arachidonic acid metabolism via the lipoxygenases pathway such as 11-/12-/15-hydroxyicosatetraenoic acid (P < 0.05).CONCLUSIONAlterations in PLT function by exposure to 3 mmol/L VitC for 8 d suggest that caution should be exerted with prolonged use of intravenous high dose VitC.
Dialysis is the primary treatment for patients with end stage renal disease (ESRD). While this treatment modality has made significant advances over the past years, ERSD patients still have unacceptably high rates of mortality (1). Indeed, CVD is the primary cause of mortality among patients with ESRD, accounting for about 45% of all deaths (2). Complicating this is the fact that ESRD patients Abstract Hemodialysis (HD) and peritoneal dialysis (PD) are the primary means of managing end stage renal disease (ESRD). However, these treatment modalities are associated with the onset of coagulation abnormalities. Effective management of coagulation risk among these patients requires the identification of surrogate markers that provide an early indication of the coagulation abnormalities. The role of sphingolipids in the manifestation and prediction of coagulation abnormalities among dialysis patients have never been investigated. Herein, we report the first instance of an in depth investigation into the sphingolipid changes among ESRD patients undergoing HD and PD. The results reveal distinct differences in terms of perturbations to specific sphingolipid biosynthetic pathways that are highly dependent on the treatment modality. Our studies also demonstrated strong correlation between specific sphingolipids and coagulation parameters, such as HexCer(d18:1/26:0) and maximal amplitude (MA), SM(d18:1/24:1) and tissue factor pathway inhibitor, and sphingosine 1-phosphate d18:1 and FX (Spearman of 0.93, 0.89, and 0.89, respectively).Furthermore, our study revealed the potential for using HexCer(d18:1/22:0), HexCer(d18:1/24:0), and
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