New opportunities in the management and treatment of refractory hypercholesterolemia using in vivo CRISPR-mediated genome/base editing.

AIMS: Refractory hypercholesterolemia (RH), caused primarily by the loss-of-function mutation of LDL receptor (LDLR) gene seen in HoFH and HeFH patients, remains a major risk factor for atherosclerotic cardiovascular disease (ASCVD). Statin and ezetimibe combination therapy lower circulating LDL by 30% in HoFH patients. PCSK9 mAB, being an LDLR-dependent therapy, is not effective in HoFH, but lowers LDL by 25% in HeFH patients. A maximum reduction of 50% was noted in HoFH patients treated with ANGPTL3 mAB, which was not enough to achieve therapeutic goal of LDL. Therefore, new approaches are warranted to offer hopes to individuals intolerant to higher dose statins and not able to achieve recommended LDL level. DATA SYNTHESIS: New approaches to lower LDL include gene therapy and gene editing. AAV-based gene therapy has shown encouraging results in animal models. Using CRISPR/Cas9-mediated genome/base editing, gain of function and loss of function have been successfully done in animal models. Recent progress in the refinement of genome/base editing has overcome the issues of off-target mutagenesis with ∼1% mutagenesis in case of PCSK9 and almost no off-target mutagenesis in inactivating ANGPTL3 in animal models showing 50% reduction in cholesterol. Current approaches using CRISPR-Cas9 genome/base editing targeting LDLR-dependent and LDLR-independent pathways are underway. CONCLUSIONS: The new information on gain of LDLR function and inactivation of ANGPTL3 together with developments in genome/base editing technology to overcome off-target insertion and deletion mutagenesis offer hope to refractory hypercholesterolemic individuals who are at a higher risk of developing ASCVD.

Autophagy perturbation upon acute pyrethroid treatment impacts adipogenic commitment of mesenchymal stem cells.

Environmental chemical exposure can cause dysregulation in adipogenesis that can result in metabolic syndrome, which includes insulin resistance, type 2 diabetes, cardiovascular disease, as well as excessive body weight. The role of autophagy in adipocyte differentiation is debatable since both positive and negative effects have been reported. Type-I and type-II synthetic pyrethroids α-cypermethrin (CPM) and permethrin (PER), respectively, are reported to increase adipogenesis in vitro and in vivo. However, it is not known how these pyrethroids affect mesenchymal stem cells (MSCs). Thus, this study focused on evaluating the effect of pyrethroids (CPM and PER) pre-treatment (24 h) on MSC commitment and the regulatory role of autophagy in adipogenic lineage commitment. The formation of adipocytes was observed through nile red staining, perilipin expression by immunoflourescence, and adipogenic markers PPARγ, C/EBPα, and FABP4 by western blotting. It was found that the adipogenic differentiation ability of MSCs was significantly increased upon CPM or PER pre-treatment at 100 µM concentration as evident by lipid accumulation and enhanced expression of adipogenic markers. To assess the involvement of autophagy, the expression of p62 and LC3II were evaluated following pre-treatment. Immunoblotting results revealed an increased expression of p62 and LC3II in CPM or PER pretreated MSCs suggesting CPM and PER mediated inhibition of autophagy at 24 h. Further, an increase was observed in adipogenesis upon CPM or PER pre-treatment in combination with chloroquine, while use of rapamycin during pre-treatment abrogated the effect of CPM and PER. Thus, this study concludes that CPM or PER pre-treatment increases the adipogenic differentiation of MSCs. Since chloroquine also demonstrated similar adipogenic response, it further highlights that 24 h pre-treatment with autophagy modulators to inhibit basal autophagy primes MSCs towards adipogenic lineage.

A Review of Progress on Targeting LDL Receptor-Dependent and -Independent Pathways for the Treatment of Hypercholesterolemia, a Major Risk Factor of ASCVD.

Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations in the LDL receptor (LDLR) gene. Statins proved to be the first blockbuster drug, helping both HoFH and HeFH individuals by inhibiting the cholesterol synthesis pathway rate-limiting enzyme HMG-CoA reductase and inducing the LDL receptor. However, statins could not achieve the therapeutic goal of LDL. Other therapies targeting LDLR include PCSK9, which lowers LDLR by promoting LDLR degradation. Inducible degrader of LDLR (IDOL) also controls the LDLR protein, but an IDOL-based therapy is yet to be developed. Among the LDLR-independent pathways, such as angiopoietin-like 3 (ANGPTL3), apolipoprotein (apo) B, apoC-III and CETP, only ANGPTL3 offers the advantage of treating both HoFH and HeFH patients and showing relatively better preclinical and clinical efficacy in animal models and hypercholesterolemic individuals, respectively. While loss-of-LDLR-function mutations have been known for decades, gain-of-LDLR-function mutations have recently been identified in some individuals. The new information on gain of LDLR function, together with CRISPR-Cas9 genome/base editing technology to target LDLR and ANGPTL3, offers promise to HoFH and HeFH individuals who are at a higher risk of developing atherosclerotic cardiovascular disease (ASCVD).

A comparative analysis of daunorubicin and its metabolite daunorubicinol interaction with apoptotic and drug resistance proteins using in silico approach.

Daunorubicin (DNR) is a chemotherapeutic drug associated with multiple side effects, including drug resistance. As the molecular mechanism related to these side effects remain unclear and mostly hypothesized, this study addresses and compares the role of DNR and its metabolite Daunorubicinol (DAUNol) to induce apoptosis and drug resistance using molecular docking, Molecular Dynamics (MD) simulation, MM-PBSA and chemical pathway analysis. The results showed that DNR's interaction was stronger with Bax protein, Mcl-1:mNoxaB and Mcl-1:Bim protein complexes than DAUNol. On the other hand, contrasting results were obtained for drug resistance proteins where stronger interaction was obtained with DAUNol compared to DNR. Further, MD simulation performed for 100 ns provided the details of protein-ligand interaction. Most notable was the interaction of Bax protein with DNR, resulting in conformational changes at α-helices 5, 6 and 9, leading to Bax activation. Finally, the chemical signalling pathway analysis also revealed the regulation of different signalling pathways by DNR and DAUNol. It was observed that DNR majorly impacted the signalling associated with apoptosis while DAUNol mainly targeted pathways related to multidrug resistance and cardiotoxicity. Overall, the results highlight that DNR biotransformation reduces its capability to induce apoptosis while enhancing its ability to induce drug resistance and off-target toxicity.Communicated by Ramaswamy H. Sarma.

Discovery of analogues of non-ß oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism.

BACKGROUND AND AIMS: Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications. METHODS AND RESULTS: Primary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) using14C-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action. In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis inhibition. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30 mg/kg dose. Concomitant decreases in non-esterified fatty acids (-34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (-71% and -64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose-response efficacy. CONCLUSIONS: Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.

NPC1L1 and ABCG5/8 induction explain synergistic fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists.

Reverse cholesterol transport (RCT) and transintestinal cholesterol efflux (TICE) are two important pathways for body cholesterol elimination. We studied these pathways in an animal model of diabetes and obesity (ob/ob) where HDL function is compromised as a result of hyperglycemia, low-grade inflammation and oxidative stress. Co-treatment of ob/ob mice with PPAR-α (fenofibrate) and LXR (T0901317) agonists increased fecal cholesterol by 12-fold; PPAR-α and LXR agonists individually showed 2.6- and 4.0-fold fecal cholesterol excretion, respectively. We investigated the mechanism of synergistic efficacy of PPAR-α and LXR agonists in fecal cholesterol excretion. LXR agonist and the combination of PPAR-α and LXR agonists had greater HDL-C elevation. Ex vivo cholesterol efflux showed correlation with the fecal cholesterol excretion but was not sufficient to explain 12-fold increases in the fecal cholesterol in the co-treated mice. Therefore, we examined TICE to explain the 12-fold increases in the fecal cholesterol. A strong positive correlation of fecal cholesterol with ATP binding cassette transporter G5 (ABCG5) and G8 and a negative correlation with NPC1L1 was observed. ABCG5, G8 and NPC1L1 are involved in intestinal cholesterol absorption. The extent of influence of PPAR-α and LXR agonists on RCT and TICE was distinctly different. PPAR-α agonist increased fecal cholesterol primarily by influencing TICE, while LXR agonist influenced fecal cholesterol excretion via both RCT and TICE mechanisms. Synergistic efficacy on fecal cholesterol excretion following co-treatment with PPAR-α and LXR agonists occurred through a combination of RCT, TICE, and the key enzyme in bile synthesis, cholesterol 7-α hydroxylase (cyp7a1). These results suggest that cholesterol efflux, biliary cholesterol excretion, and TICE collectively contributed to the 12-fold increases in the fecal cholesterol excretion in ob/ob mice co-treated with PPAR-α and LXR agonists.

Rapid degradation of ABCA1 protein following cAMP withdrawal and treatment with PKA inhibitor suggests ABCA1 is a short-lived protein primarily regulated at the transcriptional level.

OBJECTIVES: ATP-binding cassette transporter A1 (ABCA1) is a key player in the reverse cholesterol transport (RCT) and HDL biogenesis. Since RCT is compromised as a result of ABCA1 dysfunction in diabetic state, the objective of this study was to investigate the regulation of ABCA1 in a stably transfected 293 cells expressing ABCA1 under the control of cAMP response element. METHODS: To delineate transcriptional and posttranscriptional regulation of ABCA1, 293 cells were stably transfected with the full length ABCA1 cDNA under the control of CMV promoter harboring cAMP response element. cAMP-mediated regulation of ABCA1 and cholesterol efflux were studied in the presence of 8-Br-cAMP and after withdrawal of 8-Br-cAMP. The mechanism of cAMP-mediated transcriptional induction of the ABCA1 gene was studied in protein kinase A (PKA) inhibitors-treated cells. RESULTS: The transfected 293 cells expressed high levels of ABCA1, while non-transfected wild-type 293 cells showed very low levels of ABCA1. Treatments of transfected cells with 8-Br-cAMP increased ABCA1 protein by 10-fold and mRNA by 20-fold. Cholesterol efflux also increased in parallel. Withdrawal of 8-Br-cAMP caused time-dependent rapid diminution of ABCA1 protein and mRNA, suggesting ABCA1 regulation at the transcriptional level. Treatment with PKA inhibitors abolished the cAMP-mediated induction of the ABCA1 mRNA and protein, resulting dampening of ABCA1-dependent cholesterol efflux. CONCLUSIONS: These results demonstrate that transfected cell line mimics cAMP response similar to normal cells with natural ABCA1 promoter and suggest that ABCA1 is a short-lived protein primarily regulated at the transcriptional level to maintain cellular cholesterol homeostasis.

Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/ß-catenin signaling and apoptotic pathways in A375 cells.

BACKGROUND: Traditional therapy using natural products, especially flavonoids and alkaloids have been in practice for a long time. Among flavonoids, curcumin, quercetin, berberine, and epigallocatechin have been studied in greater detail in terms of their anticancer and anti-inflammatory activities. Although many studies focused on the PI3K, MAP kinase and NF-κB pathways, a thorough investigation of modulation of players in the apoptotic and Wnt/ß-catenin signaling pathway by curcumin and quercetin has not been done. Also, only few studies have been carried out on curcumin and quercetin co-treatment studies. HYPOTHESIS/PURPOSE: We hypothesized that the combination of natural products will have synergistic effects and the antiproliferative effect will be attenuated via apoptotic as well as Wnt/ß-catenin signaling pathways. STUDY DESIGN AND METHODS: To test our hypothesis, we compared potency of natural anticancer agents in four cancer cell lines, A549, HCT116, MCF7, and A375 by MTT and colony proliferation assays and investigated mechanism of anticancer activities by analyzing players in apoptotic and Wnt/ß-catenin signaling pathways in A375 cells treated with test agents individually or in combination. RESULTS: Epicatechins, up to 100 µM concentration, did not inhibit cancer cell proliferation, while curcumin inhibited proliferation in A549 and HCT116 cancer cell lines with an IC50 of 3 to 8.5 µM. Quercetin showed stronger inhibition of cell proliferation than berberine. Combination study with two most potent agents, curcumin and quercetin, in 4 cancer cell lines, suggested synergistic effect on cell proliferation with several fold decreases in IC50. Further investigation of the mechanism of action of curcumin and quercetin in melanoma cells, A375, suggested that inhibition of cell proliferation occurred through down-regulation of Wnt/ß-catenin signaling pathway proteins, DVL2, ß-catenin, cyclin D1, Cox2, and Axin2. In addition, both curcumin and quercetin induced apoptosis by down-regulating BCL2 and inducing caspase 3/7 through PARP cleavage. CONCLUSION: These results demonstrate that curcumin and quercetin inhibit cancer cell proliferation synergistically and Wnt/ß-catenin signaling and apoptotic pathways are partly responsible for antiproliferative activities.

Toward a phenomic analysis of chronic postsurgical pain following cardiac surgery.

Background: Despite the same surgical approach, up to 40% of patients develop chronic postsurgical pain (CPSP) following cardiac surgery, whereas the rest are chronic pain free. This variability suggests that CPSP is controlled partially through genetics, but the genes for CPSP are largely unknown. Aims: The aim of this study was to identify potential CPSP phenotypes by comparing patients who developed CPSP following cardiac surgery vs. those who did not. Methods: A research ethics board-approved, cross-sectional study of post-cardiac surgery pain was conducted at Toronto General Hospital from 2011 to 2015. Patients were recruited to complete a short survey of chronic pain scores and the Short-Form McGill Pain Questionnaire-2. A subset of patients completed a longer survey of eight validated pain phenotyping questionnaires and/or four psychophysical assessments. All surveys and psychophysical testing were conducted after surgery. Patients were stratified by presence of chronic pain and groups were compared using descriptive statistics. Results: Six hundred forty-three patients completed the short form survey. The mean postsurgery assessment time was 41.5 (SD = ±25.1) months. Over a quarter (27.8%) reported CPSP at the chest as a consequence of their surgery. Of patients reporting CPSP, 46.6% reported mild pain (0-3), 35.8% reported moderate pain (4-7), and 17.6% reported severe pain (7-10) in accordance with the numerical rating scale. Patients with moderate and/or severe CPSP were younger, had a greater body mass index, and had higher anxiety sensitivity, pain catastrophizing, and somatization scores. Conclusions: Chronic pain levels after cardiac surgery are associated with anxiety, catastrophizing, and sensory abnormalities in body parts outside the field innervated by injured nerves, indicating the presence of widespread central sensitization to incoming sensory inputs from intact nerves.

Contexte: Malgré qu'ils aient été soumis à la même approche chirurgicale, jusqu'à 40 % des patients souffrent de douleur chronique postopératoire après une chirurgie cardiaque, tandis que le reste des patients n'en souffrent pas. Cette variabilité porte à croire que la douleur chronique postopératoire est en partie maitrisée génétiquement, mais les gènes en cause dans la douleur chronique postopératoire sont très peu connus.But: Identifier les phénotypes de douleur chronique postopératoire possibles en comparant des patients souffrant de douleur chronique postopératoire à des patients n'en souffrant pas après une chirurgie cardiaque.Méthodes: Une étude transversale de la douleur après une chirurgie cardiaque approuvée par la commission d'éthique de la recherche a été menée à l'Hôpital général de Toronto de 2011 à 2015. Les patients ont été recrutés pour répondre à un court questionnaire portant sur les scores de douleur chronique et à une version abrégée du McGill Pain Questionnaire-2. Un sous-ensemble de patients a répondu à une enquête plus longue comprenant huit questionnaires validés portant sur le phénotypage de la douleur et/ou sur quatre mesures psychophysiques. Tous les questionnaires et les tests psychophysiques ont été menés après la chirurgie. Les patients ont été stratrifiés en fonction de la présence de douleur chronique et les groupes ont été comparés à l'aide de statistiques descriptives.Résultats: 634 patients ont répondu à la version courte de l'enquête. Le temps moyen de l'évaluation post-chirurgie était de 41,4 mois (écart-type ± 25,1). Plus d'un quart (27,8%) des participants ont rapporté de la douleur chronique postopératoire au thorax en tant que conséquence de la chirurgie. Parmi les patients rapportant de la douleur chronique post-opératoire, 46,6 % ont rapporée une douleur faible (0-3), 35,8 % ont rapporté de la douleur modérée (4-7) et 17,6 % ont rapporté de la douleur sévère (7-10), selon l'échelle d'évaluation numérique. Les patients souffrant de douleur chronique postopératoire de modérée à sévère étaient plus jeunes, avaient un indice de masse corporelle plus élevé et obtenaient des scores plus élevés en ce qui concerne la sensibilité à l'anxiété, la catastrophisation de la douleur et la somatisation.Conclusion: Les niveaux de douleur chronique après une chirurgie cardiaque sont associés à l'anxiété, à la catastrophisation et à des anomalies sensorielles dans des parties du corps à l'extérieur de la zone innervée par les nerfs par les nerfs endommagés, ce qui indique la présence d'une sensibilisation centrale généralisée aux signaux sensoriels provenant des nerfs intacts.

Comparative Evaluation of Gemcabene and Peroxisome Proliferator-Activated Receptor Ligands in Transcriptional Assays of Peroxisome Proliferator-Activated Receptors: Implication for the Treatment of Hyperlipidemia and Cardiovascular Disease.

Gemcabene, a late-stage clinical candidate, has shown efficacy for LDL-C, non-HDL cholesterol, apoB, triglycerides, and hsCRP reduction, all risk factors for cardiovascular disease. In rodents, gemcabene showed changes in targets, including apoC-III, apoA-I, peroxisomal enzymes, considered regulated through peroxisome proliferator-activated receptor (PPAR) gene activation, suggesting a PPAR-mediated mechanism of action for the observed hypolipidemic effects observed in rodents and humans. In the current study, the gemcabene agonist activity against PPAR subtypes of human, rat, and mouse were compared with known lipid lowering PPAR activators. Surprisingly, gemcabene showed no or little PPAR-α transactivation compared with reference agonists, which showed concentration-dependent transactivation against human PPAR-α of 2.4- to 30-fold (fenofibric acid), 17-fold (GW590735), and 2.3- to 25-fold (WY-14643). These agents also showed robust transactivation of mouse and rat PPAR-α in a concentration-dependent manner. The known PPAR-δ agonists, GW1516, L165041, and GW0742, showed potent agonist activity against human, mouse, and rat receptors (ranging from 165- to 396-fold). By contrast, gemcabene at the highest concentration tested (300 µM) showed no response in mouse and rat and a marginal response against human PPAR-δ receptors (3.2-fold). For PPAR-γ, gemcabene showed no agonist activity against all 3 species at 100 µM and marginal activity (3.6- to 5-fold) at 300 µM. By contrast, the known agonists, rosiglitazone, indomethacin, and muraglitazar showed strong activation against the mouse, rat, and human PPAR-γ receptors. No clear antagonist activity was observed with gemcabene against any PPAR subtypes for all 3 species over a wide range of concentrations. In summary, the transactivation studies rule out gemcabene as a direct agonist or antagonist of PPAR-α, PPAR-γ, and PPAR-δ receptors of these 3 species. These data suggest that the peroxisomal effects observed in rodents and the lipid regulating effects observed in rodents and humans are not related to a direct activation of PPAR receptors by gemcabene.

Gemcabene, a first-in-class lipid-lowering agent in late-stage development, down-regulates acute-phase C-reactive protein via C/EBP-δ-mediated transcriptional mechanism.

Inflammation plays a key role in setting the stage leading to atherosclerosis progression, and high-sensitivity C-reactive protein (CRP) has been recognized as a predictor of cardiovascular risk. As a monotherapy and in combination with statins, gemcabene markedly reduced CRP in humans. Present investigation was undertaken to understand the mechanism of CRP reduction. In human hepatoma cells, gemcabene inhibited IL-6 plus IL-1ß-induced CRP production in a concentration-dependent manner, reaching 70% inhibition at 2 mM. In TNF-α-stimulated primary human coronary artery endothelial cells, both CRP and IL-6 productions were reduced by 70% at 2 mM gemcabene concentration. To investigate the mechanism of gemcabene-mediated reduction of CRP, transfection studies were performed with human CRP regulatory sequences in luciferase/ß-gal system that showed 25-fold increase in IL-6- and IL-6 plus IL-1ß-stimulated CRP transcription. Luciferase activity was reduced by 50% by gemcabene, suggesting transcriptional down-regulation of CRP. Site-directed mutagenesis of human CRP promoter revealed that the overlapping downstream C/EBP and NF-κB binding sites are important for gemcabene-mediated CRP transcription. Gel shift assays identified the transcription factor that binds to the downstream CRP promoter as C/EBP-δ. In conclusion, gemcabene decreases CRP by C/EBP-δ and NF-κB-mediated transcriptional mechanism and suppresses IL-6 and IL-1ß-induced CRP production.

Dysfunctional HDL in diabetes mellitus and its role in the pathogenesis of cardiovascular disease.

Coronary artery disease, the leading cause of death in the developed and developing countries, is prevalent in diabetes mellitus with 68% cardiovascular disease (CVD)-related mortality. Epidemiological studies suggested inverse correlation between HDL and CVD occurrence. Therefore, low HDL concentration observed in diabetic patients compared to non-diabetic individuals was thought to be one of the primary causes of increased risks of CVD. Efforts to raise HDL level via CETP inhibitors, Torcetrapib and Dalcetrapib, turned out to be disappointing in outcome studies despite substantial increases in HDL-C, suggesting that factors beyond HDL concentration may be responsible for the increased risks of CVD. Therefore, recent studies have focused more on HDL function than on HDL levels. The metabolic environment in diabetes mellitus condition such as hyperglycemia-induced advanced glycation end products, oxidative stress, and inflammation promote HDL dysfunction leading to greater risks of CVD. This review discusses dysfunctional HDL as one of the mechanisms of increased CVD risks in diabetes mellitus through adversely affecting components that support HDL function in cholesterol efflux and LDL oxidation. The dampening of reverse cholesterol transport, a key process that removes cholesterol from lipid-laden macrophages in the arterial wall, leads to increased risks of CVD in diabetic patients. Therapeutic approaches to keep diabetes under control may benefit patients from developing CVD.

Life-style-induced metabolic derangement and epigenetic changes promote diabetes and oxidative stress leading to NASH and atherosclerosis severity.

Energy imbalance resulting from high calorie food intake and insufficient metabolic activity leads to increased body mass index (BMI) and sets the stage for metabolic derangement influencing lipid and carbohydrate metabolism and ultimately leading to insulin resistance, dyslipidemia, and type 2 diabetes. 70% of cardiovascular disease (CVD) deaths occur in patients with diabetes. Environment-induced physiological perturbations trigger epigenetic changes through chromatin modification and leads to type 2 diabetes and progression of nonalcoholic fatty liver disease (NAFLD) and CVD. Thus, in terms of disease progression and pathogenesis, energy homeostasis, metabolic dysregulation, diabetes, fatty liver, and CVD are interlinked. Since advanced glycation end products (AGEs) and low-grade inflammation in type 2 diabetes play definitive roles in the pathogenesis of liver and vascular diseases, a natural checkpoint to prevent diabetes and associated complications appears to be the identification and management of prediabetes together with weight management, since 70% of prediabetic individuals develop diabetes during their life time, and every kg of weight increase is associated with up to 9% increase in diabetes risk. A good proportion of diabetes and obesity population have fatty liver that progresses to non-alcoholic steatohepatitis (NASH) and cirrhosis, and increased risk of hepatocellular carcinoma. Diabetes and NASH both have elevated oxidative stress, impaired cholesterol elimination, and increased inflammation that leads to CVD risk. This review addresses life-style-induced metabolic pathway derangement and how it contributes to epigenetic changes, type 2 diabetes and NASH progression, which collectively lead to increased risk of CVD.

Preoperative pregabalin or gabapentin for acute and chronic postoperative pain among patients undergoing breast cancer surgery: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVE: Breast cancer surgery is associated with acute and chronic pain. We sought to systematically evaluate the effects of gabapentin and pregabalin on postoperative pain among patients undergoing breast cancer surgery. DATABASES AND DATA TREATMENT: We searched MEDLINE, EMBASE, CENTRAL, Web of Science, and ProQuest from the inception of each database to November 2015. We included studies enrolling adult patients undergoing breast cancer surgery who were randomly assigned to preoperative gabapentin or pregabalin versus placebo or active control and assessed acute (≤24 h) or chronic (≥2 months) pain. We conducted meta-analyses when possible and rated the quality of evidence (QoE) by using the GRADE approach. RESULTS: Twelve studies were eligible for review, of which eight evaluated gabapentin (n = 516) and four pregabalin (n = 209). Gabapentin reduced pain scores in the recovery room (mean difference [MD] -1.68 on a 0-10 Numeric Rating Scale (NRS), 95% CI -2.59 to -0.77; minimally important difference is 1 point; relative risk [RR] for mild pain (<4/10) 1.71, 95% CI 1.33-2.02; moderate QoE) and 24 h postoperatively (MD -0.52, 95% CI -1.02 to -0.01; RR for mild pain 1.07, 95% CI 1.00-1.13; very low QoE). Pregabalin reduced pain and morphine consumption in the recovery room (MD -6.71 mg, 95% CI -10.73 to -2.70; low QoE). No significant difference was observed in pain score at 24 h (MD -0.38, 95%, CI -0.96 to 0.21; moderate QoE). Neither drug reduced the rate of chronic postoperative pain. CONCLUSIONS: Gabapentin and pregabalin seem to reduce opioid consumption in the recovery room. Gabapentin, but not pregabalin, reduces pain at 24 h after breast cancer surgery. Neither drug affects the development of chronic postoperative pain. SIGNIFICANCE: Gabapentin and pregabalin administered perioperatively in patients undergoing breast cancer surgery improve acute postoperative pain as indicated by the reduction in opioid consumption. Further data are needed on reducing chronic postoperative pain.

A Review of Adjunctive CNS Medications Used for the Treatment of Post-Surgical Pain.

Inadequate post-operative pain management can have significant impacts on patients' quality of life. Effective management of acute pain after surgery is important for early mobilization and discharge from hospital, patient satisfaction, and overall well-being. Utilizing multimodal analgesic strategies has become the mainstay of acute post-operative pain management. A comprehensive search was performed, assessing the published or otherwise publically available literature on different central nervous system (CNS) drugs [excluding opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen] and their uses to treat acute post-surgical pain. Included among the drugs evaluated in this review are anticonvulsants, N-methyl-D-aspartic acid (NMDA) agonists, local anesthetics, α2-agonists, cannabinoids, serotonin-noradrenaline reuptake inhibitors (SNRIs), and serotonin-noradrenaline-dopamine reuptake inhibitors (SNDRIs). Timing, dosing, routes of administration, as well as mechanisms of action are discussed for these CNS drugs.

Barriers, beliefs and practice patterns for breast cancer reconstruction: A provincial survey.

BACKGROUND: The purpose of this study was to characterize beliefs and practice patterns for breast cancer reconstruction among physicians who treat patients with breast cancer, in order to delineate current clinical practice. This survey was administered prior to Cancer Care Ontario guideline publication. METHOD: Survey questions addressed four domains: survival, delayed or obscured recurrence detection, delayed adjuvant therapy, and aesthetics. The survey was administered to 1160 Ontario plastic and general surgeons and radiation and medical oncologists. Data were compared to published guidelines. RESULTS: The overall response rate was 48%, with 57% of respondents treating breast cancer. Of those treating breast cancer, 75% are affiliated with an academic center. Immediate breast reconstruction (IBR) is not available to 28%. Autologous reconstruction is thought to interfere with recurrence detection by 23% (oncologists 30%, surgeons 19%, p = 0.04). For patients not expected to require radiation therapy, IBR is not supported by 30%. Autologous IBR is believed to delay delivery of adjuvant chemotherapy by 45% (oncologists 55%, surgeons 41%, p = 0.02). Up to 42% of respondents believe delays in adjuvant therapy delivery following IBR are due to insufficient health care resources (ie. coordinating an oncologic and reconstructive surgeon). Radiation therapy following reconstruction is believed to have negative aesthetic outcomes, and increase the need for revision surgery. CONCLUSIONS: Unfavourable beliefs about certain clinical actions do not align with recent provincial guideline recommendations. Insufficient healthcare resources are perceived to be a significant barrier to IBR and timely care.

Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist.

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

A novel anti-inflammatory natural product from Sphaeranthus indicus inhibits expression of VCAM1 and ICAM1, and slows atherosclerosis progression independent of lipid changes.

A large body of evidence suggests that atherosclerosis is an inflammatory disease, in which cytokines and growth factors play a major role in disease progression. The methanolic extracts of Sphaeranthus indicus as well as its active ingredient, 7-hydroxy frullanoide (7-HF), are shown to suppress LPS-induced cytokine production from mononuclear cells, and inhibit the expression of VCAM1, ICAM1 and E-selectin by TNF-α- stimulated HUVECs in a concentration-dependent manner. We tested the hypothesis that the inhibition of cytokines and adhesion molecules should attenuate the progression of atherosclerosis, independent of changes in the lipid profile. Studies were carried out in two animal models: a high fat-fed LDLr(-/-) mouse and a high fat-fed hyperlipidemic hamster. Methanolic extract of S. indicus was dosed to hyperlipidemic LDLr(-/-) at 100 and 300 mg (equivalent to 20 and 60 mg 7-HF)/kg body weight/ day for 8 weeks, and plasma lipids as well as aortic lesion area were quantitated. Hyperlipidemic hamsters were treated with one dose of 200 mg/kg/day. S. indicus extract treatment did not alter the lipid profile in both animal models, but reduced aortic lesion area in LDLr(-/-) mice and hyperlipidemic hamsters by 22 % and 45 %, respectively. Fenofibrate, included as a reference agent, decreased aortic lesions by 26 % in LDLr (-/-) mice and 84 % in hyperlipidemic hamsters, respectively, which was driven by massive reductions in proatherogenic lipoproteins. The lipid-independent anti-atherosclerotic activity of S. indicus was associated with the reductions in the circulating levels of MCP-1, TNF-α, and IL-6 via phosphorylation and degradation of IkB-α that prevents translocation of NF-kB in the nucleus to induce proinflammatory cytokines. Our findings demonstrate that anti-inflammatory agents that lower pro-inflammatory proteins inhibit the progression of atherosclerosis. The methanolic extract of S. inducus, currently being used to treat psoriasis, offer promise to benefit individuals who have high circulating pro-inflammatory cytokines, and predisposed to coronary artery disease.

Demographic characteristics and clinical predictors of patients discharged from university hospital-affiliated pain clinic due to breach in narcotic use contract.

OBJECTIVE: The current retrospective study was completed with the aim to identify demographic characteristics and clinical predictors (if any) of the patients discharged from our pain clinic due to breach in narcotic use contract (BNUC). DESIGN: Retrospective patient charts' review and data audit. SETTING: University hospital-affiliated pain clinic in the United States. PARTICIPANTS: All patient charts in our pain clinic for a 2-year period (2011-2012). INTERVENTIONS: The patients with BNUC were delineated from the patients who had not been discharged from our pain clinic. MAIN OUTCOME MEASURES: Pain characteristics, pain management, and substance abuse status were compared in each patient with BNUC between the time of admission and the time of discharge. RESULTS: The patients with BNUC discharges showed significant variability for the discharging factors among the pain physicians within a single pain clinic model with this variability being dependent on their years of experience and their proactive interventional pain management. The patients with BNUC in our pain clinic setting were primarily middle-aged, obese, unmarried males with nondocumented stable occupational history who were receiving only noninterventional pain management. Substance abuse, doctor shopping, and potential diversion were the top three documented reasons for BNUC discharges. CONCLUSION: In 2011-2012, our pain clinic discharged 1-in-16 patients due to breach in narcotic use contract.