Orlistat Research Articles

Effects of Chitosan and N-Succinyl Chitosan on Metabolic Disorders Caused by Oral Administration of Olanzapine in Mice.

The issue of human mental health is gaining more and more attention nowadays. However, most mental disorders are treated with antipsychotic drugs that cause weight gain and metabolic disorders, which include olanzapine (OLZ). The search for and development of natural compounds for the prevention of obesity when taking antipsychotic drugs is an urgent task. The biopolymer chitosan (Chi) and its derivatives have lipid-lowering and anti-diabetic properties, which makes them potential therapeutic substances for use in the treatment of metabolic disorders. The purpose of this work was to analyze the effect of the natural biopolymer Chi, its derivative N-succinyl chitosan (SuChi), and Orlistat (ORL) as a control on the effects caused by the intake of OLZ in a mouse model. Mice were fed with pearl barley porridge mixed with OLZ or combinations OLZ + Chi, OLZ + SuChi, or OLZ + ORL for 2 months. The weight, lipid profile, blood chemokines, expression of genes associated with appetite regulation, and behavior of the mice were analyzed in dynamics. For the first time, data were obtained on the effects of Chi and SuChi on metabolic changes during the co-administration of antipsychotics. Oral OLZ increased body weight, food and water intake, and glucose, triglyceride, and cholesterol levels in blood. ORL and SuChi better normalized lipid metabolism than Chi, decreasing triglyceride and cholesterol levels. OLZ decreased the production of all chemokines tested at the 4th week of treatment and increased CXCL1, CXCL13, and CCL22 chemokine levels at the 7th week. All of the supplements corrected the level of CXCL1, CXCL13, and CCL22 chemokines but did not recover suppressed chemokines. SuChi and ORL stimulated the expression of satiety associated proopiomelanocortin (POMC) and suppressed the appetite-stimulating Agouti-related protein (AgRP) genes. All supplements improved the locomotion of mice. Taken collectively, we found that SuChi more than Chi possessed an activity close to that of ORL, preventing metabolic disorders in mice fed with OLZ. As OLZ carries positive charge and SuChi is negatively charged, we hypothesized that SuChi's protective effect can be explained by electrostatic interaction between OLZ byproducts and SuChi in the gastrointestinal tract.

Thinned young apple powder prevents obesity-induced neuronal apoptosis via improving mitochondrial function of cerebral cortex in mice

Mitochondrial dysfunction is one of the triggers for obesity-induced neuron apoptosis. Thinned young apple is getting more attention on account of the extensive biological activities because of rich polyphenols and polysaccharides. However, the neuroprotective effect of thinned young apple powder (YAP) is still unclear. The aim of the present study was to investigate the preventive effect of YAP on obesity-induced neuronal apoptosis. C57BL/6J male mice were divided into 5 groups, control (CON), high fat diet (HFD), HFD + orlistat (ORL), HFD + low-dose young apple powder (LYAP) and HFD + high-dose young apple powder (HYAP) groups and intervened for 12 weeks. It was found that the YAP effectively reduced body weight gain. Importantly, the levels of pro-apoptosis protein were lower in LYAP and HYAP groups than the HFD group, such as Bak/Bcl2 and cleaved caspase3/caspase3. Pathway analysis based on untargeted metabolomics suggested that YAP alleviated obesity-induced neuronal apoptosis by three main metabolic pathway including arginine metabolism, citrate cycle (TCA cycle) and glutathione metabolism. Meanwhile, YAP improved the protein expression of mitochondrial respiratory chain complex, maintained the homeostasis of TCA cycle intermediates, protected the balance of mitochondrial dynamics and alleviated lipid accumulation. In addition, the levels of several antioxidants in cerebral cortex were higher in HYAP group than the HFD group like superoxide dismutase (SOD) and catalase (CAT). In summary, YAP supplementation suppressed neuronal apoptosis in the cerebral cortex of HFD-induced obesity mice by improving mitochondrial function and inhibiting oxidative stress.

Fabrication of Nanocrystals for Enhanced Distribution of a Fatty Acid Synthase Inhibitor (Orlistat) as a Promising Method to Relieve Solid Ehrlich Carcinoma-Induced Hepatic Damage in Mice.

Orlistat (ORL) is an effective irreversible inhibitor of the lipase enzyme, and it possesses anticancer effects and limited aqueous solubility. This study was designed to improve the aqueous solubility, oral absorption, and tissue distribution of ORL via the formulation of nanocrystals (NCs). ORL-NC was prepared using the liquid antisolvent precipitation method (bottom-up technology), and it demonstrated significantly improved solubility compared with that of the blank crystals (ORL-BCs) and untreated ORL powder. The biodistribution and relative bioavailability of ORL-NC were investigated via the radiolabeling technique using Technetium-99m (99mTc). Female Swiss albino mice were used to examine the antitumor activity of ORL-NC against solid Ehrlich carcinoma (SEC)-induced hepatic damage in mice. The prepared NCs improved ORL's solubility, bioavailability, and tissue distribution, with evidence of 258.70% relative bioavailability. In the in vivo study, the ORL-NC treatment caused a reduction in all tested liver functions (total and direct bilirubin, AST, ALT, and ALP) and improved modifications in liver sections that were marked using hematoxylin and eosin staining (H&E) and immunohistochemical staining (Ki-67 and ER-α) compared with untreated SEC mice. The developed ORL-NC could be considered a promising formulation approach to enhance the oral absorption tissue distribution of ORL and suppress the liver damage caused by SEC.

Efficacy of anti-obesity agents: a systematic review and network meta-analysis of randomized controlled trials

Abstract Background: To conduct a network meta-analysis comparing the safety and efficacy of five anti-obesity drugs approved by the United States Food and Drug Administration (US FDA)-Bupropion/Naltrexone combination (BUP/NLX), Liraglutide (LIRA), Orlistat (ORLI), Phentiramine/Topiramate combination (PHEN/TPM) and Simaglutide (SGT) vs placebo. Methods: The study's eligibility criteria include randomized controlled trials (RCTs) with a focus on obese patients receiving BUP/NLX or LIRA or ORLI or PHEN/TPM or SGT versus placebo. We conducted a comprehensive search of electronic databases (PubMed, Embase, Cochrane Library, and Scopus) to identify relevant randomized controlled trials published, with no restrictions on the publication language or year. Three reviewers independently screened the studies, extracted data, and assessed the risk of bias using the Cochrane Risk of Bias tool. Bucher's and Bayesian Meta-regression Simulation Method were used for indirect head-to-head comparison between various active drugs. RevMan Version 5.4® along with A Network Meta- Analysis Toolkit by Cochrane Methods were used. p-value less than 0.05 was considered significant. Results: Total 28 studies were included in this meta-analysis. PHEN/TPM combination exhibited (odds ratio :0.568, p value <0.001, cl 95%) ORLI (odds ratio: 0.889, p value <0.001, cl 95%), SGT (odds ratio: 0.922, p value <0.001, cl 95%). BUP/NLX combination exhibited a high (odds ratio: 4.61, p value <0.001, cl 95%) LIRA displayed the lowest (odds ratio: 1.109, p value <0.001, cl 95%). Network meta-analysis revealed. BUP/NLX combination exhibited highest Efficacy. ORLI found as safest among the evaluated drugs. SGT had significant likelihood of adverse events (odds ratio = 1.328, p-value<0.0001, Cl 95%) compared to ORLI (odds ratio = 0.138, p-value<0.0001, Cl 95%), BUP/NLX (odds ratio = 0.197, p-value<0.0001, cl 95%), and LIRA (odds ratio = 0.456, p-value < 0.001, Cl 95%), PHEN/TPM (odds ratio = 0.456, p-value<0.0001, Cl 95%). Discussion: These findings have important clinical implications for the management of obesity. The BUP/NLX , LIRA , and SGT can be considered as effective treatment options for weight reduction. However, healthcare providers need to carefully consider the safety profiles and potential side-effects of these medications when making treatment decisions. The study relied on aggregated data, which might introduce bias. High attrition rates and heterogeneity among studies limit the findings. It only compared common gastrointestinal side effects and didn't use the GRADE approach for evidence quality. Conclusion: Study provides evidence supporting the efficacy of anti-obesity medications compared to placebo. BUP/NLX combination, LIRA, and SGT emerged as the most effective agents, considering safety profile. Findings can guide clinicians about options for obesity management. Study Registration: The study is registered with PROSPERO (CRD42023465989).

Ameliorative effects of Orlistat and metformin either alone or in combination on liver functions, structure, immunoreactivity and antioxidant enzymes in experimentally induced obesity in male rats

BackgroundPrevalence of obesity is increasing worldwide. Obesity is associated with incidences of metabolic disorders and cardiovascular diseases and the risk of having it rose sharply during the COVID-19 pandemic. Obesity is associated with oxidative stress, inflammatory markers and hepatic disorders and has become one of the silent killer diseases affecting global health. MethodsThis study examined the effects of obesity on liver functions (ALT, AST and LDH), lipid profile (TG, TC, HDL-c, LDL-c and vLDL-c), tumour necrosis factor alpha (TNF-α), inflammatory marker, C-reactive protein (CRP), leptin hormone and antioxidant enzymes (CAT, SOD and GPx) and lipid peroxidation marker (MDA) in liver homogenates besides histological structure of the liver tissues and assessment of DNA damage. Fifty male Wistar rats were used and they were divided into five treatment groups: I-Control group, II-high-fat diet (HFD) treated group (Obesity) group, III-HFD plus Orlistat (ORL), IV-HFD plus metformin (Met) and V- HFD plus ORL plus Met. ResultsExperimentally-induced obesity caused a significant increase in liver enzymes including lipid markers (triglycerides and total cholesterol), inflammatory markers, tumour markers and lipid peroxidation markers and a concurrent decline in antioxidant enzymes and damage of liver main structures characterised by presence of congestion and accumulation of mononuclear inflammatory cells in blood sinusoids. In contrast, groups treated with either ORL or Met or both group, we recorded restoration of normal hepatic structures and a decline in DNA damage, liver enzymes and antioxidant levels. The best restoration and amelioration were observed in the group treated with a combination of ORL and Met. ConclusionOur findings indicated the synergistic effect of ORL and Met in ameliorating hepatic functions and lipid profile, alleviating inflammation, genotoxicity and side effects of experimentally-induced obesity.

A polydopamine imprinted array on a binder-free carbon cloth assembled by gold carbon quantum dots as a portable flexible 3D nano-electrochemical sensor for selective trace monitoring of orlistat (xenical)

One of the cutting-edge emerging approaches being used by researchers in the field of sensors is to go beyond conventional techniques and design flexible, portable, selective sensors that can swiftly and accurately identify trace quantities of target molecules. In this research, carbon cloth (CC) as a binder-free 3D flexible material, served as the working electrode. In a single-step, hydrothermal approach AuCD nanoparticles were synthetized and used to modify the CC surface. The molecular imprinting polymer approach using in situ electropolymerization of dopamine (DA) in the presence of orlistat (OST) utilized to fabricate imprinted sensor. The surface response (Box-Behnken) methodology was used to optimize the parameters affecting the electrode performance. In the conditions of pH = 8, DA to OST ratio = 2.5, cycle number = 30, KOH = 3.5 M, elution time = 20.4 min, and 0.0005 to 1.3 nM linear range with a detection limit of 0.0002 nM, the best response was obtained for the accurate identification of the OST. The stability, selectivity, and performance of the presented sensor were evaluated under optimal conditions. Using blood serum and urine samples, satisfactory outcomes were achieved in real samples. This is the first electrochemical sensor report for OST detection to date.

In vitro and in vivo local tolerability of a synergistic anti-tuberculosis drug combination intended for pulmonary delivery.

A drug combination, vancomycin (VAN) plus tetrahydrolipstatin (THL), has demonstrated an effective synergistic action in vitro against Mycobacterium tuberculosis (Mtb). The poor oral bioavailability of VAN and THL and the predominant tropism of Mtb infection to the lungs make their pulmonary administration very attractive. To evaluate their local tolerability, bronchial cells, alveolar cells and monocytes were exposed to concentrations around and above their minimal inhibitory concentration (MIC). The VAN had no inhibitory activity on the tested human cell lines, even at a concentration 125 times higher than its MIC, whereas the THL, alone or in combination with VAN, presented a cytostatic action. Monolayer epithelium showed no significant irreversible damage at concentrations up to 100 times the combination MIC. BALB/cAnNRj mice exposed to concentration of 50 times the combination MIC delivered endotracheally 3 times a week for 3 weeks showed no clinical signs or significant weight loss. The increase of proinflammatory biomarkers (i.e., IL-1, IL-6, TNF-α and proportion of inflammatory cells) and cytotoxicity in bronchoalveolar lavage fluid (BALF) were non-significant. Lung histopathology did not show significant tissue damage. The VAN/THL combination at doses up to 50 times the combination MIC is found to be thus well tolerated by pulmonary route. This study is a promising result and encouraging further investigations of pulmonary administration of VAN/THL combination as dry powder for anti-tuberculosis treatment.

ANTICANCER EFFECTS OF DIFFERENT FATTY ACID SYNTHASE INHIBITORS ON ORAL CANCER

<h3>Objectives</h3> Overexpression of fatty acid synthase (FASN) is associated with aggressiveness, poor prognosis, and risk of metastasis in several human cancers, including oral squamous cell carcinomas (OSCC). Here, we compared the in vitro effects of 3 FASN inhibitors on malignant phenotypes of the OSCC cell line SCC-9. <h3>Study Design</h3> SCC-9 cells were treated with C75, triclosan (TCS), and orlistat (ORL) in their respective IC12.5, IC25, and IC50. We analyzed proliferation using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, cell cycle, and apoptosis by flow cytometry. Cell migration and invasion were evaluated by transwell inserts and adhesion using type I collagen or fibronectin. <h3>Results</h3> C75 showed the lowest IC50, whereas ORL presented the highest IC50. Each drug promoted distinct morphologic changes in SCC-9 cells and was able to significantly reduce FASN activity. All drugs promoted cell cycle arrest in G0/G1 and induced apoptosis at IC50. C75 reduced cell migration and invasion and increased the adhesion of SCC-9 cells. TCS reduced adhesion, migration, and invasion of SCC-9 cells. ORL reduced cell migration but did not significantly modify the adhesion and invasion of SCC-9 cells. <h3>Conclusions</h3> FASN inhibitors affected significant steps of tumor progression, and TCS showed better anticancer effects on SCC-9 cells.

Anti‐obesity effect of Premature Citrus Extract in high‐fat diet induced obesity mice

BackgroundObesity is a worldwide health threat. Premature citrus extract (PCE) are known to contain high concentrations of flavonoids, polyphenols, and organic acids with health functions. The current study aimed to investigate the anti‐obesity effect of PCE on a high‐fat diet (HFD)‐induced obesity mice.MethodMice were fed on chow or HFD with or without Orlistat (ORL), Hesperidin (HES), and PCE treatment for 10 weeks. Triglyceride (TG) content and total cholesterol (TC), and low‐density lipoprotein cholesterol (LDL‐c), and high‐density lipoprotein cholesterol (HDL‐c) levels were determined by TG, HDL and LDL Assay Kit (BioAssay System). The phosphorylation levels of AMP‐activated protein kinase (AMPK) and acetyl Co‐A carboxylase (ACC); the expression of sterol regulatory element binding protein‐2 (SREBP‐2), 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGCR), Acyl‐coenzyme A: cholesterol acyltransferases (ACAT‐1) and mitochondrial uncoupling proteins (UCP‐3) were observed via western blot analysis.ResultsPCE and HES administered group significantly reduced the weights of body, liver, and white adipose tissue compared to the HFD group. Supplementation with PCE and HES significantly decreased the levels of TG, TC, and (LDL‐c), and increased (HDL‐c) levels in serum compared to the HFD group. Furthermore, treatment with PCE and HES significantly decreased the levels of TG and TC in the liver whereas increased the levels of TG and TC in feces compared to the HFD group. Western blot analysis revealed that PCE and HES increased the phosphorylation levels of both AMPK and ACC and significantly decreased the expression levels of SREBP‐2, HMGCR, and ACAT‐1 in the liver compared to the HFD group. In addition, both PCE and HES increased the expression level of UCP‐3 in skeletal muscle tissue.ConclusionOverall results suggest that PCE and HES exerts an anti‐obesity effect via activation of AMPK and associated signaling cascades related to lipid metabolism in HFD‐induced obesity mice

Activity-Dependent Modulation of Tonic GABA Currents by Endocannabinoids in Hirudo verbana.

Endocannabinoids are lipid neuromodulators that are synthesized on demand and primarily signal in a retrograde manner to elicit depression of excitatory and inhibitory synapses. Despite the considerable interest in their potential analgesic effects, there is evidence that endocannabinoids can have both pro-nociceptive and anti-nociceptive effects. The mechanisms contributing to the opposing effects of endocannabinoids in nociception need to be better understood before cannabinoid-based therapies can be effectively utilized to treat pain. Using the medicinal leech, Hirudo verbana, this work investigates whether endocannabinoids modulate tonic inhibition onto non-nociceptive afferents. In voltage clamp recordings, we analyzed changes in the tonic inhibition in pressure-sensitive (P) cells following pre-treatment with endocannabinoids, 2-arachidonoylglycerol (2-AG) or anandamide (AEA). We also tested whether high frequency stimulation (HFS) of nociceptive (N) cells could also modulate tonic inhibition. Both endocannabinoid application and N cell HFS depressed tonic inhibition in the P cell. Depression of tonic inhibition by N cell HFS was blocked by SB 366791 (a TRPV1 inhibitor). SB 366791 also prevented 2-AG-and AEA-induced depression of tonic inhibition. HFS-induced depression was not blocked by tetrahydrolipstatin (THL), which prevents 2-AG synthesis, nor AM 251 (a CB1 receptor inverse agonist). These results illustrate a novel activity-dependent modulation of tonic GABA currents that is mediated by endocannabinoid signaling and is likely to play an important role in sensitization of non-nociceptive afferent pathways.

Approaches to studying injury-induced sensitization and the potential role of an endocannabinoid transmitter.

Endocannabinoids are traditionally thought to have an analgesic effect. However, it has been shown that while endocannabinoids can depress nociceptive signaling, they can also enhance non-nociceptive signaling. Therefore, endocannabinoids have the potential to contribute to non-nociceptive sensitization after an injury. Using Hirudo verbana (the medicinal leech), a model of injury-induced sensitization was developed in which a reproducible piercing injury was delivered to the posterior sucker of Hirudo. Injury-induced changes in the non-nociceptive threshold of Hirudo were determined through testing with Von Frey filaments and changes in the response to nociceptive stimuli were tested by measuring the latency to withdraw to a nociceptive thermal stimulus (Hargreaves apparatus). To test the potential role of endocannabinoids in mediating injury-induced sensitization, animals were injected with tetrahydrolipstatin (THL), which inhibits synthesis of the endocannabinoid transmitter 2-arachidonoylglycerol (2-AG). Following injury, a significant decrease in the non-nociceptive response threshold (consistent with non-nociceptive sensitization) and a significant decrease in the response latency to nociceptive stimulation (consistent with nociceptive sensitization) were observed. In animals injected with THL, a decrease in non-nociceptive sensitization in injured animals was observed, but no effect on nociceptive sensitization was observed.

Microalgae oil from Schizochytrium sp. alleviates obesity and modulates gut microbiota in high-fat diet-fed mice.

Omega-3 PUFAs rich in fish oil are believed to prevent obesity by improving lipid metabolism and regulating gut microbiota. Microalgae oil is considered as an alternative source of omega-3 PUFAs owing to diminishing fish resources. Schizochytrium microalgae oil (SMO), with a high DHA proportion, is a promising source for commercial DHA production. However, its weight-loss and gut microbiota-regulating properties are not well studied. Here we compared the obesity reducing effects of SMO, commercial fish oil (FO) and a weight-loss drug, Orlistat (OL), in a high-fat diet (HFD) induced obesity mouse model. We found that SMO is comparable to commercial FO and OL with regard to weight loss, and it even exhibits the weight-loss effects earlier than FO and OL. It can efficiently inhibit the expression of lipogenesis-related genes and induce the expression of lipolysis-related genes. Moreover, SMO has different gut microbiota modulating effects from those of FO and OL. It does not influence the diversity of bacterial community, but does increase the abundance of several beneficial SCFAs-producing bacteria and inhibits obesity-promoting Desulfovibrio and several pathogens. We also found that SMO recovers the HFD-disturbed metabolic capability of gut microbiota. It can increase the abundance of several metabolism-related pathways, such as those of amino acids, SCFAs and bile acid, and decrease the level of the LPS biosynthesis pathway, which probably contributes to an improvement of lipid metabolism and restoration of the colonic mucosal barrier impaired by HFD. Our data suggest that SMO can be used as a superior dietary supplement for alleviating obesity.

Combination Therapy of Metastatic Castration-Recurrent Prostate Cancer: Hyaluronic Acid Decorated, Cabazitaxel-Prodrug and Orlistat Co-Loaded Nano-System.

PurposeProstate cancer (PCa) is the second leading cause of cancer-related death among men in developed countries. Cabazitaxel (CBZ) is recommended as one of the most active chemotherapy agents for PCa. This study aimed to develop a hyaluronic acid (HA) decorated, cabazitaxel-prodrug (HA-CBZ) and orlistat (ORL) co-loaded nano-system against the prostate cancer in vitro and in vivo.MethodsCabazitaxel-prodrug was firstly synthesized by conjugating HA with CBZ through the formation of ester bonds. HA contained ORL and CBZ prodrug co-loaded lipid-polymer hybrid nanoparticles (ORL/HA-CBZ/LPNs) were constructed and characterized in terms of particle size, zeta potential, drug loading capacity and stability. The antitumor efficiency and systemic toxicity of LPNs were evaluated in vitro and in vivo.ResultsThe resulting ORL/HA-CBZ/LPNs were 150.9 nm in particle size with narrow distribution and high entrapment efficiency. The minimum combination index of 0.57 was found at a drug ratio of 1:2 (ORL:HA-CBZ, w/w) in the drug co-loaded formulations, indicating the strongest synergism effect. ORL/HA-CBZ/LPNs demonstrated an enhanced in vitro and in vivo antitumor effect compared with single drug loaded LPNs and free drug formulations.ConclusionORL/HA-CBZ/LPNs showed remarkable synergism cytotoxicity and the best tumor inhibition efficiency in mice with negligible systemic toxicity. ORL/HA-CBZ/LPNs can be highly useful for targeted prostate cancer therapy.

Cocaine-induced increases in motivation require 2-arachidonoylglycerol mobilization and CB1 receptor activation in the ventral tegmental area

A wide body of evidence supports an integral role for mesolimbic dopamine (DA) in motivated behavior. In brief, drugs that increase DA in mesolimbic terminal regions, like cocaine, enhance motivation, while drugs that decrease DA concentration reduce motivation. Data from our laboratory and others shows that phasic activation of mesolimbic DA requires signaling at cannabinoid type-1 (CB1) receptors in the ventral tegmental area (VTA), and systemic delivery of CB1 receptor antagonists reduces DA cell activity and attenuates motivated behaviors. Recent findings demonstrate that cocaine mobilizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the VTA to cause phasic activation of DA neurons and terminal DA release. It remains unclear, however, if cocaine-induced midbrain 2-AG signaling contributes to the motivation-enhancing effects of cocaine. To examine this, we trained male and female rats on a progressive ratio (PR) task for a food reinforcer. Each rat underwent a series of tests in which they were pretreated with cocaine alone or in combination with systemic or intra-VTA administration of the CB1 receptor antagonist rimonabant or the 2-AG synthesis inhibitor tetrahydrolipstatin (THL). Cocaine increased motivation, measured by augmented PR breakpoints, while rimonabant dose-dependently decreased motivation. Importantly, intra-VTA administration of rimonabant or THL, at doses that did not decrease breakpoints on their own, blocked systemic cocaine administration from increasing breakpoints in male and female rats. These data suggest that cocaine-induced increases in motivation require 2-AG signaling at CB1 receptors in the VTA and may provide critical insight into cannabinoid-based pharmacotherapeutic targets for the successful treatment of substance abuse.

Adjunction of the Lipase Inhibitor Orlistat Improves Grape Seed Extract Neuroprotection against Brain Ischemia/Reperfusion Injury in Rats

Abstract: Aim: Stroke is a public health concern for which there is currently no prophylaxis. In this study, we assessed the protective effect of Grape Seed Extract (GSE) and Orlistat (ORL) against brain ischemia/reperfusion (I/R) injury. Methods: Adult male Wistar rats were treated either with GSE (2.5 g/kg), ORL (4 mg/kg) or both drugs for one week and ischemia performed during 30 min by a bilateral common carotid artery occlusion (BCCAO), followed by 60 min reperfusion. Rats were then sacrificed, their whole brain used for infarct size determination using TTC staining or dissected into cortex, hippocampus and cerebellum for biochemical analysis of I/R-induced oxidative stress and energy failure. Results: In the three brain regions of interest, I/R disturbed protein carbonylation, xanthine oxidase (XO), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities, as well as intracellular mediators as hydrogen peroxide (H2O2), calcium and iron. Furthermore I/R altered energy fueling through the decrease of α-ketoglutarate dehydrogenase (α-KGDH) and fumarase (FH) together with mitochondrial complexes I and II along with glutamatergic excitotoxicity through glutamate dehydrogenase (GDH) and glutamine synthetase (GS) activities into cortex and hippocampal areas but not into cerebellum. In addition I/R affected mitochondrial viability as assessed by MTT staining and the moonlighting apoptosis inducer glyceraldehyde-3- phosphate dehydrogenase (GAPDH). Conclusion: Interestingly, GSE prevented efficiently the deleterious effects of I/R and the best protection was obtained when combining the two drugs, especially within cortex and hippocampus compartments. Thus, adjunction of ORL to GSE treatment is a promising strategy to improve neuroprotection from stroke. Key words: Brain I/R, GSE, Orlistat, Neuroprotection, Energy failure.

Accumulating evidence to support the safe and efficacious use of a proprietary blend of capsaicinoids in mediating risk factors for obesity.

Obesity is a significant public health concern, and finding safe and effective means for combating this condition is needed. This study investigates the safety and efficacy of supplementation of a blend of capsaicinoids on weight gain, fat mass, and blood chemistry in a high‐fat diet (HFD) model of obesity in mice and on adipocyte differentiation and gene expression in 3T3‐L1 preadipocytes. High‐fat diet (HFD)‐fed mice were treated with a proprietary capsaicinoid concentrate (Capsimax®; OmniActive Health Technologies Ltd., India) and compared to orlistat (ORL) and normal chow‐fed mice (NC). Mice fed a high‐fat diet showed significantly lower weight gain upon Capsimax® (CAP) administration than their HFD counterparts and similar to that observed with ORL animals. In addition, CAP decreased the high‐fat diet‐induced increases in adipose tissue and epididymal fat pad mass and hypertrophy after 52 days of treatment. Both the CAP and ORL groups had increased plasma concentrations of leptin. CAP extracts decreased triacylglycerol content in 3T3‐L1 preadipocytes and decreased markers of adipogenesis including peroxisome proliferator‐activated receptor (PPAR‐ɣ) and fatty acid‐binding protein 4 (FABP4). Expression of genes involved in lipogenesis such as stearoyl‐CoA desaturase (SCD) and fatty acid synthase (FSN) was decreased by CAP in a dose‐dependent manner. Thermogenic genes and markers of brown adipose tissue including uncoupling protein 1 (UCP1) and PR domain‐containing 16 (Prdm16) were induced by CAP in the preadipocyte cells. These in vivo and in vitro data support that this proprietary capsaicinoid concentrate reduces weight gain and adiposity at least in part through decreasing lipogenesis and increasing thermogenesis.

Protective effect of grape seed extract and orlistat co-treatment against stroke: Effect on oxidative stress and energy failure

Ischemic stroke is a major health concern and a leading cause of mortality worldwide. Oxidative stress is an early event in the course of stroke inducing neuro-inflammation and cell death. Grape seed extract (GSE) is a natural phytochemical mixture exhibiting antioxidant, anti-inflammatory and neuroprotective properties. Orlistat (ORL) is an anti-obesity agent and a gastro-intestinal lipase inhibitor which showed recently beneficial effects on brain lipotoxicity. Recent studies reported the increase of lipase activity upon stroke which led us to investigate the neuroprotective effect of ORL on rat brain I/R injury as well as the putative synergism with GSE. I/R insult infarcted the brain parenchyma as assessed by TTC staining, induced an oxidative stress as revealed by increased lipoperoxidation along with alteration of antioxidant enzymes activities which was corrected using the cotreatment of ORL + GSE. I/R also disturbed the main metabolic pathways involved in brain fueling as glycolysis, neoglucogenesis, glycogenolysis, TCA cycle and electron transfer chain (ETC) complexes. These disturbances were also corrected with the cotreatment ORL + GSE which maintained energetic activities near to the control level. I/R also disrupted transition metals distribution, along with associated enzymes as tyrosinase, LDH or glutamine synthetase activities and induced hippocampal inflammation as revealed by glycogen depletion from dentate gyrus area along with depressed anti-inflammatory IL1β cytokine and increased pro-inflammatory CD68 antigen. Interestingly almost all I/R-induced disturbances were corrected either partially upon ORL and GSE on their own and the best neuroprotection was obtained in the presence of both drugs (ORL + GSE) enabling robust neuroprotection of the sub granular zone within hippocampal dentate gyrus area.

For people with obesity or overweight, what are the effects of long-term orlistat, sibutramine, and rimonabant?

For people with obesity or overweight, what are the effects of long-term orlistat, sibutramine, and rimonabant?

Meta-analysis and Approach of the Real Impact of Anorexigenic Drugs in the Obesity in Humans: The Last Five Years of the Randomized Studies.

Obesity shows a multifactorial disease and presents a serious public health problem, with an alarming epidemic character. According to NHANES (National Health and Nutrition Examination Survey) from 2015 to 2016, 39.6% of American adults and 18.5% of young people were obese and 7.7% of adults and 5.6% of young people had severe obesity. Brazil ranks fifth in the world ranking, with about 18 million people reaching up to 70 million overweight individuals. Despite shortterm weight loss with diet and exercise, weight regain continues to be a concern. Anti-obesity drugs, such as Sibutramine (SIB), Phentermine (PHEN), Fenproporex (FEN), Mazindol (MAZ), Amfepramone (AMFE) and Orlistat (ORL) may play a role in weight reduction in patients whose condition is refractory to non- and maintenance of weight loss. A systematic review followed by meta-analysis of randomized clinical trials over the past five years to explore the efficacy and safety of anorexigenic drugs for weight reduction and consequent treatment of obesity. The search strategy in MEDLINE / Pubmed, Web of Science, ScienceDirect Journals (Elsevier), Scopus (Elsevier), OneFile (Gale) is as follows : - search for mesh terms (Sibutramine, Phentermine, Fenproporex, Mazindol, Amfepramone , Orlistat, Weight loss, Safety), and the use of booleans "and" between mesh terms and "or" among historical findings. It was observed that in the last five years of randomized studies no significant general complications were found, with only 5.7%. The mean overall weight loss was 6.18 (± 2.8) kg in the mean time of 12 months. The overall success rate among these drugs was 80.18%. The p-value values did not present a significant statistical difference, being p <0.05 within each drug group analyzed, for both weight and success rates. The scientific findings of randomized studies on the use of anorexigenic drugs to treat obesity have shown safety and efficiency in the last five years, with a reasonable weight loss and no significant complications.

Orlistat-Induced Gut Microbiota Modification in Obese Mice.

Introduction Accumulating evidence has indicated that alterations of gut microbiota have been involved in various metabolic diseases. Orlistat, a reversible inhibitor of pancreatic and gastric lipase, has beneficial effects on weight loss and metabolism. However, the effect of orlistat on the composition of gut microbiota remains unclear. Objective We aimed to explore the effect of orlistat on gut microbiota in high-fat diet (HFD) fed C57BL/6J obese mice. Methods C57BL/6J mice were randomly divided into three groups: control (NCD), HFD, and HFD + orlistat (ORL). Mice in the NCD group were fed chow diet, while the other groups were fed HFD for 6 months, and orlistat was added in the final 3 months in the HFD + ORL group. After sacrifice, body weight and metabolic parameters were assessed, and the gut microbial composition was analyzed by 16S rRNA gene sequencing. Results Orlistat treatment exerted beneficial effects on body weight, plasma cholesterol, and glucose tolerance. Meanwhile, orlistat treatment modified the gut microbiota, presenting as reduced total microbial abundance and obvious upregulated bacteria. Moreover, the upregulated bacteria correlated with several metabolic pathways. Conclusions Orlistat may exert beneficial effects on body weight and glucose tolerance through modifying the composition of gut microbiota.