A clinical study and future prospects for bioactive compounds and semi-synthetic molecules in the therapies for Huntington's disease.

A neurodegenerative disorder (ND) refers to Huntington's disease (HD) which affects memory loss, weight loss, and movement dysfunctions such as chorea and dystonia. In the striatum and brain, HD most typically impacts medium-spiny neurons. Molecular genetics, excitotoxicity, oxidative stress (OS), mitochondrial, and metabolic dysfunction are a few of the theories advanced to explicit the pathophysiology of neuronal damage and cell death. Numerous in-depth studies of the literature have supported the therapeutic advantages of natural products in HD experimental models and other treatment approaches. This article briefly discusses the neuroprotective impacts of natural compounds against HD models. The ability of the discovered natural compounds to suppress HD was tested using either in vitro or in vivo models. Many bioactive compounds considerably lessened the memory loss and motor coordination brought on by 3-nitropropionic acid (3-NP). Reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and enhanced mitochondrial energy generation have profoundly decreased the biochemical change. It is significant since histology showed that therapy with particular natural compounds lessened damage to the striatum caused by 3-NP. Moreover, natural products displayed varying degrees of neuroprotection in preclinical HD studies because of their antioxidant and anti-inflammatory properties, maintenance of mitochondrial function, activation of autophagy, and inhibition of apoptosis. This study highlighted about the importance of bioactive compounds and their semi-synthetic molecules in the treatment and prevention of HD.

Adalimumab therapy is associated with increased faecal short chain fatty acids in hidradenitis suppurativa.

Altered gut microbiota composition has been observed in individuals with hidradenitis suppurutiva (HS) and many other inflammatory diseases, including obesity, type 1 and type 2 diabetes. Here, we addressed whether adalimumab, a systemic anti-inflammatory therapy, may impact the microbiota biochemical profile, particularly on beneficial metabolites such as short-chain fatty acids (SCFAs). We conducted an observational single-arm pilot trial to assess gut microbiota composition by 16S rRNA gene sequence analysis and to detect metabolite signatures by gas chromatography in stool samples from participants with HS prior to and 12 weeks after commencing adalimumab therapy. HS individuals that better responded to adalimumab treatment showed a shift in the composition and function of the gut microbiota with significantly increased SCFA acetate and propionate compared to age, gender and BMI-matched healthy controls. A positive correlation was observed between propionate with Prevotella sp and Faecalibacterium prausnitsii. Increased SCFAs, changes in gut microbiota composition, function and metabolic profile following 12 weeks of adalimumab suggest that targeting SCFAs may be considered a potential biomarker to be evaluated as a complementary protective factor or as a diagnostically relevant signal in HS.

Influence of dietary supplementation of short-chain fatty acid sodium propionate in people living with HIV (PLHIV).

BACKGROUND: Non-AIDS-associated chronic diseases in HIV+ patients have been on the rise since the advent of antiretroviral therapy. Especially cardiovascular diseases and disruption in the gastrointestinal tract have limited health-related quality of life (QoL). Several of those complications have been associated with chronic systemic inflammation. Short-chain fatty acids (SCFA), with propionate as one of the major compounds, have been described as an important link between gut microbiota and the immune system, defining the pro- and the anti-inflammatory milieu through direct and indirect regulation of T-cell homeostasis. The effects of dietary supplementation of sodium propionate (SP) in people living with HIV (PLHIV) have not yet been investigated prior to this study. OBJECTIVES: To investigate the impact of SP uptake among PLHIV and its relevance to improve QoL, the study aimed to investigate metabolic, immunological, microbiome and patient-reported QoL-related changes post-SP supplementation with follow-up. METHODS: A prospective, non-randomized, controlled, monocentric interventional study was conducted in WIR, Center for Sexual Health and Medicine, in Bochum, Germany. 32 HIV+ patients with unaltered ART-regimen in the last three months were included. Participants were given SP for a duration of 12 weeks in the form of daily oral supplementation and were additionally followed-up for another 12 weeks. RESULTS: The supplementation of SP was well tolerated. We found an improvement in lipid profiles and long-term blood glucose levels. A decrease in pro-inflammatory cytokines and a depletion of effector T cells was observed. Regulatory T cells and IL-10 decreased. Furthermore, changes in taxonomic composition of the microbiome during follow-up were observed and improvement of items of self-reported life-quality assessment. CONCLUSION: Taken together, the beneficial impact of SP in PLHIV reflects its potential in improving metabolic parameters and modulating pro-inflammatory immune responses. Thus, possibly reducing the risk of cardiovascular disorders and facilitating long-term improvement of the gut flora.

The efficacy of novel metabolic targeted agents and natural plant drugs for nonalcoholic fatty liver disease treatment: A PRISMA-compliant network meta-analysis of randomized controlled trials.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease characterized by excess accumulation of fat in hepatocytes. Because no drug has been approved for NAFLD treatment, this work analyzed the effects of agents resulting from 2 research hotspots, metabolic target agents, and natural plant drugs, on NAFLD with network meta-analysis. METHODS: Public databases were searched through August 14, 2020. Randomized controlled trials that compared obeticholic acid, elafibranor, cenicriviroc, selonsertib, curcumin, silymarin, and resveratrol to placebo were included. Liver pathology improvement, hepatic biochemical indicators, and lipid metabolism indicators were analyzed. RESULTS: Thirty-five studies were included in the meta-analysis. Obeticholic acid was found to significantly increase the frequency of liver biopsy improvement compared to placebo (OR: 2.10; 95% CI: 1.60, 2.77). The ranking results among the hepatic biochemical indicators showed that obeticholic acid (94.9%) and elafibranor (86.3%) have a relative advantage in reducing alanine aminotransferase (ALT) levels, and obeticholic acid also had an advantage (95.4%) in reducing aspartate aminotransferase (AST) levels. Considering lipid metabolic indicators, elafibranor (expSMD: 0.01; 95% CI: 0.00, 0.05; SUCRA: 100%), and obeticholic acid (expSMD: 0.48; 95% CI: 0.28,0.84; SUCRA: 75.6%) significantly reduced triglyceride (TG) levels compared with placebo; moreover, obeticholic acid, but not elafibranor, caused a serious increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and a decrease in high-density lipoprotein cholesterol (HDL-C) levels. CONCLUSIONS: Novel metabolic targeted agents generally have better effects than natural plant drugs, especially obeticholic acid, and elafibranor. However, obeticholic acid showed serious adverse effects such as increasing LDL-C levels and decreasing HDL-C levels. Curcumin showed potential advantages for NAFLD but lacked statistical significance.

Protective Effect of Natural Products against Huntington's Disease: An Overview of Scientific Evidence and Understanding Their Mechanism of Action.

Huntington's disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of characteristic psychiatric disturbances and cognitive and motor dysfunction. To the best of our knowledge, there is no treatment available to completely mitigate the progression of HD. Among various therapeutic approaches, exhaustive literature reports have confirmed the medicinal benefits of natural products in HD experimental models. Building on this information, this review presents a brief overview of the neuroprotective mechanism(s) of natural products against in vitro/in vivo models of HD. Relevant studies were identified from several scientific databases, including PubMed, ScienceDirect, Scopus, and Google Scholar. After screening through literature from 2005 to the present, a total of 14 medicinal plant species and 30 naturally isolated compounds investigated against HD based on either in vitro or in vivo models were included in the present review. Behavioral outcomes in the HD in vivo model showed that natural compounds significantly attenuated 3-nitropropionic acid (3-NP) induced memory loss and motor incoordination. The biochemical alteration has been markedly alleviated with reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and increased mitochondrial energy production. Interestingly, following treatment with certain natural products, 3-NP-induced damage in the striatum was ameliorated, as seen histologically. Overall, natural products afforded varying degrees of neuroprotection in preclinical studies of HD via antioxidant and anti-inflammatory properties, preservation of mitochondrial function, inhibition of apoptosis, and induction of autophagy.

Advanced MRI of Liver Fibrosis and Treatment Response in a Rat Model of Nonalcoholic Steatohepatitis.

Background Liver biopsy is the reference standard to diagnose nonalcoholic steatohepatitis (NASH) but is invasive with potential complications. Purpose To evaluate molecular MRI with type 1 collagen-specific probe EP-3533 and allysine-targeted fibrogenesis probe Gd-Hyd, MR elastography, and native T1 to characterize fibrosis and to assess treatment response in a rat model of NASH. Materials and Methods MRI was performed prospectively (June-November 2018) in six groups of male Wistar rats (a) age- and (b) weight-matched animals received standard chow (n = 12 per group); (c) received choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) for 6 weeks or (d) 9 weeks (n = 8 per group); (e) were fed 6 weeks of CDAHFD and switched to standard chow for 3 weeks (n = 12); (f) were fed CDAHFD for 9 weeks with daily treatment of elafibranor beginning at week 6 (n = 14). Differences in imaging measurements and tissue analyses among groups were tested with one-way analysis of variance. The ability of each imaging measurement to stage fibrosis was quantified by using area under the receiver operating characteristic curve (AUC) with quantitative digital pathology (collagen proportionate area [CPA]) as reference standard. Optimal cutoff values for distinguishing advanced fibrosis were used to assess treatment response. Results AUC for distinguishing fibrotic (CPA >4.8%) from nonfibrotic (CPA ≤4.8%) livers was 0.95 (95% confidence interval [CI]: 0.91, 1.00) for EP-3533, followed by native T1, Gd-Hyd, and MR elastography with AUCs of 0.90 (95% CI: 0.83, 0.98), 0.84 (95% CI: 0.74, 0.95), and 0.65 (95% CI: 0.51, 0.79), respectively. AUCs for discriminating advanced fibrosis (CPA >10.3%) were 0.86 (95% CI: 0.76, 0.97), 0.96 (95% CI: 0.90, 1.01), 0.84 (95% CI: 0.70, 0.98), and 0.74 (95% CI: 0.63, 0.86) for EP-3533, Gd-Hyd, MR elastography, and native T1, respectively. Gd-Hyd MRI had the highest accuracy (24 of 26, 92%; 95% CI: 75%, 99%) in identifying responders and nonresponders in the treated groups compared with MR elastography (23 of 26, 88%; 95% CI: 70%, 98%), EP-3533 (20 of 26, 77%; 95% CI: 56%, 91%), and native T1 (14 of 26, 54%; 95% CI: 33%, 73%). Conclusion Collagen-targeted molecular MRI most accurately detected early onset of fibrosis, whereas the fibrogenesis probe Gd-Hyd proved most accurate for detecting treatment response. © RSNA, 2020 Online supplemental material is available for this article.

Moderate intensity exercise training combined with inulin-propionate ester supplementation increases whole body resting fat oxidation in overweight women.

BACKGROUND: Our previous work has shown that oral supplementation with inulin propionate ester (IPE) reduces intra-abdominal fat and prevents weight gain and that oral propionate intake enhances resting fat oxidation. The effects of IPE combined with exercise training on energy substrate utilisation are unknown. The aim of this study was to investigate the impact of 4-weeks IPE supplementation, in combination with a moderate intensity exercise training programme, on whole body fat oxidation and on plasma GLP-1 and PYY. METHODS: Twenty overweight healthy women participated in randomised parallel study and underwent 4 weeks of supervised exercise training either with IPE (EX/IPE group) or Placebo (EX/Placebo group) supplementation. Before and after the intervention participants conducted an experimental trial, which involved collection of expired gas and blood samples in the fasted state and during 7 h of the postprandial state. RESULTS: Within groups, the EX/IPE group significantly enhanced the amount of fat (Pre, 24.1 ±â€¯1.2 g; Post, 35.9 ±â€¯4.0 g, P < 0.05) oxidised and reduced CHO (Pre, 77.8 ±â€¯6.0 g; Post, 57.8 ±â€¯7.7 g, P < 0.05) oxidised, reduced body weight (Pre, 77.3 ±â€¯4.2 kg; Post, 76.6 ±â€¯4.1 kg, P < 0.05) and body fat mass (Pre, 37.7 ±â€¯1.9%; Post, 36.9 ±â€¯1.9%, P < 0.05). In EX/Placebo group, changes in amount of fat (Pre, 36.8 ±â€¯3.9 g; Post, 37.0 ±â€¯4.0 g) and CHO (Pre, 62.7 ±â€¯6.5 g; Post, 61.5 ±â€¯7.4 g) oxidised, body weight (Pre, 84.2 ±â€¯4.3 kg; Post, 83.6 ±â€¯4.3 kg) and body fat mass (Pre, 40.1 ±â€¯1.9%; Post, 38.7 ±â€¯1.5%) were not significant (P > 0.05). Comparing between groups, changes in the amount of fat oxidised were significantly (P < 0.05) different and a trend for difference was observed for amount of CHO oxidised (P = 0.06) and RER (P = 0.06). The interventions had no impact on fasting or postprandial plasma concentrations of GLP-1 and PYY. CONCLUSION: Moderate intensity exercise training programmes when combined with daily oral IPE supplementation may help overweight women to achieve increase in fat oxidation. The study was registered at clinicaltrials.gov as NCT04016350.

Effects of Inulin Propionate Ester Incorporated into Palatable Food Products on Appetite and Resting Energy Expenditure: A Randomised Crossover Study.

Supplementation with inulin-propionate ester (IPE), which delivers propionate to the colon, suppresses ad libitum energy intake and stimulates the release of satiety hormones acutely in humans, and prevents weight gain. In order to determine whether IPE remains effective when incorporated into food products (FP), IPE needs to be added to a widely accepted food system. A bread roll and fruit smoothie were produced. Twenty-one healthy overweight and obese humans participated. Participants attended an acclimatisation visit and a control visit where they consumed un-supplemented food products (FP). Participants then consumed supplemented-FP, containing 10 g/d inulin or IPE for six days followed by a post-supplementation visit in a randomised crossover design. On study visits, supplemented-FP were consumed for the seventh time and ad libitum energy intake was assessed 420 min later. Blood samples were collected to assess hormones and metabolites. Resting energy expenditure (REE) was measured using indirect calorimetry. Taste and appearance ratings were similar between FP. Ad libitum energy intake was significantly different between treatments, due to a decreased intake following IPE-FP. These observations were not related to changes in blood hormones and metabolites. There was an increase in REE following IPE-FP. However, this effect was lost after correcting for changes in fat free mass. Our results suggest that IPE suppresses appetite and may alter REE following its incorporation into palatable food products.

Current treatment options for nonalcoholic fatty liver disease.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the United States and is strongly associated to the metabolic syndrome. In this review, we will discuss the evidence behind the current recommendations on lifestyle modifications and available treatment options for NAFLD. RECENT FINDINGS: The unrelenting rise in obesity and diabetes epidemic has led to a large healthcare burden from NAFLD and it is projected to continue to grow over the next two decades. Lifestyle modification that leads to weight loss is effective at treating NAFLD, but these modifications require a multidisciplinary approach for success in the real world. Multiple pharmacologic treatment options have been studied with promising results, but none have been approved for treatment in the United States. Clinical trials are on-going to study further pharmacologic treatment alternatives. SUMMARY: NAFLD is the most common chronic liver disease in United States, and an independent risk factor for mortality. Implementation of lifestyle modifications through a multidisciplinary approach and careful selection of patients for pharmacologic interventions will be essential for successful management of NAFLD.

Treatment of exudative age-related macular degeneration with aflibercept combined with pranoprofen eye drops or nutraceutical support with omega-3: A randomized trial.

AIMS: The aim of this study was to determine whether a combination of intravitreal aflibercept (IVA) and pranoprofen eyedrops or nutraceutical support provides additional benefit over IVA monotherapy for the treatment of choroidal neovascularization (CNV) in age-related macular degeneration. METHODS: This was a prospective, randomized, pilot study in 60 patients with treatment-naïve CNV. Patients were randomized 1:1:1 into three groups: aflibercept monotherapy (AM), aflibercept plus pranoprofen (AP) or aflibercept plus nutraceutical (AN) tablets containing multivitamin antioxidant and mineral supplementation plus omega-3. RESULTS: At 12 months, all groups showed significant improvement in both best-corrected visual acuity (BCVA) and central retinal thickness (CRT). The mean BCVA change from baseline to 12 months was -0.26 ± 0.06 LogMAR, -0.30 ± 0.06 LogMAR and -0.24 ± 0.04 LogMAR in the AM, AP and AN groups, respectively. The mean CRT change from baseline to 12 months was -76.9 ± 10.9 µm, -129 ± 19.9 µm and -105 ± 11.6 µm in the AM, AP and AN groups, respectively. The AN group required one less IVA injection than the AM group. CONCLUSIONS: Compared with AM, both combination groups acted synergistically, although no significant benefits in BCVA were found over AM. Nutraceutical support with omega-3 leads to a reduced need for IVA.

Protective effects of p-coumaric acid against oxidant and hyperlipidemia-an in vitro and in vivo evaluation.

Dietary phenols are antioxidants with diverse physiological functions that are beneficial for human health. The objective of this research work was to investigate antioxidant activity of p-coumaric acid (p-CA) using four in vitro methods, the protective effects against oxidative stress in PC12 cells, and hypolipidemic effects on High fat-diet (HFD) mice model. The p-CA exhibited moderate antioxidant activity in the selected in vitro assay. The highest chelating activity of p-CA at 50 µg/mL was found to be 52.22%. Pretreatment with p-CA significantly enhanced cell viability of PC12 cell and suppressed AAPH-induced intracellular ROS generation and AAPH-induced LDH release. The hypolipidemic effects of p-CA (100 mg/kg BW) was directly linked to the increased expression of nuclear factor erythroid 2-related factor (Nrf2) by 2.0-fold, Glutathione peroxidase (Gpx) by 3.8-fold, Superoxide dismutase (SOD-1) by 1.6-fold, Heme oxygenase (HO-1) by 1.72-fold and NAD(P)H Quinone Dehydrogenase 1 (NQO-1) by 1.5-fold compared with HFD group. In addition to these effects, p-CA decreased total cholesterol and atherosclerosis index levels, and increased catalase (CAT) level in serum, total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) levels in liver as compared HFD group. Administration of p-CA also promoted the recovery of hyperlipidemia steatohepatitis in mice by ameliorating lipid peroxidation. These results suggested that p-CA is a potent antioxidant with potential therapeutic efficacy for treating hyperlipidemia symptoms.

Disease Progression and Pharmacological Intervention in a Nutrient-Deficient Rat Model of Nonalcoholic Steatohepatitis.

BACKGROUND: There is a marked need for improved animal models of nonalcoholic steatohepatitis (NASH) to facilitate the development of more efficacious drug therapies for the disease. METHODS: Here, we investigated the development of fibrotic NASH in male Wistar rats fed a choline-deficient L-amino acid-defined (CDAA) diet with or without cholesterol supplementation for subsequent assessment of drug treatment efficacy in NASH biopsy-confirmed rats. The metabolic profile and liver histopathology were evaluated after 4, 8, and 12 weeks of dieting. Subsequently, rats with biopsy-confirmed NASH were selected for pharmacological intervention with vehicle, elafibranor (30 mg/kg/day) or obeticholic acid (OCA, 30 mg/kg/day) for 5 weeks. RESULTS: The CDAA diet led to marked hepatomegaly and fibrosis already after 4 weeks of feeding, with further progression of collagen deposition and fibrogenesis-associated gene expression during the 12-week feeding period. Cholesterol supplementation enhanced the stimulatory effect of CDAA on gene transcripts associated with fibrogenesis without significantly increasing collagen deposition. Pharmacological intervention with elafibranor, but not OCA, significantly reduced steatohepatitis scores, and fibrosis-associated gene expression, however, was unable to prevent progression in fibrosis scores. CONCLUSION: CDAA-fed rats develop early-onset progressive NASH, which offers the opportunity to probe anti-NASH compounds with potential disease-modifying properties.

[Treatment of non-alcoholic fatty liver disease].

Non-alcoholic fatty liver disease and especially non-alcoholic steatohepatitis (NASH) and fibrosis are associated with severe liver disease and increased cardiovascular risk. It is therefore important to identify patients with NASH fibrosis. Therapeutical options include life style intervention and pharmacological treatment with vitamin E and pioglitazone; however, evidence of effect is scarce for all options. New treatments are under investigation and include glucagon-like peptide-1, farnesoid receptor as well as peroxisome proliferator-activated receptor-α/δ agonists. Bariatric surgery may be an option in selected patients.

Oxygen-independent combined photothermal/photodynamic therapy delivered by tumor acidity-responsive polymeric micelles.

Tumor hypoxia strikingly restricts photodynamic therapy (PDT) efficacy and limits its clinical applications in cancer therapy. The ideal strategy to address this issue is to develop oxygen-independent PDT systems. Herein, the rationally designed tumor pH-responsive polymeric micelles are devised to realize oxygen-independent combined PDT and photothermal therapy (PTT) under near-infrared light (NIR) irradiation. The triblock copolymer, poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(2-(piperidin-1-yl)ethyl methacrylate) (PEG-b-PCL-b- PPEMA), was prepared to co-encapsulate cypate and singlet oxygen donor (diphenylanthracene endoperoxide, DPAE) via self-assembly to obtain the micellar delivery system (C/O@N-Micelle). C/O@N-Micelle showed remarkable tumor accumulation and improved cellular internalization (2.1 times) as the pH value was changed from 7.4 during blood circulation to 6.8 in tumor tissues. The micelles could produce a potent hyperthermia for PTT of cypate under 808 nm NIR irradiation, which simultaneously induced thermal cycloreversion of DPAE generating abundant singlet oxygen for PDT without participation of tumor oxygen. Finally, the photothermally triggered PDT and PTT combination achieved efficient tumor ablation without remarkable systemic toxicity in an oxygen-independent manner. This work represents an efficient strategy for oxygen-independent combined PDT and PTT of cancers under NIR irradiation through co-encapsulation of cypate and DPAE into tumor pH-responsive polymeric micelles.

PPAR Agonists and Metabolic Syndrome: An Established Role?

Therapeutic approaches to metabolic syndrome (MetS) are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs) are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs), blood glucose, and abdominal adiposity. PPARs may be classified into the α, ß/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate) and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C). PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD) which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug-drug interactions (i.e., gemfibrozil) and myopathy should also be acknowledged.

p-Coumaric Acid, a Major Active Compound of Bambusae Caulis in Taeniam, Suppresses Cigarette Smoke-Induced Pulmonary Inflammation.

[Formula: see text]-coumaric acid ([Formula: see text]-CA) is a common compound found in medicinal herbs, including Bambusae Caulis in Taeniam (BC). It has been used to treat various diseases in China and Korea. Our previous study demonstrated that BC inhibits pulmonary and intestinal inflammation. In the present study, we used cigarette smoke (CS) to induce lung inflammation in vivo, and investigated the anti-inflammatory effects of [Formula: see text]-CA on CS-induced inflammatory mice model. Mice were treated with BC and [Formula: see text]-CA via oral injection 2[Formula: see text]h before CS exposure. The body weight and the inflammatory cells in the bronchoalveolar lavage fluid were measured. The levels of relative inflammatory factors were confirmed by enzyme-linked immunosorbent assay. The lung histological changes were examined by hematoxylin and eosin staining. Also, the protein level of nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) was evaluated by Western blotting. Our results indicated that BC and [Formula: see text]-CA inhibited CS-induced lung inflammation by regulating pro-inflammatory productions such as cytokines, chemokine, protease and NF-[Formula: see text]B. Consequently, these data demonstrated that [Formula: see text]-CA inhibited pulmonary inflammation by suppressing NF-[Formula: see text]B activity, through which pro-inflammatory mediators were regulated. Therefore, [Formula: see text]-CA, which was shown to be a major component of BC, can be considered as a strong therapeutic candidate for treating pulmonary inflammatory diseases.

CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis.

Prescription ω-3 fatty acid ethyl ester supplements are commonly used for the treatment of hypertriglyceridemia. However, the metabolic profile and effect of the metabolites formed by these treatments remain unknown. Here we utilized unbiased metabolomics to identify 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) as a significant metabolite of the ω-3-acid ethyl ester prescription Lovaza™ in humans. Administration of CMPF to mice before or after high-fat diet feeding at exposures equivalent to those observed in humans increased whole-body lipid metabolism, improved insulin sensitivity, increased beta-oxidation, reduced lipogenic gene expression, and ameliorated steatosis. Mechanistically, we find that CMPF acutely inhibits ACC activity, and induces long-term loss of SREBP1c and ACC1/2 expression. This corresponds to an induction of FGF21, which is required for long-term steatosis protection, as FGF21KO mice are refractory to the improved metabolic effects. Thus, CMPF treatment in mice parallels the effects of human Lovaza™ supplementation, revealing that CMPF may contribute to the improved metabolic effects observed with ω-3 fatty acid prescriptions.

The microbial metabolite indole-3-propionic acid improves glucose metabolism in rats, but does not affect behaviour.

CONTEXT: We have previously shown that an antidepressant-like effect of probiotics in rats was associated with a higher plasma level of the microbial tryptophan metabolite indole-3-propionic acid (IPA). OBJECTIVE: We therefore wanted to study the isolated effect of IPA on behaviour and glucose metabolism in rats. METHODS: Male Sprague-Dawley rats were fed control or IPA-enriched diet for six weeks (n = 12 per group) and assessed in the elevated plus maze, open field and forced swim test. Blood glucose, metabolic hormones and the white blood cell (WBC) composition were analysed. RESULTS: IPA (mean intake 27.3 mg/kg/day) significantly lowered fasting blood glucose level by 0.42 mM (95% CI 0.11-0.73). Similarly, fasting plasma insulin levels and the homeostatic model assessment (HOMA) index of insulin resistance were reduced, whereas plasma metabolic hormones, behaviour and WBC composition remained unaffected by IPA. CONCLUSIONS: Our findings highlight IPA as a promising candidate for treatment of metabolic disorders associated with insulin resistance.

Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders.

Over the last decade, a subfamily of G protein-coupled receptors that are agonized by endogenous and dietary free-fatty acids (FFA) has been discovered. These free-fatty acid receptors include FFA2 and FFA3, which are agonized by short-chained FFA, as well as FFA1 and FFA4, which are agonized by medium-to-long chained FFA. Ligands for FFA1 and FFA4 comprise the family of long chain polyunsaturated omega-3 fatty acids including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), suggesting that many of the long-known beneficial effects of these fats may be receptor mediated. In this regard, FFA4 has gathered considerable interest due to its role in ameliorating inflammation, promoting insulin sensitization, and regulating energy metabolism in response to FFA ligands. The goal of this review is to summarize the body of evidence in regard to FFA4 signal transduction, its mechanisms of regulation, and its functional role in a variety of tissues. In addition, recent endeavors toward discovery of small molecules that modulate FFA4 activity are also presented.

Anti-Inflammatory Effects of 3-(4'-Hydroxyl-3',5'-Dimethoxyphenyl)Propionic Acid, an Active Component of Korean Cabbage Kimchi, in Lipopolysaccharide-Stimulated BV2 Microglia.

We investigated the protective ability of 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), an active principle in Korean cabbage kimchi, against the production of proinflammatory mediators and cytokines, and the mechanisms involved in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. HDMPPA significantly suppressed the production of nitric oxide (NO) and prostaglandin E2, along with the expression of inducible NO synthase and cyclooxygenase-2 in LPS-stimulated BV2 cells, at concentrations with no cytotoxicity. HDMPPA also attenuated the LPS-induced expression and secretion of proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1ß. Furthermore, HDMPPA inhibited LPS-induced nuclear factor-κB (NF-κB) activation, which was associated with the abrogation of IκB-α degradation and phosphorylation, and subsequent decreases in NF-κB p65 levels. Moreover, the phosphorylation of mitogen-activated protein kinases (MAPKs) and Akt, a downstream molecule of phosphatidylinositol-3-kinase (PI3K), in LPS-stimulated BV2 cells was suppressed markedly by HDMPPA. This effect was associated with a significant reduction in the formation of intracellular reactive oxygen species. The findings in this study suggest that HDMPPA may exert anti-inflammatory responses by suppressing LPS-induced expression of proinflammatory mediators and cytokines through blockage of NF-κB, MAPKs, and PI3K/Akt signaling pathways and oxidative stress in microglia.