Can neuropeptides treat obesity? A review of neuropeptides and their potential role in the treatment of obesity

Obesity is a major worldwide public health issue. The physiological systems that regulate body weight are thus of great interest as targets for anti-obesity agents. Peptidergic systems are critical to the regulation of energy homeostasis by key regions in the hypothalamus and brainstem. A number of neuropeptide systems have therefore been investigated as potential treatments for obesity. Blocking orexigenic peptide signals such as neuropeptide Y, melanin-concentrating hormone, orexins, relaxin-3 and galanin-like peptide or stimulating anorectic signalling pathways used by peptides such as the melanocortins, ciliary neurotrophic factor and brain-derived neurotrophic factor, are approaches that have shown some promise, but which have also highlighted possible concerns. Manipulation of central peptidergic systems poses a number of therapeutic problems, including brain access and side effects. Given that the homeostatic defence of body weight may limit the effectiveness of any single-target therapy developed, a combination therapy approach may offer the best hope for the effective prevention and treatment of obesity.

LINKED ARTICLES

This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7     

A role for membrane potential in regulating GPCRs?

G-protein-coupled receptors (GPCRs) have ubiquitous roles in transducing extracellular signals into cellular responses. Therefore, the concept that members of this superfamily of surface proteins are directly modulated by changes in membrane voltage could have widespread consequences for cell signalling. Although several studies have indicated that GPCRs can be voltage dependent, particularly P2Y(1) receptors in the non-excitable megakaryocyte, the evidence has been mostly indirect. Recent work on muscarinic receptors has stimulated substantial interest in this field by reporting the first voltage-dependent charge movements for a GPCR. An underlying mechanism is proposed whereby a voltage-induced conformational change in the receptor alters its ability to couple to the G protein and thereby influences its affinity for an agonist. We discuss the strength of the evidence behind this hypothesis and include suggestions for future work. We also describe other examples in which direct voltage control of GPCRs can account for effects of membrane potential on downstream signals and highlight the possible physiological consequences of this phenomenon.     

The linear relationship between the deviation of observed combined toxicity of two agents from the toxicity of sham interaction and the product of their doses

研究发现，与假联合作用毒性相比两因素联合所致毒性改变（无论增强或减弱）与其剂量积之间呈线性关系．假联合作用的建立是基于这样的假设，即在联合作用中因素Ｂ的作用与等效剂量的因素Ａ的作用相同，反之亦然．本研究显示的不同的两因素联合作用中该线性关系的一致性以及大多数报道的等效线图提示，该线性关系可能对两因素联合作用具有广泛的适用性．然而，该线性关系的确切适用范围仍有待于更多实验数据检验确定．该线性关系不仅可用于两因素联合作用的定性评价，而且可用于两因素联合作用剂量－反应关系的建立．     

A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets

Type 1 diabetes mellitus (T1DM) describes a complex group of metabolic disorders associated with elevated blood glucose levels and increased risks of complications development. Exploring new drug therapies would reduce the increased diabetes-associated morbidity and mortality and will reduce the excessive health care costs. Crocin is the major active ingredient of saffron. In the current study, DM was induced by single intraperitoneal injection of streptozocin (50 mg/kg).DM progression was associated with a significant increase in blood glucose level with reduced insulin and increased glucagon secretion. Pancreatic malondialdehyde (MDA) content significantly escalated, while superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, catalase activity, thioredoxin level and serum total antioxidant capacity significantly declined. This was associated with a significant increase in pancreatic caspase-3 contents and pancreatic infiltration with inflammatory cells in β-islets. Both sitagliptin and crocin significantly reduced blood glucose levels, enhanced pancreatic insulin expression and secretion and suppressed glucagon secretion with enhancement of anti-oxidant defenses and reduction of oxidative burden, with evident anti-inflammatory impacts. Interestingly, the effect of crocin on DM indices, inflammatory and apoptotic changes was comparable to that of sitagliptin; the standard oral hypoglycemic agent. Nevertheless, crocin had a superior effect compared to sitagliptin on blood sugar level, β-islets diameter and insulin immune-reactivity. In conclusion, crocin reduced blood glucose level mainly via reduction of oxidative burden, modulation of apoptotic pathway and attenuation of pancreatic inflammation.     

Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity

BACKGROUND AND PURPOSE

Amyloid-β (Aβ) aggregation into synaptotoxic, prefibrillar oligomers is a major pathogenic event underlying the neuropathology of Alzheimer''s disease (AD). The pharmacological and neuroprotective properties of a novel Aβ aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic Aβ_1-42 and cell-derived Aβ oligomers.

EXPERIMENTAL APPROACH

Surface plasmon resonance studies measured binding of SEN1269 to Aβ_1–42. Thioflavin-T fluorescence and MTT assays were used to measure its ability to block Aβ_1–42–induced aggregation and reduction in cell viability. In vitro and in vivo long-term potentiation (LTP) experiments measured the effect of SEN1269 on deficits induced by synthetic Aβ_1–42 and cell-derived Aβ oligomers. Following i.c.v. administration of the latter, a complex (alternating-lever cyclic ratio) schedule of operant responding measured effects on memory in freely moving rats.

KEY RESULTS

SEN1269 demonstrated direct binding to monomeric Aβ_1–42, produced a concentration-related blockade of Aβ_1–42 aggregation and protected neuronal cell lines exposed to Aβ_1–42. In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by Aβ_1–42 and cell-derived Aβ oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived Aβ oligomers.

CONCLUSIONS AND IMPLICATIONS

SEN1269 protected cells exposed to Aβ_1–42, displayed central activity with respect to reducing Aβ-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to Aβ-induced neurodegeneration. It represents a promising lead for designing inhibitors of Aβ-mediated synaptic toxicity as potential neuroprotective agents for treating AD.     

Distribution of the scavenger esterases against organophosphorus compounds in human tissues

测定了人体各种组织中与有机磷化合物代谢有关的二异丙基氟磷酸酯酶（ＤＦＰａｓｅ），对氧磷酶，乙酰胆碱酯酶（ＡＣｈＥ），丁酰胆碱酯酶（ＢＣｈＥ）及羧基酯酶（ＣａＥ）的活性水平．结果表明：在肾脏，脾脏和肝脏中含有丰富的ＤＦＰａｓｅ，可催化水解梭曼．其他组织该酶活性均很低．除人血清外，其他组织均未测到对氧磷酶活性．ＡＣｈＥ和ＢＣｈＥ主要分布于中脑，桥脑，延脑，纹状体及丘脑等脑干区域，另外肝脏中ＢＣｈＥ的比活性也较高．ＣａＥ主要分布于肝脏组织中，肺脏中也有较高的ＣａＥ活性．以上结果对了解有机磷化合物在人体中的中毒及代谢提供了一定的理论基础     

A role for retinoids in the treatment of COVID-19?

The 2020 global outbreak of the novel coronavirus (SARS-CoV-2 or COVID-19) is a serious threat to international health, and thus, there is an urgent need for discovery of novel therapies or use of repurposed drugs that can make a significant impact on slowing the spread of the virus. Type 1 interferons (IFN-I) are a family cytokines of the early innate immune response to viruses that are being tested against SARS-CoV-2. However, coronaviruses similar to SARS-CoV-2 can suppress host IFN-I antiviral responses. Retinoids are a family molecules related to vitamin A that possess robust immune-modulating properties, including the ability to increase and potentiate the actions of IFN-I. Therefore, adjuvants such as retinoids, capable of increasing IFN-I-mediated antiviral responses, should be tested in combinations of IFN-I and antiviral drugs in pre-clinical studies of SARS-CoV-2.     

GABAA ρ receptor mechanisms in the rat amygdala and its role in the modulation of fear and anxiety

Rationale  

Accumulating evidence for the presence of GABA_A ρ receptors within the amygdala which differ from other members of the GABA_A receptor family in both subunit composition and functional properties has been recently obtained.     

Protective role of hydroxysteroid sulfotransferase in lithocholic acid—in—duced liver toxicity

Supplement of 1% lithocholic acid (LCA) in the diet for 5-9d resulted in elevated levels of the marker for liver damage AST and ALP activities in both FXR-null and wild-type female mice.The levels were clearly higher in wild-type mice than in FXR-null mice,in spite of the diminished expression of a bile salt export pump(Bsep) in the latter.Consistent with liver toxicity marker activities,serum and liver levels of bile acide,particularly LCA and tauro LCA,were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement.Marked increases in hepatic sulfating activity for LCA(5.5-fold) and hydroxysteroid sulfotransferase St2a(5.8-fold) were detected in liver of FXR-null mice.Liver St2a content was inversely correlated with levels of ALP.In contrast,microsomal LCA 6-hydroxylation was not increased and in fact lower in FXR-null mice compared in wild-type mice.Clear decreases in mRNA encoding Ntcp,Oatpl and Lst-1 transporters function in bild acid import were detected in LCA fed mice.These transporter levels are higher in FXR-null mice than in wild-type mice after 1% LCA supplement.No obvious changes were detected in the Mrp2,Mrp3 and Mrp4 mRNAs.These results indicate that hydroxysteroid sulfotransferase is reuired for protection against LCA-induced liver damage.     

Nickel-induced down-regulation of ΔNp63 and its role in the proliferation of keratinocytes

Epidemiological, animal, and cell studies have demonstrated that nickel compounds are human carcinogens. The mechanisms of their carcinogenic actions remain to be investigated. p63, a close homologue of the p53 tumor suppressor protein, has been linked to cell fate determination and/or maintenance of self-renewing populations in several epithelial tissues, including skin, mammary gland, and prostate. ΔNp63, a dominant negative isoform of p63, is amplified in a variety of epithelial tumors including squamous cell carcinomas and carcinomas of the prostate and mammary glands. The present study shows that nickel suppressed ΔNp63 expression in a short-time treatment (up to 48 h). Nickel treatment caused activation of NF-κB. Blockage of NF-κB partially reversed nickel-induced ΔNp63 suppression. Nickel decreased interferon regulatory factor (IRF) 3 and IRF7, IKKε, and Sp100. Over-expression of IRF3 increased ΔNp63 expression suppressed by nickel. Nickel was able to activate p21, and its activation was offset by the over-expression of ΔNp63. In turn, elevated p63 expression counteracted the ability of nickel to restrict cell growth. The present study demonstrated that nickel decreased interferon regulatory proteins IRF3 and IRF7, and activated NF-κB, resulting in ΔNp63 suppression and then p21 up-regulation. ΔNp63 plays an important role in nickel-induced cell proliferation.     

Potent inhibition of human sulfotransferase 1A1 by 17α-ethinylestradiol: role of 3'-phosphoadenosine 5'-phosphosulfate binding and structural rearrangements in regulating inhibition and activity

Sulfotransferase (SULT) 1A1 is the major drug/xenobiotic-conjugating SULT isoform in human liver because of its broad substrate reactivity and high expression level. SULT1A1 sulfates estrogens with low micromolar K(m) values consistent with its affinity for sulfation of many small phenolic compounds. Binding studies showed the unexpected ability of 17α-ethinylestradiol (EE2) to bind and inhibit SULT1A1 activity toward p-nitrophenol and β-naphthol at low nanomolar concentrations, whereas EE2 was not sulfated until significantly higher concentrations were reached. EE2 had a K(i) of 10 nM for inhibiting p-nitrophenol and β-naphthol sulfation and inhibited 17β-estradiol (E2) sulfation in intact human MCF-7 breast cancer cells with a K(i) of 19 nM. In contrast, the K(m) for EE2 sulfation by SULT1A1 was 700 nM. The K(d) for EE2 binding of pure SULT1A1 was 0.5 ± 0.15 μM; however, the K(d) for EE2 binding to the SULT1A1-PAP complex was >100-fold lower (4.3 ± 1.7 nM). The K(d) for E2 binding to SULT1A1 changed from 2.3 ± 0.9 to 1.2 ± 0.56 μM in the presence of PAP. Docking studies with E2 indicate that E2 binds in a competent orientation in the resolved structure of SULT1A1 in the both presence and absence of 3'-phosphoadenosine 5'-phosphosulfate (PAPS). However, EE2 binds in a catalytically competent orientation in the absence of PAPS but in a noncompetent orientation via formation of a charge interaction with Tyr108 if PAPS is bound first. In conclusion, EE2 is a potent inhibitor, but not a substrate, of SULT1A1 at low nanomolar concentrations, indicating the possibility of drug-drug interactions during contraceptive therapy.     

A role for metabolomics in the antidoping toolbox?

Evidence of the continuous rise of novel doping agents and novel doping strategies calls for the development of more accurate multi‐target screening methods. Direct multi‐target screening approaches are restricted to the targeted substances and their turnover. The development of effective “indirect” screening methods requires a priori a deep understanding of the metabolism of the substance. The biological passport has been demonstrated to be very effective, but it is limited to about 20 indirect parameters. The standard antidoping analytical methods are hence targeted and do not aim directly to identify unknown substances. Also, the detection of doping agents is limited by the excretion of the substance. This study considers metabolomics for the screening of performance enhancing hormone abuse by athletes, based on the following pieces of evidence: (1) hormones have a strong influence on human metabolism, changing several parameters in many tissues, organs, and bio‐fluids; (2) metabolomics has been demonstrated to be a very accurate tool to depict the metabolic status of several organisms, tissues, and for several human diseases, including hormone deficiencies; (3) metabolomics has been demonstrated to be able to distinguish hormone‐treated animals from controls in many species, without the need for a priori knowledge of the metabolism for the specific substance. The literature shows that metabolomics could be an appropriate tool to detect hormone abuse, keeping in mind the strength and the limitation of such an approach.     

Novel aβ isoforms in Alzheimer's disease - their role in diagnosis and treatment

The last decades have witnessed an explosion in studies of the role of amyloid-β (Aβ) in the progress of the neurodegenerative disorder Alzheimer's disease (AD) and it is now widely accepted that Aβ is related to the pathogenesis of AD. For example, studies have shown that Aβ is neurotoxic and that the neurotoxicity of Aβ is related to its aggregation state. The concentration of the 42 amino acid form of Aβ (Aβ1-42) is reduced in the cerebrospinal fluid (CSF) from AD patients, which is believed to reflect the AD pathology with plaques in the brain acting as sinks. Less well investigated, however, is the ability of other Aβ isoforms to distinguish AD patients from controls and to identify treatment effects in clinical trials. Recently, novel C-truncated forms of Aβ (Aβ1-14, Aβ1-15, and Aβ1-16) were identified in human CSF. The presence of these small peptides is consistent with a catabolic amyloid precursor protein cleavage pathway by β- followed by α-secretase. It has been shown that Aβ1-14, Aβ1-15, and Aβ1-16 increase dose-dependently in response to γ-secretase inhibitor treatment while Aβ1-42 levels are unchanged. Here, we review the many aspects of Aβ and its isoforms with special focus on their potential role as diagnostic and theragnostic markers.     

The subchronic oral toxicity of the β-isomer of hexachlorocyclohexane in rats

The 13-week oral toxicity of β-HCH, a nonpesticidal isomer of hexachlorocyclohexane, was investigated in rats with doses of 0, 2, 10, 50, or 250 mg/kg feed. Parameters studied comprised clinical signs, growth and food intake, biochemistry, hematology, organ weights, and histopathology. In all dose groups liver effects comprising increase of organ weight, centrilobular hepatocytic hypertrophy, and proliferation of smooth endoplasmic reticulum or increased activity of microsomal enzymes, were observed. In the 50 mg/kg group the weights of thymus and testes were affected. In the highest dose group, progressive clinical signs leading to the unscheduled sacrifice of approximately 50% of the rats were observed. Moreover, in the males of this group atrophy of the testes, characterized by a reduced size of the seminiferous tubules and a decreased number of interstitial cells was observed in association with spermatogenic arrest. The females in this group showed atrophy of the ovaries with impaired oogenesis and focal hyperplasia and metaplastic changes of the endometrial epithelium. These effects are discussed with respect to a possible estrogenic action of β-HCH.