Title: Effect of dipeptidyl peptidase-4 inhibitors on postprandial glucagon level in patients with type 2 diabetes mellitus: A systemic review and meta-analysis Chai S, Zhang R, Zhang Y, Carr RD, Zheng Y, Rajpathak S, Ji L Ref: Front Endocrinol (Lausanne), 13:994944, 2022 : PubMed
AIMS: Hyperglucagonemia occurs in the pathogenesis of type 2 diabetes mellitus (T2DM). In this meta-analysis, we summarized the effects of DPP4 inhibitors on glucagon levels in patients with T2DM. MATERIALS AND METHODS: Randomized controlled trials (RCTs) comparing the influence of DPP4 inhibitors on circulating glucagon levels with placebo or other oral antidiabetic drugs (OADs) in patients with T2DM were identified by searches of Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library). Only studies reporting changes in glucagon level presented as total area under the curve (AUC(glucagon)) using a meal or oral glucose tolerance test were included. Results were combined using a random-effects model that incorporated potential heterogeneity among the included studies. RESULTS: A total of 36 RCTs with moderate to high quality were included. Overall, the numbers of T2DM patients included for the meta-analyses comparing DPP4 inhibitors with placebo and other OADs were 4266 and 1652, respectively. Compared to placebo, DPP4 inhibitors significantly reduced circulating glucagon levels (standard mean difference [SMD]: -0.32, 95% CI: -0.40 to -0.24, P<0.001; I(2 =) 28%). Analysis of subgroups revealed that study characteristics had no significant effect on results, such as study design (parallel group or crossover), number of patients, mean patient age, proportion of men, baseline HbA1c, duration of diabetes, background therapy, treatment duration, or methods for glucagon measurement (all P for subgroup differences >0.05). Moreover, DPP4 inhibitors significantly reduced glucagon levels compared to other OADs (SMD: -0.35, 95% CI: -0.53 to -0.16, P<0.001; I(2) = 66%), and the reduction in glucagon was greater in comparison with insulin secretagogues than in comparison with non-insulin secretagogues (P for subgroup difference =0.03). SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/, identifier INPLASY202280104. CONCLUSIONS: DPP4 inhibitors are effective at reducing the circulating postprandial glucagon level in T2DM patients.
Oxidative stress has been generally considered as one trigger of organism imbalance, resulting in lipid peroxidation, DNA damage and protein oxidation, which could be relieved by antioxidant supplement or endogenous antioxidant system. In present study, 1-monocaffeoyl glycerol (1-MCG), an amphipathic caffeic acid natural derivative, was enzymatically synthesized by Lipozyme 435, and its antioxidant profile in both lipophilic and lipophobic media was evaluated. The 1-MCG was identified by HPLC-UV, HPLC-ESI-MS, and (1) H/(13) C-NMR. Subsequently, antioxidant assays in lipophilic (DPPH assay) and lipophobic (ABTS, ORAC, erythrocyte hemolysis, ROS, MDA, and GPx assays) systems were explored. The better and lasting DPPH. and ABTS(+.) inhibitions of 1-MCG than caffeic acid (CA) were related to its better solubilities in ethanol/water media and electron transfer ability. ORAC results suggested the radical scavenging activities of 1-MCG (5 to 40 microM) were higher than Trolox. Furthermore, the effectiveness of 1-MCG against AAPH-induced erythrocytes oxidation indicated that 1-MCG can effectively inhibit hemolysis. ESEM was also applied to verify the hemolysis inhibition and morphology preservation abilities of 1-MCG. Besides, results showed 1-MCG was able to prevent ROS from invasion, reduce production of MDA, up-regulated GPx activity, terminate lipid peroxidation, and maintain the integrity of the structure and function of erythrocytes. PRACTICAL APPLICATION: As an amphiphilic caffeic acid derivative, 1-monocaffeoyl glycerol was synthesized, purified, and identified. 1-Monocaffeoyl glycerol could significantly eliminate radicals including DPPH., ABTS(+.) , and AAPH in ethanol, water, and PBS system, respectively. 1-Monocaffeoyl glycerol could protect erythrocyte from AAPH induced hemolysis.
Title: Design, synthesis, and biological evaluation of rutacecarpine derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease Wu M, Ma J, Ji L, Wang M, Han J, Li Z Ref: Eur Journal of Medicinal Chemistry, 177:198, 2019 : PubMed
A series of 3-amino-substituted rutacecarpine derivatives were synthesized to identify novel multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD). Biological evaluation showed that most of the synthesized compounds inhibited butyrylcholinesterase (BuChE) and exerted antioxidant effects. Among the synthesized compounds, 6n was subjected to further biological evaluation. Lineweaver-Burk plotting and molecular modeling illustrated that 6n bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CAS) of BuChE. Furthermore, 6n modulated Abeta aggregation; chelated biometals; presented good absorption, distribution, metabolism, excretion, and toxicity properties; and showed remarkable neuroprotective activity. Previous research has shown that the optimized compound 6n has considerable potential for development as an MTDL for the treatment of AD.
The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13 S,1' R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor ( Ki of 7.8 +/- 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC50 = 0.6 +/- 0.2 nM). (13 S,1' R)-dimethylanandamide is the first potent AEA analogue with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model, 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analogue AM356. This novel analogue will serve as a very useful endocannabinoid probe.
Title: Defective neuronal migration and inhibition of bipolar to multipolar transition of migrating neural cells by Mesoderm-Specific Transcript, Mest, in the developing mouse neocortex Ji L, Bishayee K, Sadra A, Choi S, Choi W, Moon S, Jho EH, Huh SO Ref: Neuroscience, 355:126, 2017 : PubMed
Brain developmental disorders such as lissencephaly can result from faulty neuronal migration and differentiation during the formation of the mammalian neocortex. The cerebral cortex is a modular structure, where developmentally, newborn neurons are generated as a neuro-epithelial sheet and subsequently differentiate, migrate and organize into their final positions in the cerebral cortical plate via a process involving both tangential and radial migration. The specific role of Mest, an imprinted gene, in neuronal migration has not been previously studied. In this work, we reduced expression of Mest with in utero electroporation of neuronal progenitors in the developing embryonic mouse neocortex. Reduction of Mest levels by shRNA significantly reduced the number of neurons migrating to the cortical plate. Also, Mest-knockdown disrupted the transition of bipolar neurons into multipolar neurons migrating out of the sub-ventricular zone region. The migrating neurons also adopted a more tangential migration pattern upon knockdown of the Mest message, losing their potential to attach to radial glia cells, required for radial migration. The differentiation and migration properties of neurons via Wnt-Akt signaling were affected by Mest changes. In addition, miR-335, encoded in a Mest gene intron, was identified as being responsible for blocking the default tangential migration of the neurons. Our results suggest that Mest and its intron product, miR-335, play important roles in neuronal migration with Mest regulating the morphological transition of primary neurons required in the formation of the mammalian neocortex.
An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type 1 (CB(1)) receptor agonists such as delta(9)-tetrahydrocannabinol are increasingly used for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids N-arachidonoylethanolamine [AEA (or anandamide)] and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition. The present studies were conducted to determine whether such actions can lead to CB(1) agonist-like subjective effects, as reflected in CB(1)-related discriminative stimulus effects in laboratory subjects. Squirrel monkeys (n = 8) that discriminated the CB(1) full agonist AM4054 (0.01 mg/kg) from vehicle were used to study, first, the inhibitors of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) alone or in combination [FAAH (URB597, AM4303); MGL (AM4301); FAAH/MGL (JZL195, AM4302)] and, second, the ability of the endocannabinoids AEA and 2-AG to produce CB(1) agonist-like effects when administered alone or after enzyme inhibition. Results indicate that CB(1)-related discriminative stimulus effects were produced by combined, but not selective, inhibition of FAAH and MGL, and that these effects were nonsurmountably antagonized by low doses of rimonabant. Additionally, FAAH or MGL inhibition revealed CB(1)-like subjective effects produced by AEA but not by 2-AG. Taken together, the present data suggest that therapeutic effects of combined, but not selective, enhancement of AEA or 2-AG activity via enzyme inhibition may be accompanied by CB(1) receptor-mediated subjective effects.
Social insects are important models for social evolution and behavior. However, in many species, experimental control over important factors that regulate division of labor, such as genotype and age, is limited. Furthermore, most species have fixed queen and worker castes, making it difficult to establish causality between the molecular mechanisms that underlie reproductive division of labor, the hallmark of insect societies. Here we present the genome of the queenless clonal raider ant Cerapachys biroi, a powerful new study system that does not suffer from these constraints. Using cytology and RAD-seq, we show that C. biroi reproduces via automixis with central fusion and that heterozygosity is lost extremely slowly. As a consequence, nestmates are almost clonally related (r = 0.996). Workers in C. biroi colonies synchronously alternate between reproduction and brood care, and young workers eclose in synchronized cohorts. We show that genes associated with division of labor in other social insects are conserved in C. biroi and dynamically regulated during the colony cycle. With unparalleled experimental control over an individual's genotype and age, and the ability to induce reproduction and brood care, C. biroi has great potential to illuminate the molecular regulation of division of labor.
Although eusociality evolved independently within several orders of insects, research into the molecular underpinnings of the transition towards social complexity has been confined primarily to Hymenoptera (for example, ants and bees). Here we sequence the genome and stage-specific transcriptomes of the dampwood termite Zootermopsis nevadensis (Blattodea) and compare them with similar data for eusocial Hymenoptera, to better identify commonalities and differences in achieving this significant transition. We show an expansion of genes related to male fertility, with upregulated gene expression in male reproductive individuals reflecting the profound differences in mating biology relative to the Hymenoptera. For several chemoreceptor families, we show divergent numbers of genes, which may correspond to the more claustral lifestyle of these termites. We also show similarities in the number and expression of genes related to caste determination mechanisms. Finally, patterns of DNA methylation and alternative splicing support a hypothesized epigenetic regulation of caste differentiation.
Title: Complete Genome Sequence of Enterobacter sp. Strain R4-368, an Endophytic N-Fixing Gammaproteobacterium Isolated from Surface-Sterilized Roots of Jatropha curcas L Madhaiyan M, Peng N, Ji L Ref: Genome Announc, 1:, 2013 : PubMed
Enterobacter sp. strain R4-368 is one of the few characterized Jatropha endophytic diazotrophic bacteria and was isolated from surface-sterilized roots. This bacterium shows strong growth-promoting effects, being able to increase plant biomass and seed yields. Enterobacter sp. R4-368 is the second fully sequenced diazotrophic Enterobacter species. The sequence information shall facilitate the elucidation of the molecular mechanisms of plant growth promotion, nitrogen fixation in nonlegume plant species, and evolution of biological nitrogen fixation systems.
We present a high-quality (>100x depth) Illumina genome sequence of the leaf-cutting ant Acromyrmex echinatior, a model species for symbiosis and reproductive conflict studies. We compare this genome with three previously sequenced genomes of ants from different subfamilies and focus our analyses on aspects of the genome likely to be associated with known evolutionary changes. The first is the specialized fungal diet of A. echinatior, where we find gene loss in the ant's arginine synthesis pathway, loss of detoxification genes, and expansion of a group of peptidase proteins. One of these is a unique ant-derived contribution to the fecal fluid, which otherwise consists of "garden manuring" fungal enzymes that are unaffected by ant digestion. The second is multiple mating of queens and ejaculate competition, which may be associated with a greatly expanded nardilysin-like peptidase gene family. The third is sex determination, where we could identify only a single homolog of the feminizer gene. As other ants and the honeybee have duplications of this gene, we hypothesize that this may partly explain the frequent production of diploid male larvae in A. echinatior. The fourth is the evolution of eusociality, where we find a highly conserved ant-specific profile of neuropeptide genes that may be related to caste determination. These first analyses of the A. echinatior genome indicate that considerable genetic changes are likely to have accompanied the transition from hunter-gathering to agricultural food production 50 million years ago, and the transition from single to multiple queen mating 10 million years ago.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that decreases postprandial glycemic excursions by enhancing insulin secretion but with short half-life due to rapid inactivation by enzymatic N-terminal truncation. Therefore, efforts are being made to improve the stability of GLP-1 via modifying its structure or inhibiting dipeptidyl-peptidase IV (DPP IV), which is responsible for its degradation. Here we report a novel GLP-1 analog BPI3006 with -NHCO- of Ala(8) replaced by -CH(CF(3))NH- and features of its metabolic stability, GLP-1 receptor trans-activation and in vivo biological activity. BPI3006 is highly resistant to DPP IV-mediated degradation with 91.1% of parental peptide left after 24h exposure to the enzyme. BPI3006 also effectively activates its target gene promoter through GLP-1 receptor activation by measuring the transiently transfected reporter gene green fluorescence protein (GFP) expression in NIT-1 cells. Furthermore, BPI3006 could well restrain the glycemia variation in fasted normal ICR mice after a single administration followed by an oral glucose loading. In spontaneous type 2 diabetic KKA(y) mice, BPI3006 injected twice daily could significantly improve the oral glucose tolerance and hyperinsulinemia, as well as ameliorate the food and water consumption. In conclusion, BPI3006 has enhanced resistance to DPP IV leading to improved stability, and shows excellent in vivo biological activity. Thus it may be a new candidate for T2DM treatment and its novel modification may provide valuable guidance for the future development of long-acting GLP-1 analogs.
