Multitrait Genetic Analysis Identifies Novel Pleiotropic Loci for Depression and Schizophrenia in East Asians.

BACKGROUND AND HYPOTHESIS: While genetic correlations, pleiotropic loci, and shared genetic mechanisms of psychiatric disorders have been extensively studied in European populations, the investigation of these factors in East Asian populations has been relatively limited. STUDY DESIGN: To identify novel pleiotropic risk loci for depression and schizophrenia (SCZ) in East Asians. We utilized the most comprehensive dataset available for East Asians and quantified the genetic overlap between depression, SCZ, and their related traits via a multitrait genome-wide association study. Global and local genetic correlations were estimated by LDSC and ρ-HESS. Pleiotropic loci were identified by the multitrait analysis of GWAS (MTAG). STUDY RESULTS: Besides the significant correlation between depression and SCZ, our analysis revealed genetic correlations between depression and obesity-related traits, such as weight, BMI, T2D, and HDL. In SCZ, significant correlations were detected with HDL, heart diseases and use of various medications. Conventional meta-analysis of depression and SCZ identified a novel locus at 1q25.2 in East Asians. Further multitrait analysis of depression, SCZ and related traits identified ten novel pleiotropic loci for depression, and four for SCZ. CONCLUSIONS: Our findings demonstrate shared genetic underpinnings between depression and SCZ in East Asians, as well as their associated traits, providing novel candidate genes for the identification and prioritization of therapeutic targets specific to this population.

Direct inhibition of microglial activation by a µ receptor selective agonist alleviates inflammatory-induced pain hypersensitivity.

Opioids are widely used in the treatment of moderate and severe pain. Nociceptive stimulation has been reported to potentially promote microglial activation and neuroinflammation, which also causes chronic pain sensitization. The aim of this study was to demonstrate whether the novel µ receptor agonist MEL-0614 could inhibit activated microglia directly and the associated signaling pathway. Mice were administered lipopolysaccharide and formalin to induce allodynia. Von Frey test was used to detect the anti-allodynia effect of MEL-0614 before and after LPS and formalin injection. In the spinal cord, the levels of proinflammatory cytokines and microglial activation were determined after MEL-0614 administration. BV2 and primary microglia were cultured to further explore the effect of MEL-0614 on LPS-induced microglial activation and key signaling pathways involved. MEL-0614 partially prevented and reversed allodynia induced by LPS and formalin in vivo, which was not inhibited by the µ receptor antagonist CTAP. Minocycline was effective in reversing the established allodynia. MEL-0614 also downregulated the activation of microglia and related proinflammatory cytokines in the spinal cord. Additionally, in BV2 and primary microglia, MEL-0614 inhibited the LPS-induced upregulation of proinflammatory factors, which was unaffected by CTAP. The NLR family pyrin domain containing 3 (NLRP3) related signaling pathway may be involved in the interaction between MEL-0614 and microglia. The opioid agonist MEL-0614 inhibited the activation of microglia and the subsequent upregulation of proinflammatory factors both in vivo and in vitro. Notably, this effect is partially mediated by the µ receptor.

Natural variants of molybdate transporters contribute to yield traits of soybean by affecting auxin synthesis.

Soybean (Glycine max) is a crop with high demand for molybdenum (Mo) and typically requires Mo fertilization to achieve maximum yield potential. However, the genetic basis underlying the natural variation of Mo concentration in soybean and its impact on soybean agronomic performance is still poorly understood. Here, we performed a genome-wide association study (GWAS) to identify GmMOT1.1 and GmMOT1.2 that drive the natural variation of soybean Mo concentration and confer agronomic traits by affecting auxin synthesis. The soybean population exhibits five haplotypes of the two genes, with the haplotype 5 demonstrating the highest expression of GmMOT1.1 and GmMOT1.2, as well as the highest transport activities of their proteins. Further studies showed that GmMOT1.1 and GmMOT1.2 improve soybean yield, especially when cultivated in acidic or slightly acidic soil. Surprisingly, these two genes contribute to soybean growth by enhancing the activity of indole-3-acetaldehyde (IAAld) aldehyde oxidase (AO), leading to increased indole-3-acetic acid (IAA) synthesis, rather than being involved in symbiotic nitrogen fixation or nitrogen assimilation. Furthermore, the geographical distribution of five haplotypes in China and their correlation with soil pH suggest the potential significance of GmMOT1.1 and GmMOT1.2 in soybean breeding strategies.

Clinical applications of radiomics in non-small cell lung cancer patients with immune checkpoint inhibitor-related pneumonitis.

Immune checkpoint inhibitors (ICIs) modulate the body's immune function to treat tumors but may also induce pneumonitis. Immune checkpoint inhibitor-related pneumonitis (ICIP) is a serious immune-related adverse event (irAE). Immunotherapy is currently approved as a first-line treatment for non-small cell lung cancer (NSCLC), and the incidence of ICIP in NSCLC patients can be as high as 5%-19% in clinical practice. ICIP can be severe enough to lead to the death of NSCLC patients, but there is a lack of a gold standard for the diagnosis of ICIP. Radiomics is a method that uses computational techniques to analyze medical images (e.g., CT, MRI, PET) and extract important features from them, which can be used to solve classification and regression problems in the clinic. Radiomics has been applied to predict and identify ICIP in NSCLC patients in the hope of transforming clinical qualitative problems into quantitative ones, thus improving the diagnosis and treatment of ICIP. In this review, we summarize the pathogenesis of ICIP and the process of radiomics feature extraction, review the clinical application of radiomics in ICIP of NSCLC patients, and discuss its future application prospects.

Natural variation in SlSOS2 promoter hinders salt resistance during tomato domestication.

Increasing soil salinization seriously impairs plant growth and development, resulting in crop loss. The Salt-Overly-Sensitive (SOS) pathway is indispensable to the mitigation of Na + toxicity in plants under high salinity. However, whether natural variations of SOS2 contribute to salt tolerance has not been reported. Here a natural variation in the SlSOS2 promoter region was identified to be associated with root Na+/K+ ratio and the loss of salt resistance during tomato domestication. This natural variation contains an ABI4-binding cis-element and plays an important role in the repression of SlSOS2 expression. Genetic evidence revealed that SlSOS2 mutations increase root Na+/K+ ratio under salt stress conditions and thus attenuate salt resistance in tomato. Together, our findings uncovered a critical but previously unknown natural variation of SOS2 in salt resistance, which provides valuable natural resources for genetic breeding for salt resistance in cultivated tomatoes and other crops.

A genome-wide association study identifies a transporter for zinc uploading to maize kernels.

The Zn content in cereal seeds is an important trait for crop production as well as for human health. However, little is known about how Zn is loaded to plant seeds. Here, through a genome-wide association study (GWAS), we identify the Zn-NA (nicotianamine) transporter gene ZmYSL2 that is responsible for loading Zn to maize kernels. High promoter sequence variation in ZmYSL2 most likely drives the natural variation in Zn concentrations in maize kernels. ZmYSL2 is specifically localized on the plasma membrane facing the maternal tissue of the basal endosperm transfer cell layer (BETL) and functions in loading Zn-NA into the BETL. Overexpression of ZmYSL2 increases the Zn concentration in the kernels by 31.6%, which achieves the goal of Zn biofortification of maize. These findings resolve the mystery underlying the loading of Zn into plant seeds, providing an efficient strategy for breeding or engineering maize varieties with enriched Zn nutrition.

Relationship between cerebrospinal fluid YKL-40 and cognitive function changes in patients with de novo Parkinson disease / 中国神经精神疾病杂志

Objective To investigate the correlation between chitinase protein(YKL-40)in cerebrospinal fluid(CSF)and longitudinal changes of cognitive function in patients with de novo Parkinson disease(PD).Methods PD group and healthy controls group were selected from the Parkinson Progression Markers Initiative(PPMI)database and their clinical data were collected at baseline,6 months,12 months,24 months,36 months and 60 months of follow-up.PD patients were divided into Parkinson disease normally cognitive(PD-NC),PD with mild cognitive impairment(PD-MCI),and Parkinson disease with dementia(PD-D)groups and comparison of clinical data between groups.We also investigated the correlation of baseline CSF YKL-40 concentration and rate of change in YKL-40 with longitudinal changes in other CSF biomarkers and clinical cognitive assessment results.Results A total of 195 patients were enrolled in PD group and 88 in healthy controls(HC)group.Baseline CSF YKL-40 levels in PD patients(119.08 pg/mL)were significantly lower than those in HC patients(132.64 pg/mL).The level of CSF YKL-40 in PD-MCI patients(127.51 pg/mL)was significantly higher than that in PD-NC patients(114.77 pg/ml)at baseline(P<0.001).In PD patients,baseline CSF YKL-40 was positively correlated with CSF Aβ42(β=0.526,P<0.001),T-tau(β=0.425,P<0.001),P-tau(β=0.373,P<0.001),and α-syn(β=0.525,P<0.001)levels,and was not correlated with clinical assessments of cognitive function.In mixed effect model analysis,we found that the higher the baseline CSF YKL-40 concentration in PD patients,the faster the increase of CSF T-tau(β=0.034,P=0.009)and P-tau(β=0.041,P=0.001)levels,and the faster the decrease of Hopkins verbal learning test(HVLT)delayed recall(β=-0.027,P=0.029)and HVLT retention(β=-0.030,P=0.022).We also found that higher rates of CSF YKL-40 change were associated with faster increases in CSF T-tau(β=0.045,P=0.001)and P-tau(β= 0.053,P<0.001)levels and faster declines in HVLT Delayed Recall(β=-0.026,P=0.049).Conclusion Our study suggests that CSF YKL-40 holds promise as a biomarker that can monitor the severity of cognitive decline in patients with new-onset PD.

Similarities and differences in iron homeostasis strategies between graminaceous and nongraminaceous plants.

Iron (Fe) homeostasis is essential for both plant development and human nutrition. The maintenance of Fe homeostasis involves a complex network in which Fe signaling nodes and circuits coordinate tightly Fe transporters, ferric reductases, H+ -ATPases, low-molecular-mass metal chelators, and transporters of chelators and Fe-chelate complexes. Early-stage studies have revealed different strategies for Fe homeostasis between graminaceous and nongraminaceous plants. Recent progress has refreshed our understanding of previous knowledge, especially on the uptake, phloem transport and systemic signaling of Fe. This review attempts to summarize recent exciting and potentially influential studies on the various routes of Fe uptake and distribution in plants, focusing on breakthroughs that have changed our understanding of plant Fe nutrition.

Sec24C mediates a Golgi-independent trafficking pathway that is required for tonoplast localisation of ABCC1 and ABCC2.

Protein sorting is an essential biological process in all organisms. Trafficking membrane proteins generally relies on the sorting machinery of the Golgi apparatus. However, many proteins have been found to be delivered to target locations via Golgi-independent pathways, but the mechanisms underlying this delivery system remain unknown. Here, we report that Sec24C mediates the direct secretory trafficking of the phytochelatin transporters ABCC1 and ABCC2 from the endoplasmic reticulum (ER) to prevacuolar compartments (PVCs) in Arabidopsis thaliana. Genetic analysis showed that the sec24c mutants are hypersensitive to cadmium (Cd) and arsenic (As) treatments due to mislocalisation of ABCC1 and ABCC2, which results in defects in the vacuole compartmentalisation of the toxic metals. Furthermore, we found that Sec24C recognises ABCC1 and ABCC2 through direct interactions to mediate their exit from the ER to PVCs, which is independent of brefeldin A-sensitive post-Golgi trafficking pathway. These findings expand our understanding of Golgi-independent trafficking, which also provide key insights regarding the mechanism of tonoplast protein sorting and open a new perspective on the function of Sec24 proteins.

Efficacy and safety of AnluoHuaxian pills on chronic hepatitis B with normal or minimally elevated alanine transaminase and early liver fibrosis: A randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: The AnluoHuaxian pill (AHP) is a widely used patented medicine for chronic hepatitis B (CHB) patients with advanced fibrosis or cirrhosis that has been used in China for more than 15 years. However, data are lacking on whether monotherapy with AHP can be effective in CHB patients with alanine aminotransferase (ALT) levels less than 2 times the upper limit of normal (ALT<2ULN) and early liver fibrosis (F ≤ 2). AIM OF THE STUDY: We aimed to investigate whether monotherapy with AHP improves liver histology in these patients. MATERIALS AND METHODS: In this double-blind, randomized, placebo-controlled trial, 270 CHB patients with ALT<2ULN and F ≤ 2 were treated in 12 hospitals in China. The patients were randomly assigned to an intervention (AHP) group and a placebo group at a ratio of 2:1. Of these 270 enrolled patients, 147 had paired liver biopsies. The primary end point was histological change after 48 weeks of treatment. RESULTS: Per-protocol analysis revealed that the rate of histologic improvement in liver fibrosis patients in the AHP group was significantly higher than that in the placebo group (37.7% vs. 19.5%, P = 0.035) after 48 weeks of treatment, which was consistent with results from intention-to-treat and sensitivity analyses. Moreover, after adjusting for baseline characteristics, AHP was superior to placebo with respect to improving liver fibrosis (odds ratio [OR] = 2.58, 95% confidence interval [CI]: (1.01, 6.63),P = 0.049) and liver histology (OR = 3.62, 95% CI: (1.42, 9.20),P = 0.007). In noninvasive measurement of liver fibrosis (FibroScan®), the level of liver stiffness measurement (LSM) had decreased significantly at 48 weeks (5.1 kPa) compared with that at baseline (5.7 kPa) (P = 0.008) in the AHP group, whereas it did not decrease significantly in the placebo group. Cirrhosis developed in one patient in the placebo group but in no patients in the AHP group. No serious side effects occurred in the AHP-treated patients. CONCLUSIONS: Treatment of CHB patients who had ALT<2ULN and F ≤ 2 with the traditional Chinese medicine AHP for 48 weeks improves liver fibrosis. However, due to the short duration of treatment and the limited sample size of liver pathology, the long-term benefits of AHP in reducing fibrosis and the risk of cirrhosis and hepatocellular carcinoma in these patients need to be further studied in the future.

Decreasing nitrogen assimilation under drought stress by suppressing DST-mediated activation of Nitrate Reductase 1.2 in rice.

Nitrogen is an essential nutrient for plant growth and development, and plays vital roles in crop yield. Assimilation of nitrogen is thus fine-tuned in response to heterogeneous environments. However, the regulatory mechanism underlying this essential process remains largely unknown. Here, we report that a zinc-finger transcription factor, drought and salt tolerance (DST), controls nitrate assimilation in rice by regulating the expression of OsNR1.2. We found that loss of function of DST results in a significant decrease of nitrogen use efficiency (NUE) in the presence of nitrate. Further study revealed that DST is required for full nitrate reductase activity in rice and directly regulates the expression of OsNR1.2, a gene showing sequence similarity to nitrate reductase. Reverse genetics and biochemistry studies revealed that OsNR1.2 encodes an NADH-dependent nitrate reductase that is required for high NUE of rice. Interestingly, the DST-OsNR1.2 regulatory module is involved in the suppression of nitrate assimilation under drought stress, which contributes to drought tolerance. Considering the negative role of DST in stomata closure, as revealed previously, the positive role of DST in nitrogen assimilation suggests a mechanism coupling nitrogen metabolism and stomata movement. The discovery of this coupling mechanism will aid the engineering of drought-tolerant crops with high NUE in the future.

NPF transporters in synaptic-like vesicles control delivery of iron and copper to seeds.

Accumulation of iron in seeds is essential for both plant reproduction and human nutrition. Transport of iron to seeds requires the chelator nicotianamine (NA) to prevent its precipitation in the plant vascular tissues. However, how NA is transported to the apoplast for forming metal-NA complexes remains unknown. Here, we report that two members of the nitrate/peptide transporter family, NAET1 and NAET2, function as NA transporters required for translocation of both iron and copper to seeds. We show that NAET1 and NAET2 are predominantly expressed in the shoot and root vascular tissues and mediate secretion of NA out of the cells in resembling the release of neurotransmitters from animal synaptic vesicles. These findings reveal an unusual mechanism of transmembrane transport in plants and uncover a fundamental aspect of plant nutrition that has implications for improving food nutrition and human health.

A New General Maximum Intensity Projection Technology via the Hybrid of U-Net and Radial Basis Function Neural Network.

Maximum intensity projection (MIP) technology is a computer visualization method that projects three-dimensional spatial data on a visualization plane. According to the specific purposes, the specific lab thickness and direction can be selected. This technology can better show organs, such as blood vessels, arteries, veins, and bronchi and so forth, from different directions, which could bring more intuitive and comprehensive results for doctors in the diagnosis of related diseases. However, in this traditional projection technology, the details of the small projected target are not clearly visualized when the projected target is not much different from the surrounding environment, which could lead to missed diagnosis or misdiagnosis. Therefore, it is urgent to develop a new technology that can better and clearly display the angiogram. However, to the best of our knowledge, research in this area is scarce. To fill this gap in the literature, in the present study, we propose a new method based on the hybrid of convolutional neural network (CNN) and radial basis function neural network (RBFNN) to synthesize the projection image. We first adopted the U-net to obtain feature or enhanced images to be projected; subsequently, the RBF neural network performed further synthesis processing for these data; finally, the projection images were obtained. For experimental data, in order to increase the robustness of the proposed algorithm, the following three different types of datasets were adopted: the vascular projection of the brain, the bronchial projection of the lung parenchyma, and the vascular projection of the liver. In addition, radiologist evaluation and five classic metrics of image definition were implemented for effective analysis. Finally, compared to the traditional MIP technology and other structures, the use of a large number of different types of data and superior experimental results proved the versatility and robustness of the proposed method.

An improved Poisson-Nernst-Planck ion channel model and numerical studies on effects of boundary conditions, membrane charges, and bulk concentrations.

In this paper, an improved Poisson-Nernst-Planck ion channel (PNPic) model is presented, along with its effective finite element solver and software package for an ion channel protein in a solution of multiple ionic species. Numerical studies are then done on the effects of boundary value conditions, membrane charges, and bulk concentrations on electrostatics and ionic concentrations for an ion channel protein, a gramicidin A (gA), and five different ionic solvents with up to four species. Numerical results indicate that the cation selectivity property of gA occurs within a central portion of ion channel pore, insensitively to any change of boundary value condition, membrane charge, or bulk concentration. Moreover, a numerical scheme for computing the electric currents induced by ion transports across membrane via an ion channel pore is presented and implemented as a part of the PNPic finite element package. It is then applied to the calculation of current-voltage curves, well validating the PNPic model and finite element package by electric current experimental data.

Repeated Endomorphin Analogue MEL-0614 Reduces Tolerance and Improves Chronic Postoperative Pain without Modulating the P2X7R Signaling Pathway.

The clinical treatment of chronic postoperative pain (CPSP) remains challenging. The side effects of chronic morphine treatment limit its clinical application. MEL-0614, a novel endomorphin analogue that is highly selective and agonistic for µ opioid receptor (MOR), produces a more powerful analgesic effect than that of morphine. In this study, we explored the difference in antinociceptive tolerance and related mechanisms between MEL-0614 and morphine in CPSP induced in a skin/muscle incision and retraction (SMIR) mice model. We found that acute administration of MEL-0614 (1, 3, 5, and 10 nmol, i.t.) produced a dose-dependent analgesic effect that was superior to that of morphine in the SMIR mice model. Long-term MEL-0614 treatment (10 nmol, i.t.) did not induce tolerance compared with morphine. Notably, tolerance induced by morphine could be greatly prevented and/or inhibited via cross-administration or coadministration between MEL-0614 and morphine. In addition, MEL-0614 accelerated the recovery of postoperative pain, whereas morphine aggravated postoperative pain and prolonged its recovery time regardless of preoperative or postoperative treatment. In addition, MEL-0614 did not activate microglia and the P2X7R signaling pathway and showed reduced expression iba1 and P2X7R compared with that observed after morphine administration. Release of inflammatory factors was induced by continued administration of morphine during SMIR surgery, but MEL-0614 did not promote the activation of inflammatory factors. Our results showed that MEL-0614 has superior analgesic effects in CPSP and leads to tolerance to a lesser degree than morphine. Further, MEL-0614 may be used as a promising treatment option for the long-term treatment in CPSP.

Phytochrome B inhibits darkness-induced hypocotyl adventitious root formation by stabilizing IAA14 and suppressing ARF7 and ARF19.

Adventitious roots (ARs) are an important root type for plants and display a high phenotypic plasticity in response to different environmental stimuli. Previous studies found that dark-light transition can trigger AR formation from the hypocotyl of etiolated Arabidopsis thaliana, which was used as a model for the identification of regulators of AR biogenesis. However, the central regulatory machinery for darkness-induced hypocotyl AR (HAR) remains elusive. Here, we report that photoreceptors suppress HAR biogenesis through regulating the molecular module essential for lateral roots. We found that hypocotyls embedded in soil or in continuous darkness are able to develop HARs, wherein photoreceptors act as negative regulators. Distinct from wound-induced ARs that require WOX11 and WOX12, darkness-induced HARs are fully dependent on ARF7, ARF19, WOX5/7, and LBD16. Further studies established that PHYB interacts with IAA14, ARF7, and ARF9. The interactions stabilize IAA14 and inhibit the transcriptional activities of ARF7 and ARF19 and thus suppress biogenesis of darkness-induced HARs. This finding not only revealed the central machinery controlling HAR biogenesis but also illustrated that AR formation could be initiated by multiple pathways.

Differences in MicroRNA Expression in Chronic Hepatitis B Patients with Early Liver Fibrosis Based on Traditional Chinese Medicine Syndromes.

The aim of this study was to determine if microRNA (miRNA) expression is different among chronic hepatitis B (CHB) patients with early liver fibrosis classified according to traditional Chinese medicine (TCM) syndromes. Eighteen CHB-fibrosis patients and 12 CHB patients without fibrosis were enrolled. The CHB-fibrosis group included 9 patients with the TCM syndrome of Ganyu Pixu Xueyu (GYPXXY), characterized by liver stagnation, spleen deficiency, and blood stasis, and 9 patients with the TCM syndrome of Qixu Xueyu (QXXY), characterized by deficiency of qi, blood, and blood stasis. Agilent miRNA microarray was performed first in liver specimens to determine whether miRNA expression is different in patients with these two TCM syndromes of CHB-fibrosis. Gene Ontology (GO) analysis and KEGG analysis were applied to determine the roles of the differentially expressed miRNAs. QRT-PCR was performed to validate the Agilent miRNA microarray results. Compared with GYPXXY patients, 6 differentially expressed miRNAs were upregulated (miR-144-5p, miR-18a-5p, miR-148b-3p, miR-654-3p, miR-139-3p, and miR-24-1-5p) and 1 was downregulated (miR-6834-3p) in QXXY patients. According to qRT-PCR data, miR-144-5p and miR-654-3p were confirmed as upregulated in CHB-liver fibrosis patients compared to CHB patients without fibrosis, whereas the other 4 miRNAs were not significantly different. More importantly, miR-654-3p was confirmed to be significantly upregulated in QXXY patients compared with values in GYPXXY patients, whereas no significant difference was found in miR-144-5p. Moreover, the pathways of central carbon metabolism in cancer and cell cycle related to miR-654-3p and the target genes of PTEN and ATM were found to be different between QXXY patients and GYPXXY patients. These results indicate that there are different miRNAs, pathways, and target genes between QXXY patients and GYPXXY patients. However, due to the limited sample, whether miR-654-3p and the target genes PTEN and ATM could be molecular markers to differentiate TCM syndromes could not be established.

Design, synthesis, and biological activity of new endomorphin analogs with multi-site modifications.

Endomorphin (EM)-1 and EM-2 are the most effective endogenous analgesics with efficient separation of analgesia from the risk of adverse effects. Poor metabolic stability and ineffective analgesia after peripheral administration were detrimental for the use of EMs as novel clinical analgesics. Therefore, here, we aimed to establish new EM analogs via introducing different bifunctional d-amino acids at position 2 of [(2-furyl)Map4]EMs. The combination of [(2-furyl)Map4]EMs with D-Arg2 or D-Cit2 yielded analogs with enhanced binding affinity to the µ-opioid receptor (MOR) and increased stability against enzymatic degradation (t1/2 > 300 min). However, the agonistic activities of these analogs toward MOR were slightly reduced. Similar to morphine, peripheral administration of the analog [D-Cit2, (2-furyl)Map4]EM-1 (10) significantly inhibited the pain behavior of mice in multiple pain models. In addition, this EM-1 analog was associated with reduced tolerance, less effect on gastrointestinal mobility, and no significant motor impairment. Compared to natural EMs, the EM analogs synthesized herein had enhanced metabolic stability, bioavailability, and analgesic properties.

MEL endomorphins act as potent inflammatory analgesics with the inhibition of activated non-neuronal cells and modulation of pro-inflammatory cytokines.

Effective treatment of inflammatory pain is a major clinical concern for both patients and physicians. Traditional analgesics such as morphine and coxibs are not effective in all patients and have various unwanted side effects. Accumulating evidence has suggested that endomorphins (EMs), particularly EM-1, possess potent anti-inflammatory effects. However, poor bioavailability and low resistance to enzymatic degradation impede their direct application in the treatment of inflammation. A series of novel peptides based on the structure of EM-1, with lower undesired effects than their parent compounds, called MEL-EMs were discovered and synthetized in our preceding studies. Here, we selected two (MEL-0614 and MEL-N1606) to further investigate their anti-inflammatory effects. This work showed that MEL analogs exerted potent analgesic effects with the inhibition of activated glial cells and macrophages in a CFA-induced inflammatory pain model. Furthermore, multiple-dose administration of MEL analogs did not prolong CFA-induced chronic inflammatory pain, in contrast to morphine. Together, our findings revealed that MEL analogs may serve as effective candidates for chronic inflammation treatment.