Twenty natural amino acid substitution screening at the last residue 121 of influenza A virus NS2 protein reveals the critical role of NS2 in promoting virus genome replication by coordinating with viral polymerase.

Both influenza A virus genome transcription (vRNA→mRNA) and replication (vRNA→cRNA→vRNA), catalyzed by the influenza RNA polymerase (FluPol), are dynamically regulated across the virus life cycle. It has been reported that the last amino acid I121 of the viral NS2 protein plays a critical role in promoting viral genome replication in influenza mini-replicon systems. Here, we performed a 20 natural amino acid substitution screening at residue NS2-I121 in the context of virus infection. We found that the hydrophobicity of the residue 121 is essential for virus survival. Interestingly, through serial passage of the rescued mutant viruses, we further identified adaptive mutations PA-K19E and PB1-S713N on FluPol which could effectively compensate for the replication-promoting defect caused by NS2-I121 mutation in the both mini-replicon and virus infection systems. Structural analysis of different functional states of FluPol indicates that PA-K19E and PB1-S713N could stabilize the replicase conformation of FluPol. By using a cell-based NanoBiT complementary reporter assay, we further demonstrate that both wild-type NS2 and PA-K19E/PB1-S713N could enhance FluPol dimerization, which is necessary for genome replication. These results reveal the critical role NS2 plays in promoting viral genome replication by coordinating with FluPol.IMPORTANCEThe intrinsic mechanisms of influenza RNA polymerase (FluPol) in catalyzing viral genome transcription and replication have been largely resolved. However, the mechanisms of how transcription and replication are dynamically regulated remain elusive. We recently reported that the last amino acid of the viral NS2 protein plays a critical role in promoting viral genome replication in an influenza mini-replicon system. Here, we conducted a 20 amino acid substitution screening at the last residue 121 in virus rescue and serial passage. Our results demonstrate that the replication-promoting function of NS2 is important for virus survival and efficient multiplication. We further show evidence that NS2 and NS2-I121 adaptive mutations PA-K19E/PB1-S713N regulate virus genome replication by promoting FluPol dimerization. This work highlights the coordination between NS2 and FluPol in fulfilling efficient genome replication. It further advances our understanding of the regulation of viral RNA synthesis for influenza A virus.

Fine Regulation of Influenza Virus RNA Transcription and Replication by Stoichiometric Changes in Viral NS1 and NS2 Proteins.

In the influenza virus life cycle, viral RNA (vRNA) transcription (vRNA→mRNA) and replication (vRNA→cRNA→vRNA), catalyzed by the viral RNA-dependent RNA polymerase in the host cell nucleus, are delicately controlled, and the levels of the three viral RNA species display very distinct synthesis dynamics. However, the underlying mechanisms remain elusive. Here, we demonstrate that in the context of virus infection with cycloheximide treatment, the expression of viral nonstructural protein 1 (NS1) can stimulate primary transcription, while the expression of viral NS2 inhibits primary transcription. It is known that the NS1 and NS2 proteins are expressed with different timings from unspliced and spliced mRNAs of the viral NS segment. We then simulated the synthesis dynamics of NS1 and NS2 proteins during infection by dose-dependent transfection experiments in ribonucleoprotein (RNP) reconstitution systems. We found that the early-expressed NS1 protein can stimulate viral mRNA synthesis, while the late-expressed NS2 protein can inhibit mRNA synthesis but can promote vRNA synthesis in a manner highly consistent with the dynamic changes in mRNA/vRNA in the virus life cycle. Furthermore, we observed that the coexistence of sufficient NS1 and NS2, close to the status of the NS1 and NS2 levels in the late stage of infection, could boost vRNA synthesis to the highest efficiency. We also identified key functional amino acids of NS1 and NS2 involved in these regulations. Together, we propose that the stoichiometric changes in the viral NS1 and NS2 proteins during infection are responsible for the fine regulation of viral RNA transcription and replication. IMPORTANCE In order to ensure efficient multiplication, influenza virus transcribes and replicates its segmented, negative-sense viral RNA genome in highly ordered dynamics across the virus life cycle. How the virus achieves such regulation remains poorly understood. Here, we demonstrate that the stoichiometric changes in the viral NS1 and NS2 proteins during infection could be responsible for the fine regulation of the distinct dynamics of viral RNA transcription and replication. We thus propose a fundamental mechanism exploited by influenza virus to dynamically regulate the synthesis of its viral RNA through the delicate control of viral NS1 and NS2 protein expression.

The relationship between serum resolvin D1, NLRP3, cytokine levels, and adolescents with first-episode medication-naïve major depressive disorder.

BACKGROUND: Inflammation has become a critical pathological mechanism of Major Depressive Disorder (MDD). NLRP3 is a critical inflammatory pathway to maintain the immune balance. Recently, preclinical evidence showed that Resolvin D1 might potentially offer a new option for antidepressant treatment due to its protective effects through the inhibition of neuroinflammation. However, whether they have clinical value in the diagnosis and treatment evaluation of adolescent depression was unclear. METHODS: Forty-eight untreated first-episode adolescent patients with moderate to severe major depressive disorder, as well as 30 healthy adolescents (HCs, age and gender-matched), were enrolled for this study. Their ages ranged from 13 to 18 (15.75 ± 1.36) years. The patients were treated with fluoxetine for 6-8 weeks. HDRS-17 was used to evaluate the severity of depressive symptoms. Venous blood samples were collected at baseline for the two groups and at the time-point of post-antidepressant treatment for the patients. Serum concentrations of RvD1, NLRP3, IL-1ß, IL-18, and IL-4 were measured by enzyme-linked immunosorbent assays (ELISA) pre- and post-fluoxetine treatment. RESULTS: Serum levels of RvD1 and anti-inflammatory cytokine IL-4 were significantly elevated in adolescents with MDD compared to healthy adolescents, but no significant difference in NLRP3, IL-1ß, and IL-18 between the two groups. Meanwhile, RvD1 (positively) and IL-4 (negatively) were correlated with the severity of symptoms (HDRS-17 scores) after adjusting age, gender, and BMI. Interestingly, fluoxetine treatment significantly reduced the serum levels of RvD1, NLRP3, IL-1ß, and IL-18 in MDD adolescents but increased the levels of IL-4 relative to baseline. Furthermore, we observed that serum levels of RvD1 might be an excellent distinguishing indicator for depression and healthy adolescents. CONCLUSIONS: Our study is the first to compare RvD1 and NLRP3 between adolescent MDD and HCs. Our findings of reactive increase of RvD1 in adolescent MDD comprised a novel and critical contribution. Our results showed the presence of inflammation resolution unbalanced in adolescents with MDD and indicated that RvD1 might be an ideal biomarker for diagnosing and treating adolescent MDD.

miR-351 promotes atherosclerosis in diabetes by inhibiting the ITGB3/PIK3R1/Akt pathway and induces endothelial cell injury and lipid accumulation.

BACKGROUND: The miR-351 gene is significantly upregulated in diabetic mice with atherosclerosis. However, the mechanism by which its presence is important for the overall disease has not been elucidated. Therefore, this study will investigate the mechanism of miR-351 in the process of diabetes mellitus with atherosclerosis through miR-351 gene knockout mice. METHODS: In this study, miR-351-/- C57BL/6 mice were first induced to form a type 2 diabetes mellitus model with atherosclerosis by STZ injection and a high-fat diet. Pathological tests (oil red O, HE, and Masson staining) combined with biochemical indices (TC, TG, LDL-C, HDL-C, TNF-α, hs-CRP, NO, SOD, MDA, CAT, and GSH-Px) were performed to evaluate the pathological degree of atherosclerosis in each group. Mouse aortic endothelial cells were treated with oxidized low-density lipoprotein (ox-LDL) and 30 mM glucose to establish a diabetic atherosclerosis cell model. Combined with cell oil red O staining and flow cytometry, the effects of silencing miR-351 on lipid accumulation and cell apoptosis in the diabetic atherosclerosis cell model were determined. Fluorescence in situ hybridization was used to detect the localization and transcription levels of miR-351 in cells. The target genes of miR-351 were predicted by bioinformatics and verified by dual-luciferase activity reporting. Western blotting was used to detect the expression levels of phosphorylated inosine 3-kinase regulatory subunit 1 (PIK3R1)/serine/threonine kinase 1 (Akt) and apoptosis-related proteins after transfection with integrin subunit ß3 (ITGB3) small interfering ribonucleic acid (siRNA). RESULTS: The expression of the miR-351 gene was significantly increased in the high-fat wild-type (HWT) group, and its expression was significantly decreased in the knockout mice. Silencing miR-351 effectively alleviated atherosclerosis in mice. The levels of miR-351 expression, apoptosis, lipid accumulation, and oxidative stress in ox-LDL + high glucose-induced endothelial cells were significantly increased. These phenomena were effectively inhibited in lentivirus-infected miR-351-silenced cell lines. Bioinformatics predicted that miR-351-5p could directly target the ITGB3 gene. Transfection of ITGB3 siRNA reversed the downregulation of apoptosis, decreased oil accumulation, and decreased oxidative stress levels induced by miR-351 silencing. In addition, it inhibited the activation of the PIK3R1/Akt pathway. CONCLUSION: Silencing miR-351 upregulates ITGB3 and activates the PIK3R1/Akt pathway, thereby exerting anti-apoptosis and protective effects on endothelial cells.

Forestland landscape change induced spatiotemporal dynamics of subtropical urban forest ecosystem services value in forested region of China: A case of Hangzhou city.

Understanding of urban forestland both type structure and change and their effects on forest ecosystem services (ES) is important for maintaining and enhancing the quality of life as well as ensuring sustainable urban planning in cities. In Hangzhou city of Zhejiang province in Southeast China, forestland covers more than 71% of its total land area, thereby providing a high variety of ES. Many studies have focused on the effects of land use change on ES value (ESV), but these have only applied to the first-level classification of land use. So there is an urgent need for studies to measure the effects of land use change on ESV applied to the second-level classification of land use. In this present study, from a rare insight into the forestland landscape change of Hangzhou city, the spatiotemporal dynamics of urban forest ESV (UFESV) during the period of 2000-2015 are analyzed based on the combination of remote sensing and a light-use-efficiency model (CASA). The results indicate that the total value of urban forest ES increases from 9.79 × 108 Yuan in 2000 to 12.31 × 108 Yuan in 2015, with a net increase of 2.52 × 108 Yuan in Hangzhou city, and forested land has the highest UFESV, contributing about 99.49% of the total services value, although the area of forestland decreases by 101.99 km2 over the past 15 years. Carbon fixation and oxygen release and organic matter production are the two dominant service functions, accounting for 87.56% of the total on average. The construction and planning of Hangzhou's forest city has a positive impact on the value of urban forest ES during 2000-2015.

The prevalence of and factors associated with antenatal depression among all pregnant women first attending antenatal care: a cross-sectional study in a comprehensive teaching hospital.

BACKGROUND: Antenatal depression has become a common and serious problem, significantly affecting maternal and fetal health. However, evaluation and intervention methods for pregnant women in obstetric clinics are inadequate. This study aimed to determine the prevalence of and risk factors for depression among all pregnant women at their first attending antenatal care in the obstetrics clinic, a comprehensive teaching hospital, southwest of China. METHODS: From June to December 2019, 5780 pregnant women completed online psychological assessments, and data from 5728 of the women were analyzed. The women were categorized into two groups according to the presence or absence of depression. Depression was assessed by the Patient Health Questionnaire-9 (PHQ-9), with a cutoff point of 10 for depression. Anxiety and somatic symptoms were measured by the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-15 (PHQ-15), respectively. Univariate analysis and binary logistic regression analysis were used to determine the association among antenatal depression, anxiety, somatic symptoms and participants' characteristics. RESULTS: The prevalence of antenatal depression among all the pregnant women at their first attending antenatal care was 16.3%, higher in the first trimester (18.1%). Anxiety symptoms (Mild anxiety AOR = 2.937; 95% CI: 2.448-3.524) and somatic symptoms (Mild somatic symptoms AOR = 3.938; 95% CI: 2.888-3.368) were major risk factors for antenatal depression among women and the risk increased more with the anxiety level or somatic symptoms level. Gestational weeks (second trimester AOR = 0.611; 95% CI: 0.483-0.773; third trimester AOR = 0.337; 95% CI: 0.228-0.498) and urban residence (AOR = 0.786; 95% CI: 0.652-0.947) were protective factors for antenatal depression among women. CONCLUSIONS: About one in six pregnant women would experience depression, and special attention should be paid to some risk factors (i.e., early pregnancy, anxiety symptoms, somatic symptoms, rural residence). Online psychological assessments might be a time-saving and convenient screening method for pregnant women in obstetric clinics.

Discovery of a semi-synthesized cyclolignan as a potent HIV-1 non-nucleoside reverse transcriptase inhibitor.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection. In this study, we identified (+)-(7'S,8S,8'S)-3',4,4',5,5'-pentamethoxy-2,7'-cyclolignan (SG-1), a cyclolignan semi-synthesized from Machilus robusta and M. wangchiana extracts, as a potent NNRTI. SG-1 displayed anti-HIV-1 activity with an IC50 of 0.77 µmol/L by inhibiting reverse transcriptase (RT) RNA-dependent DNA polymerase activity through a direct binding. It had synergistic effects when combined with tenofovir/lamivudine or zidovudine/lamivudine. The pharmacodynamics properties of SG-1 render it a valuable lead for the development of novel NNRTIs.

Synthesis, biophysical characterization, and anti-HIV-1 fusion activity of DNA helix-based inhibitors with a p-benzyloxyphenyl substituent at the 5'-nucleobase site.

DNA helix-based HIV-1 fusion inhibitors have been discovered as potent drug candidates. Introduction of hydrophobic groups to a nucleobase provides an opportunity to design inhibitors with novel structures and mechanisms of action. In this work, two novel nucleoside analogues (1 and 2) were synthesized and incorporated into four DNA duplex- and quadruplex-based inhibitors. All the molecules showed anti-HIV-1 fusion activity. The effect of the p-benzyloxyphenyl group and the attached linker on the helix formation and thermal stability were fully compared and discussed. Surface plasmon resonance analysis further indicated that inhibitors with the same DNA helix may still have variable reaction targets, mainly attributed to the different hydrophobic modifications.

Oxazole-Containing Diterpenoids from Cell Cultures of Salvia miltiorrhiza and Their Anti-HIV-1 Activities.

Four new oxazole-containing diterpenoids, salvianans A-D (1-4), along with three known diterpenoids (5-7), were isolated from Salvia miltiorrhiza cell cultures. The structures of the new compounds were elucidated using spectroscopic methods and single-crystal X-ray diffraction. The evaluation for their anti-HIV-1 activities revealed that 2 and 3 displayed inhibitory activities with IC50 values of 0.03 and 1.2 µM, respectively. The time of addition (TOA) assay and long terminal repeat (LTR) luciferase reporter assay results indicated that compound 2 was an HIV-1 transcription inhibitor and might be a lead compound of antiviral agents acting on HIV-1 transcription.

[The in vitro HAART pharmacodynamics study with dolutegravir as the "anchor"].

This study is to evaluate the HAART pharmacodynamics with dolutegravir as the "anchor" in vitro. A nucleoside reverse transcriptase inhibitors (NRTIs) resistant recombinant virus model (VSVG/HIV-1(RT-D67N,K70R,T215F)) and an integrase inhibitors (INIs) resistant recombinant virus model (VSVG/HIV-1(IN-G140S,QI48H)) were constructed and established. The anti-viral pharmacodynamics was evaluated with drug combinations including two NRTIs along with one INI or one NNRTI. The results showed that the combination with an INI gave a stronger synergism on wild type HIV-1 replication comparing to that with an NNRTI. Comparing the two INIs as the "anchor" for HAART, DTG exhibited an equivalent CI to that of RAL on wild type HIV-1 replication; but a greater synergy than RAL on INI-resistant HIV-1 replication. Besides of the pharmacodynamics results of DTG-based drug combination, the results may contribute to clinical antiviral therapy.

QPEEG analysis of the effects of sodium valproate on adult Chinese patients with generalized tonic-clonic seizures.

Objectives EEG effects of the sustained-release form of sodium valproate (SR-VPA) are unknown, although it is widely used in Chinese patients with generalized tonicclonic seizures (GTCS). Methods Fourteen newly diagnosed, untreated GTCS patients were recruited and treated with SR-VPA. Waking EEG was recorded and analyzed by way of quantitative pharmaco-electroencephalogram (QPEEG) analysis during the three-month follow-up. Results There was a statistically significant decrease in the absolute power of the delta band (P < 0.05), theta band (P < 0.03) and partial alpha-1 band (p < 0.05) with treatment compared to before treatment, while there was no significantly different absolute power between one-month and three-months after treatment. There was a strong correlation between the decrease in absolute power and the degree of the initial abnormality in all frequency bands. Two of 14 patients experienced seizures during the second month after initiation of SR-VPA therapy. Conclusions SR-VPA selectively decreased the activity of the abnormal EEG synchronization in a use-dependent manner. The reduced theta, delta, and partial alpha-1 absolute power may reflect or confirm the efficacy of SR-VPA on patients with GTCS.

Association between adult attachment and mental health states among health care workers: the mediating role of social support.

Background: To determine the relationships between attachment style, social support, and mental health states, as well as the mediation mechanism within this relationship, we conducted a survey among healthcare workers during the coronavirus disease 2019 (COVID-19) epidemic quarantine. Methods: The survey assessed their mental health states, adult attachment style, social support, and some other relevant information. Mental health states were represented by the overall state of sleep, physical and emotional assessment. A multiple mediator model was used to explain how social support could mediate the relationship between attachment and mental health states during COVID-19 quarantine. Results: Our findings revealed that 33.3% of the participants experienced emotional issues, 8.5% had sleep problems, and 24.9% reported physical discomfort. The direct effect of adult attachment styles on mental health states during COVID-19 quarantine was significant (c' = -0.3172; p < 0.01). The total indirect effect also showed statistical significance (ab = -0.1857; p < 0.01). Moreover, the total effect of adult attachment styles on mental health states was -0.5029 (c = -0.5029; p < 0.01). Subjective social support and utilization of social support play mediating roles in the relationship between attachment style and mental health states, respectively (ab1 = -0.1287, 95% CI: -0.9120 to -0.3341, ab2 = 0.0570, 95% CI: -0.4635 to -0.1132). Conclusion: These findings highlight social support played a mediation role between attachment style and mental health states. Thus, offering social support during a crisis might be useful for those individuals with an insecure attachment.

Mapping of the influenza A virus genome RNA structure and interactions reveals essential elements of viral replication.

Influenza A virus (IAV) represents a constant public health threat. The single-stranded, segmented RNA genome of IAV is replicated in host cell nuclei as a series of 8 ribonucleoprotein complexes (vRNPs) with RNA structures known to exert essential function to support viral replication. Here, we investigate RNA secondary structures and RNA interactions networks of the IAV genome and construct an in vivo structure model for each of the 8 IAV genome segments. Our analyses reveal an overall in vivo and in virio resemblance of the IAV genome conformation but also wide disparities among long-range and intersegment interactions. Moreover, we identify a long-range RNA interaction that exerts an essential role in genome packaging. Disrupting this structure displays reduced infectivity, attenuating virus pathogenicity in mice. Our findings characterize the in vivo RNA structural landscape of the IAV genome and reveal viral RNA structures that can be targeted to develop antiviral interventions.

ACAT2 suppresses the ubiquitination of YAP1 to enhance the proliferation and metastasis ability of gastric cancer via the upregulation of SETD7.

The contributions of aberrantly expressed metabolic enzymes to gastric cancer (GC) initiation and progression have been widely appreciated in recent years. Acetyl-CoA acetyltransferase 2 (ACAT2) is one member of the acetyl- CoA thiolase family. Previous studies demonstrated that ACAT2 either promotes or suppresses tumor progression in different conditions. However, the function and mechanisms of ACAT2 in GC remain unknown. We found that the expression of this enzyme was significantly increased in GC tissues compared with normal counterparts, which prompted us to further investigate the roles of this protein in GC biology. In vitro functional studies showed that ACAT2 knockdown markedly halted the proliferation and the motility of GC cells; these functions favoring malignant phenotypes of GC cells were further validated in animal experiments. Mechanistically, ACAT2 depletion significantly reduced the transcription of SETD7, which is a histone methyltransferase and plays critical roles in GC cells. We found that the pro-tumoral functions of ACAT2 were largely dependent on SETD7. Moreover, SETD7 decreased the ubiquitination level of Yes-associated protein 1 (YAP1), thereby protecting YAP1 from proteasome degradation. Increased YAP1 protein expression remarkably activated the YAP1/TAZ-TEAD1 signaling pathway, which further boosted the malignant phenotypes in GC cells. In conclusion, these findings highlight the pro-tumoral functions and molecular underpinnings of ACAT2 in GC cells, and suggest that ACAT2 could be a promising target in GC treatment.

Generalized tonic-clonic seizures in adult patients following intravenous administration of desmopressin.

Desmopressin is a synthetic replacement for vasopressin, which is used to reduce perioperative blood loss. However, seizure attacks were observed in patients after administration of desmopressin. Here, we reported two cases of adult Chinese patients experienced generalized tonic-clonic seizures associated with severe hyponatremia caused by intravenously administered desmopressin after surgery. The patients' neurological conditions returned to baseline quickly and completely following discontinuation of desmopressin, control of the seizures, and fluid intake restriction. These cases illustrate the importance of periodic monitoring of electrolyte concentrations and fluid intake during use of desmopressin.

Initial clinical and experimental analyses of ALDOA in gastric cancer, as a novel prognostic biomarker and potential therapeutic target.

The effect of ALDOA, an important regulator of tumor metabolism and immune cell function, on gastric cancer (GC) immune infiltration has not been elucidated. Hence, we explored the feasibility of using ALDOA combined with immune molecular markers as novel prognostic or therapeutic targets for GC patients. Bioinformatic analyses were initially performed in multiple databases to assess the prognostic prediction values of ALDOA expression in GC. Subsequently, both ALDOA expression and the clinicopathological characteristics of a total of 114 GC patients who underwent curative gastrectomy were collected to demonstrate the potential association between ALDOA expression and the biological behaviors of GC. Next, the expression of ALDOA and its effect on prognosis were determined at the mRNA and protein levels, respectively, using tissue microarrays and cellular experiments. Subsequently, several molecular mechanisms were revealed based on elaborate analyses, indicating that ALDOA expression was potentially involved in the progression of GC and could be considered a promising biomarker for evaluating the prognosis of GC. High ALDOA expression was frequently found in GC cells and GC tissues at the mRNA and protein levels. Based on survival analysis, the expression of ALDOA indicated comparatively poor overall survival (OS) in GC and was identified as an independent prognostic predictor of GC. Correlation analysis showed that ALDOA expression had a positive association with lymph node metastasis in GC patients. Additionally, microRNA-1179 was found to play a key role in inhibiting the expression of ALDOA in the metabolic pathways of GC cells, which might disrupt the expression of various immune molecules and be detrimental to the prognosis of GC. ALDOA should be considered a promising molecular target for evaluating the prognosis of GC, owing to its potential role in immune regulation.

Degree of obesity and gastrointestinal adverse reactions influence the weight loss effect of liraglutide in overweight or obese patients with type 2 diabetes.

Background: Liraglutide can effectively reduce the weight of patients with type 2 diabetes. Nonetheless, its weight loss effect was highly heterogeneous in different patients in the clinical practice. Objective: To identify the factors most associated with the weight loss effect of liraglutide in obese or overweight patients with type 2 diabetes with poorly controlled oral medication in northeast China. Design: A prospective study. Methods: A prospective study was performed in subjects with type 2 diabetes who were taking oral medication and had a body mass index (BMI) of ⩾24 kg/m2. Liraglutide was administered for at least 12 weeks, while the original hypoglycemic regimen was kept unchanged (Phase I). Later, liraglutide treatment was continued or stopped as necessary or as subjects thought fit in the 13-52 weeks that followed (Phase II), and the potential factors affecting the effect of weight loss of liraglutide were analyzed. Results: Of the 127 recruited subjects, 90 had comprehensive follow-up data at week 12. In Phase I, the subjects' blood sugar levels and weight decreased significantly(P < 0.001). Among all the significant factors, the gastrointestinal adverse reactions score (GARS) was more correlated with BMI change (ΔBMI; r = 0.43) and waist circumference change (ΔWC; r = 0.32) than the baseline BMI (BMI0) and WC (WC0). At week 12, linear regression showed that BMI0 independently affected ΔBMI and ΔWC, whereas WC0 only affected ΔWC. The GARS was significantly associated with ΔBMI and ΔWC, and this association continued until week 52, even after most subjects had discontinued liraglutide treatment. Conclusion: The degree of obesity and gastrointestinal adverse reactions were the most promising predictors of weight loss in liraglutide treatment.

Progranulin inhibits fibrosis by interacting with and up-regulating DNAJC3 during mouse skin wound healing.

Scars place a heavy burden on both individuals and society. Our previous study found that reduction of progranulin (PGRN) promotes fibrogenesis in mouse skin wound healing. However, the underlying mechanisms have not been elucidated. Here, we report that PGRN overexpression decreases the expression of profibrotic genes alpha-smooth muscle actin (αSMA), serum response factor (SRF), and connective tissue growth factor (CTGF), thereby inhibiting skin fibrosis during wound repair. Bioinformatics analysis suggested that the heat shock protein (Hsp) 40 superfamily C3 (DNAJC3) is a potential downstream molecule of PGRN. Further experiments showed that PGRN interacts with and upregulates DNAJC3. Moreover, this antifibrotic effect was rescued by DNAJC3 knockdown. In summary, our study suggests that PGRN inhibits fibrosis by interacting with and upregulating DNAJC3 during wound healing in mouse skin. Our study provides a mechanistic explanation of the effect of PGRN on fibrogenesis in skin wound healing.

Maresin-1 improves LPS-induced depressive-like behavior by inhibiting hippocampal microglial activation.

Maresin-1 is an antiphlogistic agonist synthesized by macrophages from docosahexaenoic acid (DHA). It has both anti-inflammatory and pro-inflammatory properties and has been found to enhance neuroprotection and cognitive function. However, there is limited knowledge of its effects on depression and the potential mechanism remains unclear. In this study, the effects of Maresin-1 on lipopolysaccharide (LPS)-induced depressive symptoms and neuroinflammation were investigated in mice and the possible cellular and molecular mechanisms were further clarified. Maresin-1 treatment (5 µg/kg, i.p.) led to improved tail suspension times, as well as distances moved in an open-field test but it did not improve reductions in sugar-water consumption in mice with depressive-like behaviors induced by LPS (1 mg/kg, i.p.); TSPO PETCT scanning showed that Maresin-1 reduced the standardized uptake value (SUV) of [18 F] DPA-714 in brain regions associated with depression (e.g., hippocampus and pre-frontal cortex), while immunofluorescence of hippocampal and indicated that Maresin-1 inhibited microglial activation reducing the expression of the pro-inflammatory cytokine IL-1ß and NLRP3. The RNA sequencing of mouse hippocampi showed that genes expressed differentially between Maresin-1-treated and LPS-treated tissue were associated with tight connections between cells and the stress-activated MAPK cascade negative regulatory pathways. Overall, this study demonstrates that peripheral application of Maresin-1 could partially relieve LPS-induced depressive-like behaviors and showed for the first time that this effect was related to its anti-inflammatory action on microglia, thus providing new clues for the pharmacological mechanism underlying the anti-depression properties of Maresin-1.