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1.
Small ; : e2312046, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38829034

ABSTRACT

Accurate construction of artificial nano-chaperones' structure is crucial for precise regulation of protein conformational transformation, facilitating effective treatment of proteopathy. However, how the ligand-anchors of nano-chaperones affect the spatial conformational changes in proteins remains unclear, limiting the development of efficient nano-chaperones. In this study, three types of gold nanoparticles (AuNPs) with different core/ligands interface anchor structures (Au─NH─R, Au─S─R, and Au─C≡C─R, R = benzoic acid) are synthesized as an ideal model to investigate the effect of interfacial anchors on Aß and amylin fibrillization. Computational results revealed that the distinct interfacial anchors imparted diverse distributions of electrostatic potential on the nanointerface and core/ligands bond strength of AuNPs, leading to differential interactions with amyloid peptides. Experimental results demonstrated that all three types of AuNPs exhibit site-specific inhibitory effects on Aß40 fibrillization due to preferential binding. For amylin, amino-anchored AuNPs demonstrate strong adsorption to multiple sites on amylin and effectively inhibit fibrillization. Conversely, thiol- and alkyne-anchored AuNPs adsorb at the head region of amylin, promoting folding and fibrillization. This study not only provided molecular insights into how core/ligands interfacial anchors of nanomaterials induce spatial conformational changes in amyloid peptides but also offered guidance for precisely engineering artificial-chaperones' nanointerfaces to regulate the conformational transformation of proteins.

2.
Acta Pharm Sin B ; 14(6): 2567-2580, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38828157

ABSTRACT

The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity. Here, we show that carrimycin, a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials, decreases the efficiency of programmed -1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion. Carrimycin binds directly to the coronaviral frameshift-stimulatory element (FSE) RNA pseudoknot, interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes. Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses. Because the FSE mechanism is essential in all coronaviruses, carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA. This finding may open a new direction in antiviral drug discovery for coronavirus variants.

3.
Am J Cancer Res ; 14(4): 1904-1913, 2024.
Article in English | MEDLINE | ID: mdl-38726286

ABSTRACT

Addressing the critical challenge of early ovarian cancer (OC) detection, our study focuses on identifying novel biomarkers by analyzing preoperative peripheral blood exosomes from high-grade serous ovarian cancer (HGSC) patients and healthy controls. Utilizing high-performance liquid chromatography-mass spectrometry-based quantitative proteomics, we isolated and analyzed peripheral blood exosomes to identify differentially expressed proteins (DEPs). This comprehensive analysis, supported by gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) database assessments, revealed 28 proteins with decreased abundance and 33 with increased abundance in HGSC patients compared to controls. Notably, Zinc Finger Protein 587B (ZNF587B) exhibited a significant reduction in abundance, confirmed by decreased mRNA and protein levels in HGSC and normal ovarian tissues, consistent with omes exosomal protein expression levels. Immunohistochemical staining further confirmed reduced ZNF587B protein levels in HGSC tissues. The significant correlation between ZNF587B expression levels and tumor stage underscores its potential as a valuable biomarker for early liquid biopsy screening of OC. Our findings suggest ZNF587B plays a crucial role in early HGSC detection, highlighting the importance of further research to validate its clinical utility and improve ovarian cancer patient outcomes.

4.
Hepatol Int ; 2024 May 13.
Article in English | MEDLINE | ID: mdl-38740699

ABSTRACT

BACKGROUND: Evidence concerning long-term outcome of robotic liver resection (RLR) and laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) patients is scarce. METHODS: This study enrolled all patients who underwent RLR and LLR for resectable HCC between July 2016 and July 2021. Propensity score matching (PSM) was employed to create a 1:3 match between the RLR and LLR groups. A comprehensive collection and analysis of patient data regarding efficacy and safety have been conducted, along with the evaluation of the learning curve for RLR. RESULTS: Following PSM, a total of 341 patients were included, with 97 in the RLR group and 244 in the LLR group. RLR group demonstrated a significantly longer operative time (median [IQR], 210 [152.0-298.0] min vs. 183.5 [132.3-263.5] min; p = 0.04), with no significant differences in other perioperative and short-term postoperative outcomes. Overall survival (OS) was similar between the two groups (p = 0.43), but RLR group exhibited improved recurrence-free survival (RFS) (median of 65 months vs. 56 months, p = 0.006). The estimated 5-year OS for RLR and LLR were 74.8% (95% CI: 65.4-85.6%) and 80.7% (95% CI: 74.0-88.1%), respectively. The estimated 5-year RFS for RLR and LLR were 58.6% (95% CI: 48.6-70.6%) and 38.3% (95% CI: 26.4-55.9%), respectively. In the multivariate Cox regression analysis, RLR (HR: 0.586, 95% CI (0.393-0.874), p = 0.008) emerged as an independent predictor of reducing recurrence rates and enhanced RFS. The operative learning curve indicates that approximately after the 11th case, the learning curve of RLR stabilized and entered a proficient phase. CONCLUSIONS: OS was comparable between RLR and LLR, and while RFS was improved in the RLR group. RLR demonstrates oncological effectiveness and safety for resectable HCC.

5.
Open Forum Infect Dis ; 11(5): ofae241, 2024 May.
Article in English | MEDLINE | ID: mdl-38756766

ABSTRACT

Background: Pregnant women with chronic hepatitis B (CHB) exhibit unique clinical features in terms of postpartum immune system reconstitution and recovery from pregnancy-related changes. However, current studies focus primarily on the outcomes of maternal-infant transmission and postpartum hepatitis flares. We aimed to evaluate the profiles of hepatitis B core-related antigen (HBcrAg) and pregenomic RNA (pgRNA) in pregnant women with CHB. Methods: This retrospective analysis included treatment-naïve pregnant women with CHB who were followed up regularly in an outpatient clinic from 2014 to 2021. Baseline HBcrAg and pgRNA levels were compared in patients with different disease phases. Changes in these parameters were examined in a subset of patients receiving antiviral prophylaxis. HBcrAg and pgRNA levels were measured before treatment, at 32 weeks of gestation, and postpartum. Results: The final analysis included a total of 121 patients, 100 of whom were hepatitis B e antigen (HBeAg)-positive (96 and 4 in the immune-tolerant and -indeterminate phases, respectively) and 21 of whom were HBeAg-negative (6 and 15 in the immune-active and -inactive carrier phases, respectively). The HBeAg-negative group vs the HBeAg-positive group had lower levels of baseline HBcrAg (median [interquartile range {IQR}], 3.7 [3.0-5.9] vs 8.6 [8.4-8.7] log10 U/mL; P < .01) and pgRNA (median [IQR], 0.0 [0.0-2.5] vs 7.8 [7.6-8.1] log10 copies/mL; P < .01). The serum levels of HBcrAg and pgRNA were highest in immune-tolerant carriers and lowest in immune-inactive carriers. In HBeAg-positive patients, the correlation coefficients of HBcrAg and pgRNA with hepatitis B virus (HBV) DNA were 0.40 and 0.43, respectively; in HBeAg-negative patients, they were 0.53 and 0.51, respectively (all P < .05). The correlation coefficients with hepatitis B surface antigen (HBsAg) were 0.55 and 0.52 (P < .05) in HBeAg-positive patients, respectively, while in HBeAg-negative patients they were 0.42 and 0.37, respectively (P > .05). Among 96 patients receiving antiviral prophylaxis, we detected a rapid decrease in HBV DNA to an undetectable level during treatment but relatively stable levels of pgRNA and HBcrAg. Conclusions: HBcrAg and pgRNA levels are lower in HBeAg-negative patients than in HBeAg-positive patients. These 2 markers are significantly associated with HBV DNA irrespective of HBeAg status, while they are significantly associated with HBsAg only in HBeAg-positive patients.

6.
Sci Adv ; 10(20): eadl3511, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38748808

ABSTRACT

Cervical cancer, primarily squamous cell carcinoma, is the most prevalent gynecologic malignancy. Organoids can mimic tumor development in vitro, but current Matrigel inaccurately replicates the tissue-specific microenvironment. This limitation compromises the accurate representation of tumor heterogeneity. We collected para-cancerous cervical tissues from patients diagnosed with cervical squamous cell carcinoma (CSCC) and prepared uterine cervix extracellular matrix (UCEM) hydrogels. Proteomic analysis of UCEM identified several tissue-specific signaling pathways including human papillomavirus, phosphatidylinositol 3-kinase-AKT, and extracellular matrix receptor. Secreted proteins like FLNA, MYH9, HSPA8, and EEF1A1 were present, indicating UCEM successfully maintained cervical proteins. UCEM provided a tailored microenvironment for CSCC organoids, enabling formation and growth while preserving tumorigenic potential. RNA sequencing showed UCEM-organoids exhibited greater similarity to native CSCC and reflected tumor heterogeneity by exhibiting CSCC-associated signaling pathways including virus protein-cytokine, nuclear factor κB, tumor necrosis factor, and oncogenes EGR1, FPR1, and IFI6. Moreover, UCEM-organoids developed chemotherapy resistance. Our research provides insights into advanced organoid technology through native matrix hydrogels.


Subject(s)
Carcinoma, Squamous Cell , Extracellular Matrix , Hydrogels , Organoids , Uterine Cervical Neoplasms , Humans , Female , Organoids/metabolism , Organoids/pathology , Organoids/drug effects , Extracellular Matrix/metabolism , Hydrogels/chemistry , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/genetics , Cervix Uteri/pathology , Cervix Uteri/metabolism , Tumor Microenvironment , Signal Transduction , Animals , Proteomics/methods , Mice
7.
Biology (Basel) ; 13(5)2024 Apr 28.
Article in English | MEDLINE | ID: mdl-38785787

ABSTRACT

The assassin bug Sycanus bifidus has a wide distribution across southern China. This study explored its distribution and evolution by analyzing mitochondrial and nuclear ribosomal RNA genes, revealing how Pleistocene climate and geological changes shaped its phylogeography. We identified two main clades, A and B, that diverged in the Middle Pleistocene. Hainan Island's populations form a unique group within Clade A, suggesting that the Qiongzhou Strait served as a dispersal corridor during glaciation. Rising sea levels likely separated the Hainan population afterward. Ecological niche modeling showed that both populations have been viable since the last interglacial period, with demographic analyses indicating possible expansions during the Middle and Late Pleistocene, driven by favorable climates. This study highlights the significant effects of Pleistocene sea-level and climatic changes on the distribution and evolution of S. bifidus in China.

8.
Int J Mol Sci ; 25(10)2024 May 07.
Article in English | MEDLINE | ID: mdl-38791126

ABSTRACT

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.


Subject(s)
Fatty Acid-Binding Proteins , Fatty Liver , Glutathione Transferase , Up-Regulation , Glutathione Transferase/metabolism , Glutathione Transferase/genetics , Animals , Humans , Mice , Fatty Acid-Binding Proteins/metabolism , Fatty Acid-Binding Proteins/genetics , Fatty Liver/metabolism , Fatty Liver/drug therapy , Up-Regulation/drug effects , Liver/metabolism , Liver/pathology , Liver/drug effects , Diet, High-Fat/adverse effects , Male , Mice, Inbred C57BL , Hepatocytes/metabolism , Hepatocytes/drug effects , Lipid Metabolism/drug effects , Oleic Acid/metabolism , Hep G2 Cells , Triglycerides/metabolism , Isoenzymes
9.
J Am Chem Soc ; 146(19): 13399-13405, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38698691

ABSTRACT

Structural motifs containing nitrogen-nitrogen (N-N) bonds are prevalent in a large number of clinical drugs and bioactive natural products. Hydrazine (N2H4) serves as a widely utilized building block for the preparation of these N-N-containing molecules in organic synthesis. Despite its common use in chemical processes, no enzyme has been identified to catalyze the incorporation of free hydrazine in natural product biosynthesis. Here, we report that a hydrazine transferase catalyzes the condensation of N2H4 and an aromatic polyketide pathway intermediate, leading to the formation of a rare N-aminolactam pharmacophore in the biosynthesis of broad-spectrum antibiotic albofungin. These results expand the current knowledge on the biosynthetic mechanism for natural products with N-N units and should facilitate future development of biocatalysts for the production of N-N-containing chemicals.


Subject(s)
Hydrazines , Hydrazines/chemistry , Hydrazines/metabolism , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/pharmacology , Streptomyces/enzymology , Streptomyces/metabolism , Lactams/chemistry , Lactams/metabolism , Pharmacophore
10.
Water Res ; 257: 121659, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38692255

ABSTRACT

Various heavy metals are reported to be able to accelerate horizontal transfer of antibiotic resistance genes (ARGs). In real water environmental settings, ubiquitous complexing agents would affect the environmental behaviors of heavy metal ions due to the formation of metal-organic complexes. However, little is known whether the presence of complexing agents would change horizontal gene transfer due to heavy metal exposure. This study aimed to fill this gap by investigating the impacts of a typical complexing agent ethylenediaminetetraacetic acid (EDTA) on the conjugative transfer of plasmid-mediated ARGs induced by a range of heavy metal ions. At the environmentally relevant concentration (0.64 mg L-1) of metal ions, all the tested metal ions (Mg2+, Ca2+, Co2+, Pb2+, Ni2+, Cu2+, and Fe3+) promoted conjugative transfer of ARGs, while an inhibitory effect was observed at a relatively higher concentration (3.20 mg L-1). In contrast, EDTA (0.64 mg L-1) alleviated the effects of metal ions on ARGs conjugation transfer, evidenced by 11 %-66 % reduction in the conjugate transfer frequency. Molecular docking and dynamics simulations disclosed that this is attributed to the stronger binding of metal ions with the lipids in cell membranes. Under metal-EDTA exposure, gene expressions related to oxidative stress response, cell membrane permeability, intercellular contact, energy driving force, mobilization, and channels of plasmid transfer were suppressed compared with the metal ions exposure. This study offers insights into the alleviation mechanisms of complexing agents on ARGs transfer induced by free metal ions.


Subject(s)
Drug Resistance, Microbial , Edetic Acid , Edetic Acid/pharmacology , Edetic Acid/chemistry , Drug Resistance, Microbial/genetics , Gene Transfer, Horizontal , Plasmids , Metals, Heavy/chemistry , Escherichia coli/drug effects , Escherichia coli/genetics , Metals , Ions
11.
Curr Probl Cardiol ; 49(7): 102629, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38723797

ABSTRACT

Transcatheter aortic valve implantation (TAVI) is a promising treatment strategy for high-risk surgical patients, and trials investigating its effectiveness in intermediate- and lower-risk patients are underway. Data are inconsistent regarding the superiority of using local anesthesia with conscious sedation alone versus general anesthesia (GA) as the anesthesia management of choice for elderly frail patients. Historically, TAVI procedure is performed under GA with transesophageal echocardiography. This approach gives operators stable hemodynamic control of the patient and helps decrease the risk of many of the operation's documented complications, including paravalvular leak and valve malpositioning. However, some studies have criticized the dependence of GA on mechanical ventilation and an increased need for catecholamine and/or vasopressor agents. Alternatively, to further capitalize on the minimally invasive nature of TAVI, some authors have advocated for the use of local anesthesia (LA) and/or conscious sedation approach, which would decrease procedure time, length of hospital stay, and minimize the need for postoperative inotropes. Ultimately and at present, the choice of anesthesia is based on the personal experience and preference of the Heart Team involved in the TAVI procedure, which will dictate the best possible management plan for each patient. Many patients currently undergoing TAVI are elderly and have multiple comorbidities, making their care complex. Anesthetic care is shifting from GA to sedation and regional block, but life-threatening complications are still relatively common and safety during planning and conduct of these procedures by the heart team, with the anesthesiologist at the center, is paramount.


Subject(s)
Anesthesia, General , Anesthesia, Local , Aortic Valve Stenosis , Randomized Controlled Trials as Topic , Transcatheter Aortic Valve Replacement , Humans , Anesthesia, General/methods , Anesthesia, Local/methods , Aortic Valve Stenosis/surgery , Propensity Score , Transcatheter Aortic Valve Replacement/methods
12.
Curr Probl Cardiol ; 49(7): 102614, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38692447

ABSTRACT

Pulmonary hypertension (PH) with high pulmonary vascular resistance (PVR) is a very often diagnosed contraindication for orthotopic heart transplantation (OHT). It is a direct consequence of left ventricle failure characterized by high diastolic pressure obstructing the collection of blood from the pulmonary vessels. The occurrence of this situation grows with the increasing time of waiting for OHT, and with the progression of heart failure. Mechanical circulatory support (MCS) devices, particularly left ventricular assist devices (LVADs), have emerged as pivotal interventions for patients with fixed PH, offering a potential bridge to transplantation. The pathophysiological impact of PH in heart transplant candidates is profound, as it is associated with increased perioperative risk and heightened mortality post-transplantation. The selection of heart transplant candidates thus mandates a careful evaluation of PH, with an emphasis on distinguishing between reversible and fixed forms of the condition. Reversible PH can often be managed with medical therapies; however, fixed PH presents a more daunting challenge, necessitating more aggressive interventions like MCS. Patients are supported with LVADs until evidence of pulmonary afterload reversal is evident and then can be considered for heart transplantation. However, in those who are non-responders or have complications while being supported, their option for transplant is revoked. Despite these advancements, the heterogeneity of MCS devices and their mechanisms of action necessitates a nuanced understanding of their efficacy.


Subject(s)
Heart Failure , Heart Transplantation , Heart-Assist Devices , Hypertension, Pulmonary , Humans , Hypertension, Pulmonary/therapy , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/physiopathology , Heart Failure/therapy , Heart Failure/physiopathology , Treatment Outcome , Vascular Resistance/physiology
13.
Insect Sci ; 2024 Apr 09.
Article in English | MEDLINE | ID: mdl-38594229

ABSTRACT

Honeybees and bumblebees play a crucial role as essential pollinators. The special gut microbiome of social bees is a key factor in determining the overall fitness and health of the host. Although bees harbor relatively simple microbial communities at the genus level, recent studies have unveiled significant genetic divergence and variations in gene content within each bacterial genus. However, a comprehensive and refined genomics-based taxonomic database specific to social bee gut microbiomes remains lacking. Here, we first provided an overview of the current knowledge on the distribution and function of social bee gut bacteria, as well as the factors that influence the gut population dynamics. We then consolidated all available genomes of the gut bacteria of social bees and refined the species-level taxonomy, by constructing a maximum-likelihood core genome phylogeny and calculating genome-wide pairwise average nucleotide identity. On the basis of the refined species taxonomy, we constructed a curated genomic reference database, named the bee gut microbe genome sequence database (BGM-GDb). To evaluate the species-profiling performance of the curated BGM-GDb, we retrieved a series of bee gut metagenomic data and inferred the species-level composition using metagenomic intra-species diversity analysis system (MIDAS), and then compared the results with those obtained from a prebuilt MIDAS database. We found that compared with the default database, the BGM-GDb excelled in aligned read counts and bacterial richness. Overall, this high-resolution and precise genomic reference database will facilitate research in understanding the gut community structure of social bees.

14.
Materials (Basel) ; 17(7)2024 Mar 24.
Article in English | MEDLINE | ID: mdl-38611994

ABSTRACT

The impacts of various aggregate particle sizes and cement contents on the internal structure of pervious concrete were investigated. Accordingly, test blocks with different aggregate particle sizes and cement contents were dissected and photographed. Subsequently, the captured images were processed using the ImageJ software (1.53i) to analyze the profiles of the test blocks and identify the internal mesoscopic parameters of the pervious concrete. This study discusses the relationship between microscopic parameters and macroscopic factors based on experimental results. It also fits functional equations linking the permeability coefficient with pore parameters, matrix parameters, and compressive strength. The results indicated that, as the aggregate size increased, the internal pore diameter of the pervious concrete increased, whereas the total area and width of the cement matrix decreased. This resulted in a low permeability coefficient and high compressive strength of the test block. Increasing the cement content in pervious concrete reduced the porosity and increased the width and area of the internal matrix. Consequently, the permeability coefficient decreased, and the compressive strength of the test block increased.

15.
Ying Yong Sheng Tai Xue Bao ; 35(3): 587-596, 2024 Mar 18.
Article in English | MEDLINE | ID: mdl-38646745

ABSTRACT

To investigate the longitudinal variation patterns of sapwood, heartwood, bark and stem moisture content along the trunk of artificial Larix olgensis, we constructed mixed effect models of moisture content based on beta regression by combining the effects of sampling plot and sample trees. We used two sampling schemes to calibrate the model, without limiting the relative height (Scheme Ⅰ) and with a limiting height of less than 2 m (Scheme II). The results showed that sapwood and stem moisture content increased gradually along the trunk, heartwood moisture content decreased slightly and then increased along the trunk, and bark moisture content increased along the trunk and then levelled off before increasing. Relative height, height to crown base, stand area at breast height per hectare, age, and stand dominant height were main factors driving moisture content of L. olgensis. Scheme Ⅰ showed the stable prediction accuracy when randomly sampling moisture content measurements from 2-3 discs to calibrate the model, with the mean absolute percentage error (MAPE) of up to 7.2% for stem moisture content (randomly selected 2 discs), and the MAPE of up to 7.4%, 10.5% and 10.5% for sapwood, heartwood and bark moisture content (randomly selected 3 discs), respectively. Scheme Ⅱ was appropriate when sampling moisture content measurements from discs of 1.3 and 2 m height and the MAPE of sapwood, heartwood, bark and stem moisture content reached 7.8%, 11.0%, 10.4% and 7.1%, respectively. The prediction accuracies of all mixed effect beta regression models were better than the base model. The two-level mixed effect beta regression models, considering both plot effect and tree effect, would be suitable for predicting moisture content of each part of L. olgensis well.


Subject(s)
Larix , Plant Stems , Water , Larix/growth & development , Larix/chemistry , Plant Stems/chemistry , Plant Stems/growth & development , Water/analysis , Water/chemistry , Regression Analysis , Wood/chemistry , Models, Theoretical , Forecasting
16.
Cell Metab ; 36(4): 857-876.e10, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38569472

ABSTRACT

Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.


Subject(s)
Leptin , Obesity , Animals , Mice , Histone Deacetylase 6 , Leptin/metabolism , Obesity/metabolism , Receptors, Leptin/genetics , Receptors, Leptin/metabolism , Weight Gain , Weight Loss
17.
Cell Rep ; 43(4): 114077, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38592974

ABSTRACT

Enhancer-derived RNAs (eRNAs) play critical roles in diverse biological processes by facilitating their target gene expression. However, the abundance and function of eRNAs in early embryos are not clear. Here, we present a comprehensive eRNA atlas by systematically integrating publicly available datasets of mouse early embryos. We characterize the transcriptional and regulatory network of eRNAs and show that different embryo developmental stages have distinct eRNA expression and regulatory profiles. Paternal eRNAs are activated asymmetrically during zygotic genome activation (ZGA). Moreover, we identify an eRNA, MZGAe1, which plays an important function in regulating mouse ZGA and early embryo development. MZGAe1 knockdown leads to a developmental block from 2-cell embryo to blastocyst. We create an online data portal, M2ED2, to query and visualize eRNA expression and regulation. Our study thus provides a systematic landscape of eRNA and reveals the important role of eRNAs in regulating mouse early embryo development.


Subject(s)
Embryonic Development , Enhancer Elements, Genetic , Gene Expression Regulation, Developmental , Animals , Embryonic Development/genetics , Mice , Enhancer Elements, Genetic/genetics , RNA/metabolism , RNA/genetics , Female , Embryo, Mammalian/metabolism , Zygote/metabolism , Gene Regulatory Networks , Male
18.
Biomed Pharmacother ; 174: 116617, 2024 May.
Article in English | MEDLINE | ID: mdl-38643542

ABSTRACT

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid commonly used for treating cholestatic liver disease. However, its efficacy on non-alcoholic steatohepatitis (NASH) was controversial. This study aimed to investigate the impact of a high dosage of UDCA on a mouse model of NASH. Forty 6-week-old mice were fed a high-fat high-cholesterol (HFHC) diet for 12 weeks to establish a mouse model of NASH, and then divided into four groups: two groups transitioned to a normal diet, and the other two groups maintained the HFHC diet. Each group was administered a daily dosage of 300 mg/kg of UDCA or saline for a period of 8 weeks. The 16 s ribosomal RNA genes extracted from mice fecal pellets were sequenced using next-generation sequencing techniques. Serum bile acid profiles were quantified using liquid chromatography electrospray ionization tandem mass spectrometry method. The results showed that UDCA treatment ameliorated liver inflammation, without affecting liver fibrosis. UDCA treatment reduced the relative abundance of the genera Bacteroides, Parabacteroides, and Intestinimonas, whereas increased the relative abundance of the genera norank_f_Muribaculaceae and Parasutterella in the HFHC-maintaining groups. The serum levels of total bile acids and total primary bile acids increased, whereas those of endogenous primary bile acids decreased after UDCA treatment. Correlation analysis showed that primary bile acids were negatively correlated with the genera norank_f_Christensenellaceae and unclassified_f_Ruminococcaceae. In conclusion, a high dosage of UDCA can alleviate liver inflammation, probably by modifying the composition of gut microbiota and serum bile acid profiles in NASH mice.


Subject(s)
Bile Acids and Salts , Disease Models, Animal , Gastrointestinal Microbiome , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease , Ursodeoxycholic Acid , Animals , Ursodeoxycholic Acid/pharmacology , Ursodeoxycholic Acid/administration & dosage , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/microbiology , Non-alcoholic Fatty Liver Disease/pathology , Gastrointestinal Microbiome/drug effects , Bile Acids and Salts/metabolism , Bile Acids and Salts/blood , Male , Mice , Diet, High-Fat , Liver/drug effects , Liver/metabolism , Liver/pathology
19.
Gene ; 917: 148466, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-38615984

ABSTRACT

This study presents the sequencing and annotation of mitochondrial genomes from five Rhingia species of the family Syrphidae, focusing on codon bias. Each species possessed 22 tRNAs genes, 13 protein-coding genes, 2 rRNAs genes, and a control region, without any observed gene rearrangements. Nucleotide composition analysis revealed a higher AT content compared with GC content, indicating AT enrichment. Neutrality plot, Parity rule 2 bias, and effective number of codons plot analyses collectively indicated that natural selection primarily influences the codon usage bias in the five Rhingia species. Relative synonymous codon usage analysis identified the optimal codons for Rhingia binotata, R. fromosana, R. campestris, R. louguanensis, and R. xanthopoda as 10, 14, 10, 11, and 12, respectively, all ending with A/U and exhibiting AT preference. Phylogenetic analysis, based on maximum likelihood and Bayesian inference methods applied to three datasets, confirmed the monophyly of Rhingia. In conclusion, this research establishes a foundation for understanding the phylogenetic evolution and codon usage patterns in Rhingia, offering valuable for future studies.


Subject(s)
Base Composition , Codon Usage , Diptera , Genome, Mitochondrial , Phylogeny , Animals , Diptera/genetics , Diptera/classification , RNA, Transfer/genetics , Evolution, Molecular , Codon/genetics , Selection, Genetic
20.
J Environ Manage ; 359: 120996, 2024 May.
Article in English | MEDLINE | ID: mdl-38669885

ABSTRACT

Enhalus acoroides, the largest seagrass species in terms of morphology, has been observed to be declining significantly. In an effort to restore seagrass meadows, we conducted a transplantion utilizing dislodged rhizome fragments of E. acoroides as the donor materials. The growth of transplanted seagrass was monitored over a period of three years, and the impact of seagrass recolonization on sedimentary environment was assessed through analysis of sediment microbial diversity. The transplanted plants displayed notable growth, resulting in the successful recolonization of experimental plots by seagrass. The 3-year data also revealed the following findings: 1) the new shoot recruitment rate (per year) (NSR) of transplanted seagrass was 2.33 in the first year, 1.36 in the second year, and 0.83 in the third year, indicating a rapid initial growth rate of E. acoroides that subsequently slowed down; 2) the numbers of shoots and aboveground biomass of transplanted seagrass had increased by 13.0 and 15.9-fold, respectively, whereas only 3.3 and 5.3-fold increases of the natural seagrass were observed, suggesting that the transplantation of seagrass leads to a significantly accelerated recovery compared to its natural regeneration process. Furthermore, the restoration of E. acoroides resulted in a higher microbial diversity in the submarine sediments within the restoration area, as compared to the adjacent unvegetated area. This suggests that the re-vegetation of E. acoroides has a positive influence on the overall health of the sedimentary environment. This study strongly advocates for the active transplantation of dislodged E. acoroides plants resulting from human activities as a potential approach for future coastal management, specifically for the restoration of E. acoroides meadows.


Subject(s)
Geologic Sediments , Rhizome , Geologic Sediments/microbiology , Biodiversity , Biomass
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