ABSTRACT
Background: Identification and resection of the thyroid pyramidal lobe is important for thyroid cancer surgery in order to prevent interval cancer in residual thyroid tissue. Purpose: The purpose of this study was to determine how often a thyroid pyramidal lobe is found in patients with and without previous thyroidectomy and to optimise the protocol for identifying thyroid pyramidal lobes during routine thyroid ultrasonography. Material and Methods: In this prospective study, a total of 1579 patients who received routine thyroid ultrasound scans at a single centre were enrolled. A dedicated standard scanning protocol was established containing both static images of the anterior neck superior to the thyroid as well as a transverse cine loop starting from the isthmus to the hyoid bone. The presence and features of thyroid pyramidal lobes were evaluated and compared. Results: Detection rate of thyroid pyramidal lobes in patients without thyroidectomy improved from 39.5% (480/1215) to 49.7% (640/1215) with protocol adding cine-loop as compared to protocol without cine-loop. The cine-loops were particularly helpful in the detection of thyroid pyramidal lobes when it is separated from the main lobe or in thyroidectomy patients. By adding assessment with cine-loop into the dedicated protocol, we have further detected different pathologies occurring on thyroid pyramidal lobes including benign and malignant solid nodules and pseudo-nodules of Hashimoto's thyroiditis. Conclusion: The addition of dynamic assessment with cine-loop increases the detection rate of thyroid pyramidal lobes. By paying attention to the thyroid pyramidal lobe in pre-operative diagnostic sonographic images, we can help to avoid incomplete removal of the thyroid gland during thyroidectomy.
ABSTRACT
Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re â LS circuit notably alleviated chronic itch-induced anxiety, with no impact on anxiety induced by restraint stress. Last, GABAergic neurons in lateral hypothalamus (LH) receive monosynaptic inhibition from LS GABAergic neurons to mediate chronic itch-induced anxiety. These findings underscore the potential significance of the Re â LS â LH pathway in regulating anxiety-like comorbid symptoms associated with chronic itch.
Subject(s)
Anxiety , GABAergic Neurons , Hypothalamic Area, Lateral , Pruritus , Animals , Mice , GABAergic Neurons/metabolism , Chronic Disease , Disease Models, Animal , Midline Thalamic Nuclei/metabolism , Male , Behavior, Animal , Neural Pathways , Neuronal Plasticity , Septal NucleiABSTRACT
OBJECTIVE: Studies have shown that electroacupuncture (EA) can alleviate cognitive impairments from Alzheimer's disease (AD) by regulating the expression of adenosine monophosphate-activated protein kinase (AMPK), but the specific mechanism involved remains to be elucidated. Therefore, this study explores the potential mechanism by which EA improves cognitive function from the perspective of mitochondrial dynamics. METHODS: The four-month-old transgenic mice with amyloid precursor protein (APP)/presenilin 1 (PS1) and AMPKα1-subunit conditional knockout (AMPKα1-cKO) were used for experiments. To evaluate the effects of EA treatment on cognitive function, the T-maze and Morris water maze were used. In addition, chemical exchange saturation transfer, thioflavin staining, transmission electron microscopy, mitochondrial membrane potential, and Western blotting were used to examine the potential mechanisms underlying the effects of EA on APP/PS1 mice. RESULTS: Both APP/PS1 mice and AMPKα1-cKO mice exhibited dysfunction in mitochondrial dynamics accompanied by learning and memory impairment. Inactivation of the AMPK/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) pathway increased pathological amyloid-ß (Aß) deposition and aggravated the dysfunction in mitochondrial dynamics. In addition, EA rescued learning and memory deficits in APP/PS1 mice by activating the AMPK/PGC-1α pathway, specifically by reducing pathological Aß deposition, normalizing energy metabolism, protecting the structure and function of mitochondria, increasing the levels of mitochondrial fusion proteins, and downregulating the expression of fission proteins. However, the therapeutic effect of EA on cognition in APP/PS1 mice was hindered by AMPKα1 knockout. CONCLUSION: The regulation of hippocampal mitochondrial dynamics and reduction in Aß deposition via the AMPK/PGC-1α pathway are critical for the ability of EA to ameliorate cognitive impairment in APP/PS1 mice. Please cite this article as: Jia WW, Lin HW, Yang MG, Dai YL, Ding YY, Xu WS, Wang SN, Cao YJ, Liang SX, Wang ZF, Chen C, Liu WL. Electroacupuncture activates AMPKα1 to improve learning and memory in the APP/PS1 mouse model of early Alzheimer's disease by regulating hippocampal mitochondrial dynamics. J Integr Med. 2024; Epub ahead of print.
ABSTRACT
Passive daytime radiative cooling (PDRC) emerges as a promising cooling strategy with an attractive feature of no energy and refrigerant consumption. In the current study, for the purpose of achieving cost-efficient fabrication of a PDRC polymeric material, a microporous polymeric coating is prepared by a novel "inverse emulsion"-"breath figure" (Ie-BF) method using water droplets as pore-formation template, and the porous morphologies of both the surface and bulk layer can be dynamically manipulated by tuning the emulsion composition as well as environmental conditions. Therefore, the solar reflectivity of the Ie-BF coating can be efficiently tuned within a rather wide range (21-91%) by facile modulation of porosity and thickness. The Ie-BF coating with a thickness of only 125 µm exhibits a high solar reflectance of 85.4% and a long-wave infrared emissivity of 96.3%, realizing a subambient radiative cooling of 6.7 °C and a cooling power of â¼76 W m-2 in the open air. Moreover, by employing the reversible feature of in situ pore formation and erasure combined with the additional attachment of a carbon black layer, the composite film could be easily switched between cooling and heating modes by solvent post-treatment. This research establishes a cost-efficient strategy with high flexibility in the structural manipulation concerning the construction of porous polymeric PDRC coating.
ABSTRACT
Photodynamic therapy (PDT) is a well-established treatment modality, typically conducted with single-wavelength irradiation, which may not always be optimal for varying tumor locations and sizes. To address this, photosensitizers with absorption wavelengths ranging from 550 to 760 nm are being explored. Herein, a series of 5,15-diaryltetrabenzoporphyrins (Ar2TBPs) were synthesized. All compounds displayed obvious absorption at 550-700 nm (especially at â¼668 nm), intense fluorescence, efficient generation of singlet oxygen and good photodynamic antitumor effects. Notably, compound I3 (5,15-bis[(4-carboxymethoxy)phenyl]tetrabenzoporphyrin) showed excellent cytotoxicity against Eca-109 cell line upon red light irradiation, with an IC50 value of 0.45 µM, and phototherapeutic index of 25.8. Flow cytometry revealed that I3 could induce distinct cell apoptosis. In vivo studies revealed that compound I3 selectively accumulated at tumor site and exhibited outstanding PDT effect with antitumor activity under single-time administration and light irradiation, and revealed more efficiency than the clinical photosensitizer Verteporfin. These findings underscore the considerable promise of I3 as a robust theranostic agent, offering capabilities in real-time fluorescence imaging and serving as a potent photosensitizer for personalized and precise photodynamic therapy of tumors.
ABSTRACT
To discover effective photosensitizers for photodynamic therapy (PDT), a series of new meso-tetraphenyltetrabenzoporphyrin (m-Ph4TBP) derivatives were designed, prepared, and characterized. All m-Ph4TBPs own two characteristic absorption bands in the range of 450-500 and 600-700 nm and have the ability to generate singlet oxygen upon photoexcitation. Most of the m-Ph4TBPs demonstrated high photoactivity, among which compounds I4, I6, I12, and I13 induced apoptosis and also exhibited excellent photodynamic activities in vivo. Nonetheless, the liver organs of the I4 and I6-PDT groups showed clear calcifications, whereas the liver tissues of the other PDT groups showed no calcification. It was indicated that compared to phenolic m-Ph4TBPs, glycol m-Ph4TBPs exhibited superior biological safety in mice. According to comprehensive evaluations, m-Ph4TBP I12 displayed excellent photodynamic antitumor efficacy and biological safety and can be regarded as a promising antitumor drug candidate.
ABSTRACT
Interferons (IFNs) activate JAK-STAT pathways to induce downstream effector genes for host defense against invaded pathogens and tumors. Here both type I (ß) and II (γ) IFNs are shown that can activate the transcription factor IRF3 in parallel with STAT1. IRF3-deficiency impairs transcription of a subset of downstream effector genes induced by IFN-ß and IFN-γ. Mechanistically, IFN-induced activation of IRF3 is dependent on the cGAS-STING-TBK1 axis. Both IFN-ß and IFN-γ cause mitochondrial DNA release into the cytosol. In addition, IFNs induce JAK1-mediated tyrosine phosphorylation of cGAS at Y214/Y215, which is essential for its DNA binding activity and signaling. Furthermore, deficiency of cGAS, STING, or IRF3 impairs IFN-ß- or IFN-γ-mediated antiviral and antitumor activities. The findings reveal a novel IRF3 activation pathway parallel with the canonical STAT1/2 activation pathways triggered by IFNs and provide an explanation for the pleiotropic roles of the cGAS-STING-IRF3 axis in host defense.
ABSTRACT
Vascular leiomyomas are infrequent benign soft tissue neoplasms arising from vascular wall. These lesions are more frequent in females, predominantly seen in lower extremities presenting as slowly enlarging freely mobile palpable soft tissue lesions, often painful. The role of imaging in small peripheral soft tissue masses is often limited to preoperative mapping with a long list of potential differentials. We are presenting 2 case studies of palpable masses with similar pathology, soft tissue vascular leiomyomas where its MR features can be helpful in inclusion of this entity not only in differential diagnosis of enhancing small peripheral soft tissue masses but can suggest a diagnosis in appropriate clinical scenario.
ABSTRACT
Aim: A study of the enhancement of photodynamic activities of pyropheophorbide-a using PG-Ag-PPa nanoconjugates. Materials & methods: The nanoconjugates were formulated from silver nanoparticles and PPa via amide linkage, then characterized, and their photodynamic activities were examined. Results: The nanoconjugates displayed a higher rate of reactive oxygen species generation, commendable cellular uptake by Eca-109 cancer cells, higher photocytotoxicity toward the cancer cells and better bio-safety. They revealed strong antibacterial activity against Escherichia coli following internal reactive oxygen species generation and membrane disintegration. The in vivo anticancer studies confirmed higher cytotoxicity of the nanoconjugates toward cancer cells and better safety than PPa. Conclusion: Therefore, PG-Ag-PPa nanoconjugates could be considered potential nano photosensitizers for photodynamic therapy of tumors and bacterial infection with good bio-safety.
[Box: see text].
ABSTRACT
In the design of photoharvesting and photoresponsive supramolecular systems in aqueous medium, the fabrication of amphiphilic photoswitches enables a noninvasive functional response through photoirradiation. Although most aqueous supramolecular assemblies are driven by high-energy and biodamaging UV light, we have previously reported a design of amphiphilic donor-acceptor Stenhouse adducts (DASAs) controlled by white light. Herein, we present a series of DASA amphiphiles (DAs) with minor structural modifications on the alkyl linker chain length connecting the DASA motif with the hydrophilic moiety. The excellent photoswitchability in organic medium and the photoresponsiveness in aqueous medium, driven by visible light, were investigated by UV-vis absorption spectroscopy. The assembled supramolecular nanostructures were confirmed by electron microscopy, while the supramolecular packing was revealed by X-ray diffraction analysis. Upon visible-light irradiation, significant transformations of the DA geometry enabled transformations of the supramolecular assemblies on a microscopic scale, subsequently disassembling macroscopic soft scaffolds of DAs. The current work shows promising use for the fabrication of visible-light-controlled macroscopic scaffolds, offering the next generation of biomedical materials with visible-light-controlled microenvironments and future soft-robotic systems.
ABSTRACT
KANNO is a new human blood group that was recently discovered. The KANNO antigen shares the PRNP gene with the prion protein and the prion protein E219K polymorphism determines the presence or absence of the KANNO antigen and the development of anti-KANNO alloantibodies. These alloantibodies specifically react with prion proteins, which serve as substrates for conversion into pathological isoforms in some prion diseases and may serve as effective targets for resisting prion infection. These findings establish a potential link between the KANNO blood group and human prion disease via the prion protein E219K polymorphism. We reviewed the interesting correlation between the human PRNP gene's E219K polymorphism and the prion proteins it expresses, as well as human red blood cell antigens. Based on the immune serological principles of human blood cells, the prion protein E219K polymorphism may serve as a foundation for earlier molecular diagnosis and future drug development for prion diseases.
ABSTRACT
Injectable hydrogels show great promise for bone tissue engineering applications due to their high biocompatibility and drug delivery capabilities. The bone defects in osteoporosis are usually characterized by an oxidative and inflammatory microenvironment that impairs the regeneration capability of bone tissues. To attenuate the reactive oxygen species (ROS) and promote bone regeneration, an anti-oxidative hydrogel with osteogenic capacity was developed in this study. The poorly water soluble, natural antioxidant, resveratrol, was encapsulated in thiolated Pluronic F-127 micelles with over 50-times-enhanced solubility. The injectable hydrogel was facilely formed because of the new thioester bond between the free thiol group in modified F-127 and the arylate group in hyaluronic acid (HA)-acrylate. The resveratrol-loaded hydrogel showed good viscoelastic properties and in vitro stability and was cyto-compatible with bone-marrow-derived mesenchymal stem cells (BMSCs). The hydrogel allowed for a sustained release of resveratrol for at least two weeks and effectively enhanced the osteogenic differentiation of BMSCs by the up-regulation of osteogenic markers, including ALP, OCN, RUNX-2, and COL1. Moreover, the hydrogel exhibited anti-oxidative and anti-inflammatory abilities through the scavenging of intracellular ROS in RAW264.7 cells and inhibiting the gene expression and secretion of pro-inflammatory cytokines TNF-α and IL-1ß under LPS exposure. In summary, the results suggest that our multifunctional hydrogel loaded with resveratrol bearing osteogenic, anti-oxidative, and anti-inflammatory actions is easily prepared and represents a promising resveratrol delivery platform for the repair of osteoporotic bone defects.
ABSTRACT
Organophosphorus compounds (OPs) are widely used and have the potential to be harmful environmental toxicants to humans. Long non-coding RNA (lncRNA) plays a crucial regulatory role in cytotoxicity. This study aimed to investigate the effects of OPs on the expression of lncRNAs in cells. The effects of the industrial OPs TNPP and TCPP on both CYTOR and cellular viability were examined in the following human renal cell lines: HEK293T and HK-2. Both TCPP and TNPP downregulated CYTOR expression, increased reactive oxygen species levels, and induced apoptosis; the upregulated expression of CYTOR resulted in a reduction in apoptosis. The results of the luciferase reporter assay and the knock-down assay indicate that CEBPA binds to the upstream promoter region of CYTOR and regulates its transcription. Furthermore, TCPP and TNPP were found to downregulate the phosphorylation of ERK in the signaling pathway that is upstream of CEBPA. These results indicate that TCPP and TNPP can decrease the level of CEBPA by reducing ERK phosphorylation; this leads to a decrease in CYTOR expression, which further promotes cellular reactive oxygen species and apoptosis. Therefore, the ERK/CEBPA/CYTOR axis is one of the pathways by which organophosphates produce cytotoxicity, leading to renal cell injury. This study presents evidence for both the abnormal expression of lncRNA that is caused by organophosphates and the regulatory function of lncRNA regarding downstream cellular viability.
ABSTRACT
AIMS: Comorbid anxiodepressive-like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been implicated to play a key role in regulating neuronal excitability. However, the role of HCN channels in the LHb during CADS has not yet been characterized. This study aimed to investigate the effect of HCN channels in the LHb on CADS during chronic pain. METHODS: After chronic neuropathic pain induction by spared nerve injury (SNI), mice underwent a sucrose preference test, forced swimming test, tail suspension test, open-field test, and elevated plus maze test to evaluate their anxiodepressive-like behaviors. Electrophysiological recordings, immunohistochemistry, Western blotting, pharmacological experiments, and virus knockdown strategies were used to investigate the underlying mechanisms. RESULTS: Evident anxiodepressive-like behaviors were observed 6w after the SNI surgery, accompanied by increased neuronal excitability, enhanced HCN channel function, and increased expression of HCN2 isoforms in the LHb. Either pharmacological inhibition or virus knockdown of HCN2 channels significantly reduced LHb neuronal excitability and ameliorated both pain and depressive-like behaviors. CONCLUSION: Our results indicated that the LHb neurons were hyperactive under CADS in chronic pain, and this hyperactivation possibly resulted from the enhanced function of HCN channels and up-regulation of HCN2 isoforms.
Subject(s)
Depression , Habenula , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels , Animals , Habenula/metabolism , Habenula/drug effects , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , Mice , Male , Depression/metabolism , Neuralgia/metabolism , Neuralgia/psychology , Mice, Inbred C57BL , Chronic Pain/metabolism , Chronic Pain/psychology , Potassium ChannelsABSTRACT
BACKGROUND: Ovarian serous cystadenocarcinoma, accounting for about 90% of ovarian cancers, is frequently diagnosed at advanced stages, leading to suboptimal treatment outcomes. Given the malignant nature of the disease, effective biomarkers for accurate prediction and personalized treatment remain an urgent clinical need. METHODS: In this study, we analyzed the microbial contents of 453 ovarian serous cystadenocarcinoma and 68 adjacent non-cancerous samples. A univariate Cox regression model was used to identify microorganisms significantly associated with survival and a prognostic risk score model constructed using LASSO Cox regression analysis. Patients were subsequently categorized into high-risk and low-risk groups based on their risk scores. RESULTS: Survival analysis revealed that patients in the low-risk group had a higher overall survival rate. A nomogram was constructed for easy visualization of the prognostic model. Analysis of immune cell infiltration and immune checkpoint gene expression in both groups showed that both parameters were positively correlated with the risk level, indicating an increased immune response in higher risk groups. CONCLUSION: Our findings suggest that microbial profiles in ovarian serous cystadenocarcinoma may serve as viable clinical prognostic indicators. This study provides novel insights into the potential impact of intratumoral microbial communities on disease prognosis and opens avenues for future therapeutic interventions targeting these microorganisms.
Subject(s)
Cystadenocarcinoma, Serous , Immunotherapy , Ovarian Neoplasms , Humans , Female , Cystadenocarcinoma, Serous/immunology , Cystadenocarcinoma, Serous/mortality , Cystadenocarcinoma, Serous/pathology , Ovarian Neoplasms/immunology , Ovarian Neoplasms/mortality , Ovarian Neoplasms/therapy , Ovarian Neoplasms/microbiology , Ovarian Neoplasms/pathology , Prognosis , Immunotherapy/methods , Middle Aged , Microbiota , Biomarkers, Tumor , Aged , Survival Analysis , AdultABSTRACT
CCL17 is produced by conventional dendritic cells (cDCs), signals through CCR4 on regulatory T cells (Tregs), and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that cDCs from CCL17-deficient mice display a pro-tolerogenic phenotype and transcriptome that is not phenocopied in mice lacking its cognate receptor CCR4. In the plasma of CCL17-deficient mice, CCL3 was the only decreased cytokine/chemokine. We found that CCL17 signaled through CCR8 as an alternate high-affinity receptor, which induced CCL3 expression and suppressed Treg functions in the absence of CCR4. Genetic ablation of CCL3 and CCR8 in CD4+ T cells reduced CCL3 secretion, boosted FoxP3+ Treg numbers, and limited atherosclerosis. Conversely, CCL3 administration exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, while FoxP3 expression was reduced. Together, we identified a non-canonical chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Tregs.
ABSTRACT
BACKGROUND: Borneol, a highly lipid-soluble bicyclic terpene mainly extracted from plants, is representative of monoterpenoids. Modern medicine has established that borneol exhibits a range of pharmacological activities and used in the treatment of many diseases, particularly Cardio-cerebrovascular diseases (CVDs). The crucial role in enhancing drug delivery and improving bioavailability has attracted much attention. In addition, borneol is also widely utilized in food, daily chemicals, fragrances, and flavors industries. PURPOSE: This review systematically summarized the sources, pharmacological activities and mechanisms, clinical trial, pharmacokinetics, toxicity, and application of borneol. In addition, this review describes the pharmacological effects of borneol ester and the combination of borneol with nanomaterial. This review will provide a valuable resource for those pursuing researches on borneol inspiring the pharmacological applications in the medicine, food and daily chemical products, and developing of new drugs containing borneol or its derivatives. METHODS: This review searched the keywords ("borneol" or "bornyl esters") and ("pharmacology" or "Traditional Chinese medicine" or "Cardio-cerebrovascular diseases" or "blood-brain barrier" or "ischemic stroke" or "nanomaterials" or "neurodegenerative diseases" or "diabetes" or "toxicity") in Web of Science, PubMed, Google Scholar and China National Knowledge Infrastructure (CNKI) from January 1990 to May 2024. The search was limited to articles published in English and Chinese. RESULTS: Borneol exhibits extensive pharmacological activities including anti-inflammatory effects, analgesia, antioxidation, and has the property of crossing biological barriers and treating CVDs. The intrinsic molecular mechanisms are involved in multiple components, such as regulation of various key factors (including Tumor necrosis factor-α, Nuclear factor kappa-B, Interleukin-1ß, Malondialdehyde), inhibiting transporter protein function, regulating biochemical levels, and altering physical structural changes. In addition, this review describes the pharmacological effects of borneol ester and the combination of borneol with nanomaterial. CONCLUSION: The pharmacological properties and applications of borneol are promising, including anti-inflammatory, analgesic, antimicrobial, and antioxidant properties, as well as enhancing drug delivery and treating CVDs. However, its clinical application is hindered by the limited research on safety, efficacy, and pharmacokinetics. Therefore, this review systemically summarized the advances on pharmacological activities and mechanisms of the borneol. Standardized clinical trials and exploration of synergistic effects with other drugs were also are outlined.
Subject(s)
Camphanes , Camphanes/pharmacology , Humans , Animals , Anti-Inflammatory Agents/pharmacologyABSTRACT
BACKGROUND: Maternal diabetes mellitus can influence the development of offspring. Gestational diabetes mellitus (GDM) creates a short-term intrauterine hyperglycaemic environment in offspring, leading to glucose intolerance in later life, but the long-term effects and specific mechanism involved in skeletal muscle dysfunction in offspring remain to be clarified. METHODS: Pregnant mice were divided into two groups: The GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while the control (CTR) group was treated with vehicle buffer. Only pregnant mice whose random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. The growth of the offspring was monitored, and the glucose tolerance test was performed at different time points. Body composition analysis and immunohistochemical methods were used to evaluate the development of lean mass at 8 weeks. The exercise capacity and grip strength of the male mouse offspring were assessed at the same period. Transmission electron microscopy was used to observe the morphology inside skeletal muscle at 8 weeks and as a foetus. The genes and proteins associated with mitochondrial biogenesis and oxidative metabolism were investigated. We also coanalyzed RNA sequencing and proteomics data to explore the underlying mechanism. Chromatin immunoprecipitation and bisulfite-converted DNA methylation detection were performed to evaluate this phenomenon. RESULTS: Short-term intrauterine hyperglycaemia inhibited the growth and reduced the lean mass of male offspring, leading to decreased endurance exercise capacity. The myofiber composition of the tibialis anterior muscle of GDM male offspring became more glycolytic and less oxidative. The morphology and function of mitochondria in the skeletal muscle of GDM male offspring were destroyed, and coanalysis of RNA sequencing and proteomics of foetal skeletal muscle showed that mitochondrial elements and lipid oxidation were consistently impaired. In vivo and in vitro myoblast experiments also demonstrated that high glucose concentrations impeded mitochondrial organisation and function. Importantly, the transcription of genes associated with mitochondrial biogenesis and oxidative metabolism decreased at 8 weeks and during the foetal period. We predicted Ppargc1α as a key upstream regulator with the help of IPA software. The proteins and mRNA levels of Ppargc1α in the skeletal muscle of GDM male offspring were decreased as a foetus (CTR vs. GDM, 1.004 vs. 0.665, p = 0.002), at 6 weeks (1.018 vs. 0.511, p = 0.023) and 8 weeks (1.006 vs. 0.596, p = 0.018). In addition, CREB phosphorylation was inhibited in GDM group, with fewer activated pCREB proteins binding to the CRE element of Ppargc1α (1.042 vs. 0.681, p = 0.037), Pck1 (1.091 vs. 0.432, p = 0.014) and G6pc (1.118 vs. 0.472, p = 0.027), resulting in their decreased transcription. Interestingly, we found that sarcopenia and mitochondrial dysfunction could even be inherited by the next generation. CONCLUSIONS: Short-term intrauterine hyperglycaemia significantly reduced lean mass in male offspring at 8 weeks, resulting in decreased exercise endurance and metabolic disorders. Disrupted organisation and function of the mitochondria in skeletal muscle were also observed among them. Foetal exposure to hyperglycaemia decreased the ratio of phosphorylated CREB and reduced the transcription of Ppargc1α, which inhibited the transcription of downstream genes involving in mitochondrial biogenesis and oxidative metabolism. Abnormal mitochondria, which might be transmitted through aberrant gametes, were also observed in the F2 generation.
Subject(s)
Cyclic AMP Response Element-Binding Protein , Diabetes, Gestational , Hyperglycemia , Muscle, Skeletal , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Prenatal Exposure Delayed Effects , Signal Transduction , Animals , Female , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Pregnancy , Mice , Male , Muscle, Skeletal/metabolism , Diabetes, Gestational/metabolism , Hyperglycemia/metabolism , Prenatal Exposure Delayed Effects/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Diabetes Mellitus, Experimental/metabolism , Mitochondria/metabolism , Blood Glucose/metabolismABSTRACT
Neoehrlichia mikurensis (N. mikurensis) is an emerging tick-borne pathogen that can cause neoehrlichiosis. Rodents are considered the major host for N. mikurensis. Currently, N. mikurensis has been detected in rodents in several studies from China and other countries. However, no research on N. mikurensis infection in rodents has been reported in the Liupan mountain region. The region of Liupan Mountain, located in northwestern China, is the center of the triangle formed by the cities of Xi'an, Yinchuan, and Lanzhou, with multiple tourist sites in the region. To survey whether there is N. mikurensis in hosts, rodents were captured in this region in September 2020. A nested polymerase chain reaction was used to detect the DNA of N. mikurensis, followed by nucleotide sequencing and phylogenetic analysis. In the region, among 88 rodents, 3 rodents were detected positive for N. mikurensis, a detection rate of 3.4%. Based on phylogenetic analysis of the partial groEL gene sequences, N. mikurensis from rodents in Liupan Mountain clustered in the same evolutionary branch with those found in rodents from Japan, Russia, and northeastern China, and also in ticks and clinical cases from Heilongjiang Province in northeastern China.
ABSTRACT
BACKGROUND: B-cell CLL/lymphoma 6 member B (BCL6B) operates as a sequence-specific transcriptional repressor within the nucleus, playing crucial roles in various biological functions, including tumor suppression, immune response, stem cell self-renew, and vascular angiogenesis. However, whether BCL6B is involved in endothelial cell (EC) development has remained largely unknown. ETS variant transcription factor 2 (ETV2) is well known to facilitate EC differentiation. This study aims to determine the important role of BCL6B in EC differentiation and its potential mechanisms. METHODS: Doxycycline-inducible human induced pluripotent stem cell (hiPSC) lines with BCL6B overexpression or BCL6B knockdown were established and subjected to differentiate into ECs and vessel organoids (VOs). RNA sequencing analysis was performed to identify potential signal pathways regulated by BCL6B during EC differentiation from hiPSCs. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of pluripotency and vascular-specific marker genes expression. EC differentiation efficiency was determined by Flow cytometry analysis. The performance of EC was evaluated by in vitro Tube formation assay. The protein expression and the vessel-like structures were assessed using immunofluorescence analysis or western blot. Luciferase reporter gene assay and chromatin immunoprecipitation (ChIP)-PCR analysis were used to determine the regulatory relationship between BCL6B and ETV2. RESULTS: Functional ECs and VOs were successfully generated from hiPSCs. Notably, overexpression of BCL6B suppressed while knockdown of BCL6B improved EC differentiation from hiPSCs. Additionally, the overexpression of BCL6B attenuated the capacity of derived hiPSC-ECs to form a tubular structure. Furthermore, compared to the control VOs, BCL6B overexpression repressed the growth of VOs, whereas BCL6B knockdown had little effect on the size of VOs. RNA sequencing analysis confirmed that our differentiation protocol induced landscape changes for cell/tissue/system developmental process, particularly vascular development and tube morphogenesis, which were significantly modulated by BCL6B. Subsequent experiments confirmed the inhibitory effect of BCL6B is facilitated by the binding of BCL6B to the promoter region of ETV2, led to the suppression of ETV2's transcriptional activity. Importantly, the inhibitory effect of BCL6B overexpression on EC differentiation from hiPSCs could be rescued by ETV2 overexpression. CONCLUSIONS: BCL6B inhibits EC differentiation and hinders VO development by repressing the transcriptional activity of ETV2.