Uterine torsion complicated by severe placental abruption in the second trimester: a case report and literature review.

BACKGROUND: Uterine torsion is a rare obstetric event that can occur during pregnancy and is difficult to diagnose. Its occurrence may lead to serious adverse pregnancy outcomes. CASE INTRODUCTION: The patient was a 33-year-old woman at 30+ 5 weeks' gestation with a singleton pregnancy. The pregnancy course, including fetal growth, and prenatal examinations were regular. Except for a small amount of vaginal bleeding in early pregnancy and treatment with progesterone, there were no prenatal abnormalities, and the patient denied any trauma or sexual history. The patient was admitted to the emergency department with persistent severe pain in the lower abdomen and slight vaginal bleeding during night sleep. Abdominal pain started two hours prior to admission and was accompanied by nausea, vomiting, and dizziness. Examination revealed positive abdominal tenderness, high uterine tone, and no significant intermittent period of uterine contractions, and measurement of the fetal heart rate by means of the nonstress test revealed a rate of 60 beats per minute. Therefore, placental abruption was highly suspected. Subsequently, an emergency cesarean section was performed under general anesthesia. The newborn boy, with Apgar scores of 0-3-4 after birth and weighing 1880 g, was transferred to the neonatal intensive care unit (NICU) and died two days later due to ineffective rescue. After the uterine incision was sutured, the examination revealed that the uterine incision was located on the posterior wall of the uterus, and the uterus was twisted 180° to the right. The diagnosis after cesarean section was 180° uterine torsion to the right, severe placental abruption, and severe neonatal asphyxia. On the fifth day after surgery, the patient recovered and was discharged from the hospital. CONCLUSIONS: Posterior uterine incision cesarean section may be performed in unexpected circumstances and is also feasible as a safe option for resetting if torsion is not complete. Abdominal pain during pregnancy is less likely to be diagnosed as uterine torsion, which often leads to premature birth, fetal asphyxia, placental abruption, and even perinatal death. Therefore, for abdominal pain during pregnancy, obstetricians should consider the possibility of uterine torsion.

Effect of in situ simulation training for emergency caesarean section on maternal and infant outcomes.

BACKGROUND: Emergency caesarean section (ECS) is an effective method for rapid termination of pregnancy and for saving maternal and foetal life in emergencies. Experts recommend that the interval from decision of operation to the decision to delivery interval (DDI) should be shortened as much as possible. Studies have shown that improving communication skills among staff by performing simulation drills shortens DDI, thus reducing the occurrence of adverse obstetric events and protecting maternal and child safety. In situ simulation (ISS) training is a simulation-based training approach for clinical team members conducted in a real-world clinical setting. In August 2020, Anhui Maternal and Child Health Hospital began ISS training on the rapid obstetric response team (RRT) in our hospital area for emergency caesarean section. This study aimed to investigate the effect of implementing in situ simulation training for emergency caesarean section on maternal and child outcomes by comparing maternal and child-related data on emergency caesarean section in two hospital areas. METHODS: Data on cases of emergency caesarean delivery implemented in two hospital districts from August 2020 to August 2022 were collected: 19 in the untrained group and 26 in the training group. The two groups were compared concerning the interval from the decision of operation to the decision to delivery interval (DDI), the interval from the decision of operation to the initiation of skin incision, the interval from skin incision to the decision to delivery interval, and the neonatal situation. RESULTS: Primary outcome comparison: The training group had a significantly shorter interval between the DDI compared to the untrained group (8.14 ± 3.13 vs. 11.03 ± 3.52, P = 0.006). Secondary outcomes comparison: The training group had a significantly shorter interval between the decision to cut skin compared to the untrained group (6.45 ± 2.21 vs. 9.95 ± 4.02, P = 0.001). However, there was no significant difference in the interval between cutting skin and infant delivery between the two groups (2.24 ± 0.08 vs. 2.18 ± 0.13, P > 0.05). Additionally, the Apgar score at 1 min after birth was higher in the training group compared to the untrained group (7.29 ± 2.38 vs. 6.04 ± 1.46, P < 0.05). CONCLUSIONS: The DDI for emergency caesarean section procedures can be significantly shortened, and neonatal Apgar scores at 1 min improved by implementing in situ simulation training for emergency caesarean section in obstetric rapid response teams. In situ simulation training is an effective tool for training in emergency caesarean section procedures and is worth promoting.

Antioxidative effect of Periplaneta americana extract on dextran sulfate sodium-induced ulcerative colitis through activation of the Nrf2 signal.

CONTEXT: Periplaneta americana L. (Blattariae) is used as a treatment for ulcerative colitis (UC) in Chinese traditional medicine. OBJECTIVE: To evaluate the antioxidative activity of P. americana whole body ethanol extract (PAE) on UC mice and whether glycine and proline could be used for quality control and identification of active PAE components. MATERIALS AND METHODS: NCM460 cells were pre-incubated in PAE, AA-L, AA-M, and AA-H (low, high and medium doses of proline and glycine), then treated with recombinant human TNF-α. The glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen (ROS) levels were determined. UC mice were fed with water containing 2.5% dextran sulfate sodium (w/v) after pre-treatment with different doses of PAE once a day for 7 days. ELISA was used to detect the concentrations of inflammation-related factors. Colon tissues of mice were used to detect the activity of myeloperoxidase (MPO), GSH, MDA, and SOD. Histological changes were observed using H&E staining. The expression of target proteins was determined by western blotting. RESULTS: In vivo, PAE treatment reduced the DAI score more than in the model group, restoring the weight and colonic length. It also reduced the severity of colitis, and inflammatory and oxidative stress intensity. Additionally, western blotting showed that the Nrf2 pathway was activated by PAE. In vitro PAE significantly alleviated TNF-α-induced cell damage and oxidative stress, which is relevant to the activation of the Nrf2 pathway. CONCLUSIONS: PAE may relieve oxidative stress through the Nrf2 signaling pathway, and proline and glycine may be used as active components of its antioxidative stress activity.

A novel mouse model of diabetes, atherosclerosis and fatty liver disease using an AAV8-PCSK9-D377Y injection and dietary manipulation in db/db mice.

Preclinical mouse models of cardiometabolic diseases are crucial to study the pathological mechanisms of cardiometabolic diseases and to explore potential new therapeutic agents. Using double-knockouts in the background of ApoE-/- or Ldlr-/- mice requires an extensive amount of breeding and is costly. A significant breakthrough in atherosclerosis research is the use of AAV8-PCSK9-D377Y (a gain-of-function mutant of PCSK9 which promotes LDLR degradation) injection which can induce hyperlipidemia, increased endothelial stiffness, vascular calcification, aneurysm, and atherosclerotic plaque development in normal C57BL/6J mice. The purpose of this study was to assess the possibility that the injection of AAV8-PCSK9 vectors in db/db mice (a well-established animal model of type 2 diabetes mellitus) produces a novel mouse model of diabetes, atherosclerosis and fatty liver disease to study the pathomechanisms of cardiometabolic disease and its complications. Db/db mice were injected with AAV8-PCSK9-D377Y (AAV8-PCSK9 for simplicity) or AAV8-control and fed with high-cholesterol diets for 8 weeks. Levels of total cholesterol (TC) and triglyceride (TG) were significantly elevated in AAV8-PCSK9-injected mice compared to the controls. AAV8-PCSK9 injection led to increased serum level of PCSK9, serious liver steatosis, hypercholesterolemia and atherosclerotic plaque as determined by aortic arch/roots histopathological staining, with Oil Red O, Masson-trichrome and hematoxylin-eosin staining. RNA sequencing and bioinformatics were used to assess the global gene expression in liver tissues. We conclude that AAV8-PCSK9 injection in db/db mice is a promising and time-efficient approach to induce diabetic atherosclerosis with fatty liver. This mouse model can be a new one to investigate the etiology and therapeutics of atherosclerosis with diabetes and fatty liver beyond the traditional model established in ApoE-/- mice or LDLR-/- mice receiving streptozotocin (STZ) injection.

Pharmacological inhibition of IRAK1 and IRAK4 prevents endothelial inflammation and atherosclerosis in ApoE-/- mice.

Inflammation associated endothelial dysfunction represents a pivotal contributor to atherosclerosis. Increasingly, evidence has demonstrated that interleukin 1 receptor (IL1-R) / toll-like receptor (TLR) signaling participates in the development of atherosclerosis. Recent large-scale clinical trials have supported the therapeutic potential of anti-inflammatory therapies targeting IL-1ß and IL-6 in reducing atherosclerosis. The present study examined the pharmacological effects of IL-1R-associated kinase 1 and 4 inhibitors (IRAK1/4i) in regulating inflammation of the endothelium and atherosclerosis. We demonstrate that dual pharmacological inhibition of IRAK1 and IRAK4 by an IRAK1/4i is more effective against LPS induced endothelial inflammation, compared with IRAK1 inhibitor or IRAK4 inhibitor monotherapy. IRAK1/4i showed little endothelial cell toxicity at concentrations from 1 µM up to 10 µM. Inhibition of IRAK1/4 reduced endothelial activation induced by LPS in vitro as evidenced by attenuated monocyte adhesion to the endothelium. Mechanistically, blockade of IRAK1/4 ameliorated the transcriptional activity of NF-κB. To assess the pharmacological effects of IRAK1/4i on atherosclerosis in vivo, ApoE-/- mice were orally administered IRAK1/4i (20 mg/kg/d) for 8 weeks. We show that IRAK1/4i reduced atherosclerotic lesion size in the aortic sinus and increased hepatic LDLR protein levels as well as lowered LDL-C level, without affecting other lipid parameters or glucose tolerance. Taken together, our findings demonstrate that dual pharmacological inhibition of IRAK1 and IRAK4 attenuates endothelial inflammation, lowers LDL-C levels and reduces atherosclerosis. Our study reinforces the evolving standing of anti-inflammatory approaches in cardiovascular therapeutics.

Comparative Proteomic Analysis of Liver Tissues and Serum in db/db Mice.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) affects one-quarter of individuals worldwide. Liver biopsy, as the current reliable method for NAFLD evaluation, causes low patient acceptance because of the nature of invasive sampling. Therefore, sensitive non-invasive serum biomarkers are urgently needed. RESULTS: The serum gene ontology (GO) classification and Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed the DEPs enriched in pathways including JAK-STAT and FoxO. GO analysis indicated that serum DEPs were mainly involved in the cellular process, metabolic process, response to stimulus, and biological regulation. Hepatic proteomic KEGG analysis revealed the DEPs were mainly enriched in the PPAR signaling pathway, retinol metabolism, glycine, serine, and threonine metabolism, fatty acid elongation, biosynthesis of unsaturated fatty acids, glutathione metabolism, and steroid hormone biosynthesis. GO analysis revealed that DEPs predominantly participated in cellular, biological regulation, multicellular organismal, localization, signaling, multi-organism, and immune system processes. Protein-protein interaction (PPI) implied diverse clusters of the DEPs. Besides, the paralleled changes of the common upregulated and downregulated DEPs existed in both the liver and serum were validated in the mRNA expression of NRP1, MUP3, SERPINA1E, ALPL, and ALDOB as observed in our proteomic screening. METHODS: We conducted hepatic and serum proteomic analysis based on the leptin-receptor-deficient mouse (db/db), a well-established diabetic mouse model with overt obesity and NAFLD. The results show differentially expressed proteins (DEPs) in hepatic and serum proteomic analysis. A parallel reaction monitor (PRM) confirmed the authenticity of the selected DEPs. CONCLUSION: These results are supposed to offer sensitive non-invasive serum biomarkers for diabetes and NAFLD.

Periplaneta americana extract ameliorates dextran sulfate sodium-induced ulcerative colitis via immunoregulatory and PI3K/AKT/NF-κB signaling pathways.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with a low cure rate. Periplaneta americana is a traditional American Cockroach and reportedly has potential therapeutic roles for UC treatment; however, its mechanisms remain unclear. To address this, we investigated the therapeutic effects and underlying molecular mechanisms of Ento-A, a Periplaneta americana extract, in a dextran sulfate sodium (DSS)-induced chronic and recurrent UC mouse model. Ento-A treatment decreased pro-inflammatory cytokine secretion, disease activity index (DAI), colon mucosa damage index (CMDI), histopathological scores (HS), and increased colon length. Additionally, Ento-A effectively increased interleukin-4 (IL-4), and forkhead transcription factor protein 3 (Foxp3) expression levels, while it abated interferon-γ (IFN-γ) and IL-17 levels in spleen lymphocytes. Conversely, in mesenteric lymph nodes, IL-4 and Foxp3 expression were decreased, while IFN-γ and IL-17 expression was increased. Furthermore, Ento-A blocked p-PI3K, p-AKT,*and p-NF-κB activation. In conclusion, Ento-A improved UC symptoms and exerted therapeutic effects by regulating immune responses and inhibiting PI3K/AKT/NF-κB signaling.

Wasp venom from Vespa magnifica acts as a neuroprotective agent to alleviate neuronal damage after stroke in rats.

CONTEXT: Acute ischaemic stroke (AIS) is a major cause of disability and death, which is a serious threat to human health and life. Wasp venom extracted from Vespa magnifica Smith (Vespidae) could treat major neurological disorders. OBJECTIVE: This study investigated the effects of wasp venom on AIS in rats. MATERIAL AND METHODS: We used a transient middle cerebral artery occlusion (MCAO) model in Sprague-Dawley rats (260-280 g, n = 8-15) with a sham operation group being treated as negative control. MCAO rats were treated with wasp venom (0.05, 0.2 and 0.6 mg/kg, i.p.) using intraperitoneal injection. After treatment 48 h, behavioural tests, cortical blood flow (CBF), TTC staining, H&E staining, Nissl staining, TUNEL assay, immunohistochemistry (IHC) and ELISA were employed to investigate neuroprotective effects of wasp venom. RESULTS: Compared with the MCAO group, wasp venom (0.6 mg/kg) improved neurological impairment, accelerated CBF recovery (205.6 ± 52.92 versus 216.7 ± 34.56), reduced infarct volume (337.1 ± 113.2 versus 140.7 ± 98.03) as well as BBB permeability as evidenced by changes in claudin-5 and AQP4. In addition, function recovery of stroke by wasp venom treatment was associated with a decrease in TNF-α, IL-1ß, IL-6 and inhibition activated microglia as well as apoptosis. Simultaneously, the wasp venom regulated the angiogenesis factors VEGF and b-FGF in the brain. CONCLUSIONS: Wasp venom exhibited a potential neuroprotective effect for AIS. In the future, we will focus on determining whether the observed actions were due to a single compound or the interaction of multiple components of the venom.

Piezo-Photocatalytic Synergy in BiFeO3 @COF Z-Scheme Heterostructures for High-Efficiency Overall Water Splitting.

Solar-driven overall water splitting is an ideal way to generate renewable energy while still challenging. For the first time, this work combined covalent organic frameworks (COFs) and piezoelectric material by covalent linkages to form Z-scheme core@shell heterostructure for overall water splitting. Benefiting from the synergistic effect between the polarized electric field and photo-generated charges, as well as the precise adjustment of shell thickness, the carrier separation and utilization efficiency is greatly improved. The optimal BiFeO3 @TpPa-1-COF photocatalyst revealed hydrogen (H2 ) and oxygen (O2 ) production rates of 1416.4 and 708.2 µmol h-1 g-1 under the excitation of ultrasonication coupled with light irradiation, which is the best performance among various piezo- and COF-based photocatalysts. This provides a new sight for the practical application of highly efficient photocatalytic overall water splitting.

Roll-to-plate additive manufacturing.

In this paper, we propose a roll-to-plate (R2P) projection micro-stereolithography (PSL) 3D printer, where layers of photopolymer are transferred and photopolymerized through a flexible membrane. Benefitting from the "coat-expose-peel" procedure, highly viscous material can be printed quickly with good vertical resolution. Most importantly, the multinozzle dispensing method enables the fabrication of multimaterial architectures with high throughput, low material consumption, and low cross-contamination. R2P-PSL exhibits superior features for flexible 3D printing in terms of material complexity. For this purpose, we envision infinite scenarios involving potential applications in bionics, biotechnology, microcircuit graphics, photonic devices, microfluidics and material science.

Completeness of circle of Willis and white matter hyperintensities in patients with severe internal carotid artery stenosis.

BACKGROUND: We investigated whether completeness of the circle of Willis (CoW) protected patients with severe internal carotid artery (ICA) stenosis against white matter hyperintensities (WMHs). METHODS: We included 115 patients with unilateral ICA stenosis ≥ 70%. The completeness of CoW was assessed and WMHs were rated on a visual scale. The score of deep and periventricular WMHs was compared between patients with complete and incomplete CoW and between the two hemispheres, ipsilateral and contralateral to stenosed ICA. RESULTS: We included 115 patients with severe ICA stenosis, 60 patients had a complete CoW (52.17%) and 55 had an incomplete CoW (47.83%). The patients with incomplete CoW had higher score of deep WMHs (OR = 1.82, 95% CI 1.08-3.06, P = 0.023) and periventricular WMHs (OR = 4.53, 95% CI 2.09-9.81, P = 0.000) than those with complete CoW. In the patients with incomplete CoW, the score of deep WMHs (OR = 4.14, 95% CI 1.33-12.93, P = 0.014) and periventricular WMHs (OR = 5.46, 95% CI 1.16-25.62, P = 0.032) was higher in the hemisphere ipsilateral to stenosed ICA than that in the contralateral hemisphere. In the patients with complete CoW, there was no significant difference in the score of deep WMHs (OR = 2.10, 95% CI 0.37-11.91, P = 0.401) and periventricular WMHs (OR = 2.83, 95% CI 0.99-8.05, P = 0.051) between the ipsilateral and contralateral hemispheres to stenosed ICA. CONCLUSION: The completeness of CoW protected patients with severe ICA stenosis against WMHs.

Beneficial effect of compound essential oil inhalation on central fatigue.

BACKGROUNDS: Although the physical and mental enhancement effect of essential oils have been proved, the beneficial effect of essential oil in central fatigue remains unclear. In this study, we extracted essential oils from nine aromatic plants to make a compound essential oil, and detected the therapeutic effect of central fatigue by daily aerial diffusion. METHODS: Thirty-three rats were randomly and equally divided into control group, chronic sleep deprivation group, and compound essential oil inhalation group. Central fatigue was generated by chronic sleep deprivation. RESULTS: After 21-day various interferences, it is found that the sleep deprivation rats showed an evident decrease in physical endurance, negative emotion, and cognitive dysfunction compared with the control group, and the group that treated with the compound essential oil behaved significantly better than central fatigue group. CONCLUSION: We concluded that this formula of essential oils could alleviate central fatigue on rats, and our study provides a new direction of application of aromatic therapy, which could be expanded to insomnia, depression and other healthy issue in the further research.

Five New Phenolic Compounds with Antioxidant Activities from the Medicinal Insect Blaps rynchopetera.

Five new phenolic compounds rynchopeterines A-E (1-5), in addition to thirteen known phenolics, were isolated from Blaps rynchopetera Fairmaire, a kind of medicinal insect utilized by the Yi Nationality in Yunnan Province of China. Their structures were established on the basis of extensive spectroscopic analyses (1D and 2D NMR, HR-MS, IR) along with calculated electronic circular dichroism method. Rynchopeterines A-E (1-4) exhibited significant antioxidant activities with IC50 values of 7.67-12.3 µg/mL measured by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Besides, rynchopeterines B (2) and C (3) showed mild cytotoxicity against tumor cell Caco-2 and A549.

Cytotoxicity of the Defensive Secretion from the Medicinal Insect Blaps rynchopetera.

Blaps rynchopetera Fairmaire has long been used as a folk medicine by the Yi and Bai ethnic groups in China to treat fever, cough, gastritis, boils, and tumors. In the present study, the cytotoxicity of the defensive secretion (TDS) of B. rynchopetera against AGS Caco-2, HepG2 U251 and Bel-7402 was tested, and the results revealed that TDS had potent cytotoxicity against testing cells with IC50 values of 45.8, 17.4, 53.6, 98.4 and 23.4 µg/mL, respectively. Gas chromatography-mass spectrometry (GC-MS) analysis was employed to clarify the cytotoxic constituents in TDS of B. rynchopetera and five volatile compounds, including 2-ethyl-2,5-cyclohexadiene-1,4-dione (3, 31.00%), 1-tridecene (5, 28.02%), 2-methyl-2,5-cyclohexadiene-1,4-dione (2, 22.86%), hydroquinone (4, 1.33%), and p-benzoquinone (1, 1.01%), were identified. Chemical constituent investigation on TDS further supported the presence of 5 above compounds. A cytotoxic assay indicated that compounds 1, 2, 3 and 4 exhibited significant cytotoxicity against the testing cell lines, implying that benzoquinones and hydroquinone played important roles in the cytotoxicity of TDS of B. rynchopetera. TDS is a cytotoxic natural material and further studies investigating mechanisms and inhibitory activities on other cell lines is warranted.

High-frequency rTMS of the left dorsolateral prefrontal cortex for post-stroke depression: A systematic review and meta-analysis.

OBJECTIVE: This meta-analysis investigated the therapeutic efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) for treatment of post-stroke depression (PSD). METHODS: Ten articles with 266 patients in rTMS group and 258 patients in control group were included. The primary outcome was performed to examine the efficacy of rTMS for PSD. Secondary outcomes of response rates and remission rates and subgroup analyses were further explored. RESULTS: Our meta-analysis revealed a significant pooled effect size (the standard mean difference (SMD) was -1.45 points (95% CI, -2.04 to -0.86; p < 0.00001)). The odds ratio (OR) of the response rate and remission rate were 8.41 (95% CI, 2.52-28.12, p = 0.0005) and 6.04 (95% CI, 1.5-24.39, p = 0.01). Moreover, rTMS treatment for PSD patients in subacute phase and targeting the left DLPFC at 5-cm anterior to the left motor hotspot or the midpoint of the middle frontal gyrus showed significant antidepressant effect. In addition, the Hamilton Depression Rating Scale (HAMD) was sensitive to detect depressive changes in patients. CONCLUSIONS: Our meta-analysis elucidated that the application of high-frequency rTMS over the left DLPFC was an effective treatment alternative for PSD. SIGNIFICANCE: Our meta-analysis may help to develop more reasonable treatment strategies in clinical practice for PSD patients.

Ento-A alleviates DSS-induced experimental colitis in mice by remolding intestinal microbiota to regulate SCFAs metabolism and the Th17 signaling pathway.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by changes in the metabolism of short chain fatty acids (SCFAs), dysregulation of gut microbiota, and an imbalance of Treg/Th17. Herein, we explore the effects of the Ento-A (an alcohol extract of Periplaneta americana L.) on a mouse model of UC. First, a chronic and recurrent UC model was constructed in BALB/c mice by 2.2% DSS administration. UC mice were continuously treated for 14 days with Ento-A (50, 100, 200 mg/kg, i.g.) or a negative control. Ento-A alleviated many of the pathological changes observed in UC mice, such as body weight loss, disease activity index, changes in colon length, and colonic mucosal damage index. Ento-A also decreased levels of proinflammatory cytokines (IL-1ß, IL-6, IL-17A, and TNF-α), increased levels of anti-inflammatory cytokines (IL-10 and TGF-ß1) and repaired the intestinal mucosal barrier. Additionally, Ento-A regulated the proportions of Th17 cells, and Treg cells in mesenteric lymph nodes harvested from treated mice (as assessed by Flow cytometry), and the expression levels of IL-17A and Foxp3 in colon (as assessed by immunohistochemistry). 16 S rRNA gene sequencing revealed that Ento-A regulated gut microbiota. GC-MS analysis demonstrated that Ento-A also restored SCFAs content in the intestinal tract. Finally, transcriptomic analysis revealed that Ento-A regulated the IL-17 signaling pathway. In summary, Ento-A regulates the diversity and abundance of intestinal flora in UC mice, enhancing the secretion of SCFAs, subsequently regulating the IL-17 signaling pathway, and ultimately repairing the intestinal mucosal barrier.

Changes in proteomic cargo of circulating extracellular vesicles in response to lifestyle intervention in adolescents with hepatic steatosis.

BACKGROUND: Recent studies suggest that proteomic cargo of extracellular vesicles (EVs) may play a role in metabolic improvements following lifestyle interventions. However, the relationship between changes in liver fat and circulating EV-derived protein cargo following intervention remains unexplored. METHODS: The study cohort comprised 18 Latino adolescents with obesity and hepatic steatosis (12 males/6 females; average age 13.3 ± 1.2 y) who underwent a six-month lifestyle intervention. EV size distribution and concentration were determined by light scattering intensity; EV protein composition was characterized by liquid chromatography tandem-mass spectrometry. RESULTS: Average hepatic fat fraction (HFF) decreased 23% by the end of the intervention (12.5% [5.5] to 9.6% [4.9]; P = 0.0077). Mean EV size was smaller post-intervention compared to baseline (120.2 ± 16.4 nm to 128.4 ± 16.5 nm; P = 0.031), although the difference in mean EV concentration (1.1E+09 ± 4.1E+08 particles/mL to 1.1E+09 ± 1.8E+08 particles/mL; P = 0.656)) remained unchanged. A total of 462 proteins were identified by proteomic analysis of plasma-derived EVs from participants pre- and post-intervention, with 113 proteins showing differential abundance (56 higher and 57 lower) between the two timepoints (adj-p <0.05). Pathway analysis revealed enrichment in complement cascade, initial triggering of complement, creation of C4 and C2 activators, and regulation of complement cascade. Hepatocyte-specific EV affinity purification identified 40 proteins with suggestive (p < 0.05) differential abundance between pre- and post-intervention samples. CONCLUSIONS: Circulating EV-derived proteins, particularly those associated with the complement cascade, may contribute to improvements in liver fat in response to lifestyle intervention.

Abnormal intrinsic functional hubs and connectivity in patients with post-stroke depression.

OBJECTIVE: The present study aimed to investigate the specific alterations of brain networks in patients with post-stroke depression (PSD), and further assist in elucidating the brain mechanisms underlying the PSD which would provide supporting evidence for early diagnosis and interventions for the disease. METHODS: Resting-state functional magnetic resonace imaging data were acquired from 82 nondepressed stroke patients (Stroke), 39 PSD patients, and 74 healthy controls (HC). Voxel-wise degree centrality (DC) conjoined with seed-based functional connectivity (FC) analyses were performed to investigate the PSD-related connectivity alterations. The relationship between these alterations and depression severity was further examined in PSD patients. RESULTS: Relative to both Stroke and HC groups, (1) PSD showed increased centrality in regions within the default mode network (DMN), including contralesional angular gyrus (ANG), posterior cingulate cortex (PCC), and hippocampus (HIP). DC values in contralesional ANG positively correlated with the Patient Health Questionnaire-9 (PHQ-9) scores in PSD group. (2) PSD exhibited increased connectivity between these three seeds showing altered DC and regions within the DMN: bilateral medial prefrontal cortex and middle temporal gyrus and ipsilesional superior parietal gyrus, and regions outside the DMN: bilateral calcarine, ipsilesional inferior occipital gyrus and contralesional lingual gyrus, while decreased connectivity between contralesional ANG and contralesional supramarginal gyrus. Moreover, these FC alterations could predict PHQ-9 scores in PSD group. INTERPRETATION: These findings highlight that PSD was related with increased functional connectivity strength in some areas within the DMN, which might be attribute to the specific alterations of connectivity between within DMN and outside DMN regions in PSD.

TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase.

Nonalcoholic fatty liver disease (NAFLD) encompasses a disease continuum from simple steatosis to nonalcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD, although several drugs are in advanced stages of clinical development. Because of the complex pathophysiology and heterogeneity of NAFLD, the identification of potential therapeutic targets is clinically important. Here, we demonstrated that tripartite motif 56 (TRIM56) protein abundance was markedly downregulated in the livers of individuals with NAFLD and of mice fed a high-fat diet. Hepatocyte-specific ablation of TRIM56 exacerbated the progression of NAFLD, while hepatic TRIM56 overexpression suppressed it. Integrative analyses of interactome and transcriptome profiling revealed a pivotal role of TRIM56 in lipid metabolism and identified the lipogenesis factor fatty acid synthase (FASN) as a direct binding partner of TRIM56. TRIM56 directly interacted with FASN and triggered its K48-linked ubiquitination-dependent degradation. Finally, using artificial intelligence-based virtual screening, we discovered an orally bioavailable small-molecule inhibitor of FASN (named FASstatin) that potentiates TRIM56-mediated FASN ubiquitination. Therapeutic administration of FASstatin improved NAFLD and NASH pathologies in mice with an optimal safety, tolerability, and pharmacokinetics profile. Our findings provide proof of concept that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues to treat NAFLD.