Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.

The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity.

Targeting the p53-MDM2 pathway to reactivate tumor p53 is a chemotherapeutic approach. However, the involvement of this pathway in CD8+ T cell-mediated antitumor immunity is unknown. Here, we report that mice with MDM2 deficiency in T cells exhibit accelerated tumor progression and a decrease in tumor-infiltrating CD8+ T cell survival and function. Mechanistically, MDM2 competes with c-Cbl for STAT5 binding, reduces c-Cbl-mediated STAT5 degradation and enhances STAT5 stability in tumor-infiltrating CD8+ T cells. Targeting the p53-MDM2 interaction with a pharmacological agent, APG-115, augmented MDM2 in T cells, thereby stabilizing STAT5, boosting T cell immunity and synergizing with cancer immunotherapy. Unexpectedly, these effects of APG-115 were dependent on p53 and MDM2 in T cells. Clinically, MDM2 abundance correlated with T cell function and interferon-γ signature in patients with cancer. Thus, the p53-MDM2 pathway controls T cell immunity, and targeting this pathway may treat patients with cancer regardless of tumor p53 status.

Cancer SLC43A2 alters T cell methionine metabolism and histone methylation.

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.

Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy.

Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8+ T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion were CD8+ T cell- and MHC-I-dependent, as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.

Plasmodium yoelii surface-related antigen (PySRA) modulates the host pro-inflammatory responses via binding to CD68 on macrophage membrane.

Malaria, one of the major infectious diseases in the world, is caused by the Plasmodium parasite. Plasmodium antigens could modulate the inflammatory response by binding to macrophage membrane receptors. As an export protein on the infected erythrocyte membrane, Plasmodium surface-related antigen (SRA) participates in the erythrocyte invasion and regulates the immune response of the host. This study found that the F2 segment of P. yoelii SRA activated downstream MAPK and NF-κB signaling pathways by binding to CD68 on the surface of the macrophage membrane and regulating the inflammatory response. The anti-PySRA-F2 antibody can protect mice against P. yoelii, and the pro-inflammatory responses such as IL-1ß, TNF-α, and IL-6 after infection with P. yoelii are attenuated. These findings will be helpful for understanding the involvement of the pathogenic mechanism of malaria with the exported protein SRA.

Investigating the causal relationship of gut microbiota with GERD and BE: a bidirectional mendelian randomization.

BACKGROUND: Gut microbiota(GM) have been proven associated with lots of gastrointestinal diseases, but its causal relationship with Gastroesophageal reflux disease(GERD) and Barrett's esophagus(BE) hasn't been explored. We aimed to uncover the causal relation between GM and GERD/BE and potential mediators by utilizing Mendelian Randomization(MR) analysis. METHODS: Summary statistics of GM(comprising 301 bacteria taxa and 205 metabolism pathways) were extracted from MiBioGen Consortium(N = 18,340) and Dutch Microbiome Project(N = 7,738), GERD and BE from a multitrait meta-analysis(NGERD=602,604, NBE=56,429). Bidirectional two-sample MR analysis and linkage disequilibrium score regression(LDSC) were used to explore the genetic correlation between GM and GERD/BE. Mediation MR analysis was performed for the risk factors of GERD/BE, including Body mass index(BMI), weight, type 2 diabetes, major depressive disorder(MDD), smoking initiation, alcohol consumption, and dietary intake(including carbohydrate, sugar, fat, protein intake), to detect the potential mediators between GM and GERD/BE. RESULTS: 11 bacterial taxa and 13 metabolism pathways were found associated with GERD, and 18 taxa and 5 pathways exhibited causal relationship with BE. Mediation MR analysis suggested weight and BMI played a crucial role in these relationships. LDSC identified 1 taxon and 4 metabolism pathways related to GERD, and 1 taxon related to BE. Specie Faecalibacterium prausnitzii had a suggestive impact on both GERD(OR = 1.087, 95%CI = 1.01-1.17) and BE(OR = 1.388, 95%CI = 1.03-1.86) and LDSC had determined their correlation. Reverse MR indicated that BE impacted 10 taxa and 4 pathways. CONCLUSIONS: This study established a causal link between gut microbiota and GERD/BE, and identified the probable mediators. It offers new insights into the role of gut microbiota in the development and progression of GERD and BE in the host.

Human biomonitoring without in-person interaction: public health engagements during the COVID-19 pandemic and future implications.

BACKGROUND: Public health initiatives, including human biomonitoring, have been impacted by unique challenges since the onset of the COVID-19 pandemic, compounding a decades-long trend of declining public participation. To combat low public participation rates, public health professionals often employ extensive engagement approaches including in-person interactions related to enrollment and sampling, success of which is an essential component of a statistically defensible study. The onset of the COVID-19 pandemic challenged public health programs to diversify engagement and sampling approaches, limiting direct interactions for the health and safety of the population. This study explores biomonitoring recruitment strategies through non-contact mechanisms and evaluate the application feasibility for population-based studies. METHODS: The Iowa Biomonitoring Program at the State Hygienic Laboratory developed a human biomonitoring study that utilized a multifaceted, distance-based approach. Traditional techniques, such as mailed recruitment invitations and phone-based discussions, were coupled with internet-based surveys and self-collected, shipped urine and water samples. Participation rates were evaluated by employing different mailing methods, and the demographics of enrolled participants were examined. RESULTS: This non-human contact approach achieved a nearly 14% participation rate among a rural population, well above our target rates. Our improved mailing strategy for targeting initially unresponsive participants yielded a significantly increase in the participation rates. The respondents were predominantly individuals with educational attainment of at least high school level. Among all the eligible participants, 83% submitted self-collected samples, a rate comparable to the National Health and Nutrition Examination Survey which involved in-person interviews. CONCLUSIONS: The practice of engaging a rural population during the COVID-19 pandemic by transitioning from face-to-face interactions to a combination of mailing and internet-based approaches resulted in higher-than-expected participant recruitment and sample collection rates. Given the declining trend in the response rates for population-based survey studies, our results suggest conducting human biomonitoring without direct human interaction is feasible, which provides further opportunity to improve response rates and the relevance and reach of public health initiatives.

Depression mediated the relationships between precentral-subcortical causal links and motor recovery in spinal cord injury patients.

Depression after brain damage may impede the motivation and consequently influence the motor recovery after spinal cord injury (SCI); however, the neural mechanism underlying the psychological effects remains unclear. This study aimed to examine the casual connectivity changes of the emotion-motivation-motor circuit and the potential mediating effects of depression on motor recovery after SCI. Using the resting-state functional magnetic resonance imaging data of 35 SCI patients (24 good recoverers, GR and 11 poor recoverers, PR) and 32 healthy controls (HC), the results from the conditional Granger causality (GC) analysis demonstrated that the GR group exhibited sparser emotion-motivation-motor GC network compared with the HC and PR groups, though the in-/out-degrees of the emotion subnetwork and the motor subnetwork were relatively balanced in the HC and GR group. The PR group showed significantly inhibitory causal links from amygdala to supplementary motor area and from precentral gyrus to nucleus accumbens compared with GR group. Further mediation analysis revealed the indirect effect of the 2 causal connections on motor function recovery via depression severity. Our findings provide further evidence of abnormal causal connectivity in emotion-motivation-motor circuit in SCI patients and highlight the importance of emotion intervention for motor function recovery after SCI.

USP16-mediated histone H2A lysine-119 deubiquitination during oocyte maturation is a prerequisite for zygotic genome activation.

Maternal-to-zygotic transition (MZT) is the first and key step in the control of animal development and intimately related to changes in chromatin structure and histone modifications. H2AK119ub1, an important epigenetic modification in regulating chromatin configuration and function, is primarily catalyzed by PRC1 and contributes to resistance to transcriptional reprogramming in mouse embryos. In this study, the genome-wide dynamic distribution of H2AK119ub1 during MZT in mice was investigated using chromosome immunoprecipitation and sequencing. The results indicated that H2AK119ub1 accumulated in fully grown oocytes and was enriched at the TSSs of maternal genes, but was promptly declined after meiotic resumption at genome-wide including the TSSs of early zygotic genes, by a previously unidentified mechanism. Genetic evidences indicated that ubiquitin-specific peptidase 16 (USP16) is the major deubiquitinase for H2AK119ub1 in mouse oocytes. Conditional knockout of Usp16 in oocytes did not impair their survival, growth, or meiotic maturation. However, oocytes lacking USP16 have defects when undergoing zygotic genome activation or gaining developmental competence after fertilization, potentially associated with high levels of maternal H2AK119ub1 deposition on the zygotic genomes. Taken together, H2AK119ub1 level is declined during oocyte maturation by an USP16-dependent mechanism, which ensures zygotic genome reprogramming and transcriptional activation of essential early zygotic genes.

Neural efficiency and proficiency adaptation of effective connectivity corresponding to early and advanced skill levels in athletes of racket sports.

This study explored how the neural efficiency and proficiency worked in athletes with different skill levels from the perspective of effective connectivity brain network in resting state. The deconvolved conditioned Granger causality (GC) analysis was applied to functional magnetic resonance imaging (fMRI) data of 35 elite athletes (EAs) and 42 student-athletes (SAs) of racket sports as well as 39 normal controls (NCs), to obtain the voxel-wised hemodynamic response function (HRF) parameters representing the functional segregation and effective connectivity representing the functional integration. The results showed decreased time-to-peak of HRF in the visual attention brain regions in the two athlete groups compared with NC and decreased response height in the advanced motor control brain regions in EA comparing to the nonelite groups, suggesting the neural efficiency represented by the regional HRF was different in early and advanced skill levels. GC analysis demonstrated that the GC values within the middle occipital gyrus had a linear trend from negative to positive, suggesting a stepwise "neural proficiency" of the effective connectivity from NC to SA then to EA. The GC values of the inter-lobe circuits in EA had the trend to regress to NC levels, in agreement with the neural efficiency of these circuits in EA. Further feature selection approach suggested the important role of the cerebral-brainstem GC circuit for discriminating EA. Our findings gave new insight into the complementary neural mechanisms in brain functional segregation and integration, which was associated with early and advanced skill levels in athletes of racket sports.

Design and Synthesis of Low Dielectric Poly(aryl ether ketone) from Incorporation Bulky Fluorene Groups and Regular Hydroquinone Structure.

To decrease the dipole polarization rate and reduce the dielectric constant of poly(aryl ether ketone) (PAEK) resin, 1,4-di(4-fluorobenzoyl) cyclohexane (DFBCH), a weakly polarizing cyclohexane-based monomer, was designed and synthesized as the primary reactant. The bulky fluorene group was incorporated to increase the free volume of the resin, further reducing the dielectric constant. Additionally, hydroquinone with a symmetric and regular structure was utilized to enhance the molecular chain's regularity and reduce dipole relaxation, further lowering the resin's dielectric constant and dielectric loss. The PFQEKs series resins exhibited excellent thermal stability with glass transition temperature (Tg) ranging from 222 to 239 °C and 5% weight loss (Td5%) ranging from 458 to 463 °C, with different monomer ratios. As the hydroquinone content increased, the dielectric constant (Dk) and dielectric loss (Df) of the resin decreased significantly, with Dk ranging from 2.92 to 2.77 and Df ranging from 0.011 to 0.008 at 10 GHz.

Unusual presentation of a case of fetal hepatic mass: a case report.

BACKGROUND: Giant hepatic hemangiomas are rare and can cause serious complications that contribute to a high risk of perinatal mortality. The purpose of this article is to review the prenatal imaging features, treatment, pathology, and prognosis of an atypical fetal giant hepatic hemangioma and to discuss the differential diagnosis of fetal hepatic masses. CASE PRESENTATION: A gravida 9, para 0 woman at 32 gestational weeks came to our institution for prenatal ultrasound diagnosis. A complex, heterogeneous hepatic mass measuring 5.2 × 4.1 × 3.7 cm was discovered in the fetus using conventional two-dimensional ultrasound. The mass was solid and had both a high peak systolic velocity (PSV) of the feeding artery and intratumoral venous flow. Fetal magnetic resonance imaging (MRI) revealed a clear, hypointense T1-W and hyperintense T2-W solid hepatic mass. Prenatal diagnosis was very difficult due to the overlap of benign and malignant imaging features on prenatal ultrasound and MRI. Even postnatally, neither contrast-enhanced MRI nor contrast-enhanced computed tomography (CT) was useful in accurately diagnosing this hepatic mass. Due to persistently elevated Alpha-fetoprotein (AFP), a laparotomy was performed. Histopathological examination of the mass showed atypical features such as hepatic sinus dilation, hyperemia, and hepatic chordal hyperplasia. The patient was ultimately diagnosed with a giant hemangioma, and the prognosis was satisfactory. CONCLUSIONS: When a hepatic vascular mass is found in a third trimester fetus a hemangioma should be considered as a possible diagnosis. However, prenatal diagnosis of fetal hepatic hemangiomas can be challenging due to atypical histopathological findings. Imaging and histopathological assays can provide useful information for the diagnosis and treatment of fetal hepatic masses.

Relaxed 3D genome conformation facilitates the pluripotent to totipotent-like state transition in embryonic stem cells.

The 3D genome organization is crucial for gene regulation. Although recent studies have revealed a uniquely relaxed genome conformation in totipotent early blastomeres of both fertilized and cloned embryos, how weakened higher-order chromatin structure is functionally linked to totipotency acquisition remains elusive. Using low-input Hi-C, ATAC-seq and ChIP-seq, we systematically examined the dynamics of 3D genome and epigenome during pluripotent to totipotent-like state transition in mouse embryonic stem cells (ESCs). The spontaneously converted 2-cell-embryo-like cells (2CLCs) exhibited more relaxed chromatin architecture compared to ESCs, including global weakening of both enhancer-promoter interactions and TAD insulation. While the former correlated with inactivation of ESC enhancers and down-regulation of pluripotent genes, the latter might facilitate contacts between the putative new enhancers arising in 2CLCs and neighboring 2C genes. Importantly, disruption of chromatin organization by depleting CTCF or the cohesin complex promoted the ESC to 2CLC transition. Our results thus establish a critical role of 3D genome organization in totipotency acquisition.

Role of CxxC-finger protein 1 in establishing mouse oocyte epigenetic landscapes.

During oogenesis, oocytes gain competence and subsequently undergo meiotic maturation and prepare for embryonic development; trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1) impairs H3K4me3 accumulation and causes changes in chromatin configurations. This study investigated the changes in genomic H3K4me3 landscapes in oocytes with Cxxc1 knockout and the effects on other epigenetic factors such as the DNA methylation, H3K27me3, H2AK119ub1 and H3K36me3. H3K4me3 is overall decreased after knocking out Cxxc1, including both the promoter region and the gene body. CXXC1 and MLL2, which is another histone H3 methyltransferase, have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. Cxxc1 deletion caused a decrease in DNA methylation levels and affected H3K27me3 and H2AK119ub1 distributions, particularly at regions with high DNA methylation levels. The changes in epigenetic networks implicated by Cxxc1 deletion were correlated with the transcriptional changes in genes in the corresponding genomic regions. This study elucidates the epigenetic changes underlying the phenotypes and molecular defects in oocytes with deleted Cxxc1 and highlights the role of CXXC1 in orchestrating multiple factors that are involved in establishing the appropriate epigenetic states of maternal genome.

Dental Caries Prevention Knowledge, Attitudes, and Practice among Patients at a University Hospital in Guangzhou, China.

Background and Objectives: This study aimed to assess the knowledge, attitudes, and practice (KAP) of patients regarding dental caries prevention in a university hospital in Guangzhou, China. Materials and Methods: A hospital-based KAP survey was conducted in a cross-sectional manner at the First Affiliated Hospital in Guangzhou, China, from 1 September to 30 September 2022. Questionnaires were distributed to eligible patients, resulting in the participation of 251 individuals. The questionnaire consisted of five sections capturing socio-demographic data and exploring participants' knowledge, attitudes, practice, and accurate preventive dental caries knowledge. Descriptive statistics and a generalized linear model with univariate tests were used for analysis. Results: The study results show that the knowledge score 7.97 (±0.91) and attitudes score 7.67 (±0.89) among the participants were good while the practice score was 6.80 (±0.81) moderate. The majority of participants identified tooth infections (81.3%), bacteria (92%), and sugar (89.2%) as the main causes of gum bleeding and tooth decay. Brushing (96%) and fluoride (80.5%) were also recognized as essential for preventing tooth decay. Of oral diseases, 94% were recognized as potentially affecting overall health. The vast majority ranging from 92.8% to 98%, believed that oral health is crucial to overall health and that regular check-ups and proper brushing habits are beneficial. There is a significant association of gender with age (p = 0.018), occupation (p = 0.050), lifestyle habit (p = 0.012), and knowledge score; whole education is significantly associated with practice score (p = 0.050). Conclusions: The majority of patients exhibited accurate knowledge and attitudes with moderate practice towards dental caries prevention, with socio-demographic factors playing a major role. However, effective implementation of dental health education programs across the healthcare system is still required to further enhance outcomes.

CNOT6L couples the selective degradation of maternal transcripts to meiotic cell cycle progression in mouse oocyte.

Meiotic resumption-coupled degradation of maternal transcripts occurs during oocyte maturation in the absence of mRNA transcription. The CCR4-NOT complex has been identified as the main eukaryotic mRNA deadenylase. In vivo functional and mechanistic information regarding its multiple subunits remains insufficient. Cnot6l, one of four genes encoding CCR4-NOT catalytic subunits, is preferentially expressed in mouse oocytes. Genetic deletion of Cnot6l impaired deadenylation and degradation of a subset of maternal mRNAs during oocyte maturation. Overtranslation of these undegraded mRNAs caused microtubule-chromosome organization defects, which led to activation of spindle assembly checkpoint and meiotic cell cycle arrest at prometaphase. Consequently, Cnot6l-/- female mice were severely subfertile. The function of CNOT6L in maturing oocytes is mediated by RNA-binding protein ZFP36L2, not maternal-to-zygotic transition licensing factor BTG4, which interacts with catalytic subunits CNOT7 and CNOT8 of CCR4-NOT Thus, recruitment of different adaptors by different catalytic subunits ensures stage-specific degradation of maternal mRNAs by CCR4-NOT This study provides the first direct genetic evidence that CCR4-NOT-dependent and particularly CNOT6L-dependent decay of selective maternal mRNAs is a prerequisite for meiotic maturation of oocytes.

A reachable probability approach for the analysis of spatio-temporal dynamics in the human functional network.

The dynamic architecture of the human brain has been consistently observed. However, there is still limited modeling work to elucidate how neuronal circuits are hierarchically and flexibly organized in functional systems. Here we proposed a reachable probability approach based on non-homogeneous Markov chains, to characterize all possible connectivity flows and the hierarchical structure of brain functional systems at the dynamic level. We proved at the theoretical level the convergence of the functional brain network system, and demonstrated that this approach is able to detect network steady states across connectivity structure, particularly in areas of the default mode network. We further explored the dynamically hierarchical functional organization centered at the primary sensory cortices. We observed smaller optimal reachable steps to their local functional regions, and differentiated patterns in larger optimal reachable steps for primary perceptual modalities. The reachable paths with the largest and second largest transition probabilities between primary sensory seeds via multisensory integration regions were also tracked to explore the flexibility and plasticity of the multisensory integration. The present work provides a novel approach to depict both the stable and flexible hierarchical connectivity organization of the human brain.

Vinegar-processed Curcuma phaeocaulis promotes anti-angiogenic activity and reduces toxicity in zebrafish and rat models.

CONTEXT: Processing with vinegar could enhance the efficacy and reduce the toxicity of Curcuma phaeocaulis Valeton. (Zingiberaceae), a Chinese herbal medicine with anti-inflammatory and antitumor activities. OBJECTIVE: This study investigated the vinegar processing effects by evaluating anti-angiogenic effect and toxicity of C. phaeocaulis through zebrafish and rat models. MATERIALS AND METHODS: Zebrafish embryos (AB and FLk-GFP strain) were applied to evaluate toxicity, cardiotoxicity and anti-angiogenic activity of volatile oil, and water decoction of the raw and vinegar-processed C. phaeocaulis. Meanwhile, a blood stasis syndrome rat model was applied to study the toxicity by measuring the ovarian and uterine coefficient. RESULTS: Curcuma phaeocaulis volatile oil and its vinegar-processed products in zebrafish had an LC50 of 67.315 and 95.755 µg/mL, respectively. Curcuma phaeocaulis water decoction and its vinegar-processed products had an LC50 of 161.440 and 206.239 µg/mL, respectively. The toxicity of vinegar-processed products was significantly lower than the raw, and the development characteristic of zebrafish embryos at different times confirmed these results. The volatile oil of vinegar-processed products could inhibit the growth of intersegmental blood vessels at the dose of 20 µg/mL, while the raw materials did not exhibit such effect at the same concentration. The rat experiment also confirmed that the volatile oil could reduce toxicity of ovarian and uterine. DISCUSSION AND CONCLUSIONS: The study indicated that processing using vinegar could decrease toxicity and increase anti-angiogenic activity of C. phaeocaulis, which could be applied for clinical treatment. Further in-depth study on the synergism and detoxification mechanism of vinegar processing technology is needed.

IGF-1/IGF-1R blockade ameliorates diabetic kidney disease through normalizing Snail1 expression in a mouse model.

This study investigated the role of insulin-like growth factor-1/insulin-like growth factor-1 receptor (IGF-1/IGF-1R) in the genesis and progression of diabetic kidney disease (DKD) in a streptozotocin (STZ)-induced mouse diabetes model. We showed elevated IGF-1 expression in the DKD kidneys after 16 wk of diabetic onset. Intraperitoneal administration of IGF-1R inhibitor (glycogen synthase kinase-3ß, GSK4529) from week 8 to week 16 postdiabetes induction ameliorated urinary albumin excretion and kidney histological changes due to diabetes, including amelioration of glomerulomegaly, inflammatory infiltration, and tubulointerstitial fibrosis. The GSK4529 treatment also attenuated alterations in renal tubular expression of E-cad and matrix protein fibronectin. Moreover, renal fibrosis in DKD (without treatment) was associated with Snail1 overexpression that was effectively prevented by IGF-1R inhibition. Further experiments in cultured renal epithelial cells (NRK) showed that IGF-1 silencing reproduced in vivo effects of IGF-1R inhibition with markedly attenuated Snail1 expression and near normalization of the Ecad1 and fibronectin expression pattern. Further Snail1 silencing prevented high-glucose-induced changes without affecting IGF-1 expression, consistent with Snail1 acting downstream to IGF-1. The antifibrotic effects were also shown with benazepril or insulin treatment but to a much lesser degree. In summary, in STZ-induced diabetic mice, activation of IGF-1 in diabetic kidneys induces fibrogenesis through Snail1 upregulation. The diabetes-related histological and functional changes, as well as fibrogenesis, can be attenuated by IGF-1/IGF-1R inhibition.

Spinel LiMn2O4 Nanofiber: An Efficient Electrocatalyst for N2 Reduction to NH3 under Ambient Conditions.

The production of ammonia (NH3) in the industrial scale basically relies on the traditional technology of Haber-Bosch, which is operated under harsh conditions with high energy consumption and a huge number of greenhouse gas emissions. Electrochemical N2 reduction reaction (NRR) is a promising route for artificial N2-to-NH3 fixation with less energy consumption. However, an effective electrocatalyst, as a prerequisite of the NRR, is of significance. Here, we report that a spinel LiMn2O4 nanofiber acts as a noble-metal-free electrocatalyst for NH3 synthesis with excellent performance under ambient conditions. The electrocatalyst, which was tested in 0.1 M HCl, has an excellent Faradaic efficiency of 7.44% and a NH3 yield of 15.83 µg h-1 mgcat.-1 at -0.50 V versus reversible hydrogen electrode. Moreover, it also possesses excellent electrochemical and structure stability.