Intranasal Delivery of circATF7IP siRNA via Lipid Nanoparticles Alleviates LPS-induced Depressive-Like Behaviors.

Major depressive disorder (MDD) is a prevalent mental disorder that significantly impacts social and psychological function, but no effective medication is currently available. Circular RNAs (circRNAs) have been reported to participate in the pathogenesis of MDD which are envisioned as promising therapeutic targets. However, nonviral-based delivery strategies targeting circRNA against MDD are not thoroughly investigated. Here, it is identified that circATF7IP is significantly upregulated in plasma samples and positively correlated with 24-Hamilton Depression Scale (HAMD-24) scores of MDD patients. Synergistic amine lipid nanoparticles (SALNPs) are designed to deliver siRNA targeting circATF7IP (si-circATF7IP) into the hippocampus brain region by intranasal administration. Intranasal delivery of SALNP-si-circATF7IP successfully alleviated the depressive-like behaviors in the LPS-induced mouse depression model via decreasing CD11b+CD45dim microglia population and pro-inflammatory cytokine productions (TNF-α and IL-6). These results indicate that the level of circATF7IP positively correlates with MDD pathogenesis, and SALNP delivery of si-circATF7IP via intranasal administration is an effective strategy to ameliorate LPS-induced depressive-like behaviors.

Direct Implantation of Patient Brain Tumor Cells into Matching Locations in Mouse Brains for Patient-Derived Orthotopic Xenograft Model Development.

Background: Despite multimodality therapies, the prognosis of patients with malignant brain tumors remains extremely poor. One of the major obstacles that hinders development of effective therapies is the limited availability of clinically relevant and biologically accurate (CRBA) mouse models. Methods: We have developed a freehand surgical technique that allows for rapid and safe injection of fresh human brain tumor specimens directly into the matching locations (cerebrum, cerebellum, or brainstem) in the brains of SCID mice. Results: Using this technique, we successfully developed 188 PDOX models from 408 brain tumor patient samples (both high-and low-grade) with a success rate of 72.3% in high-grade glioma, 64.2% in medulloblastoma, 50% in ATRT, 33.8% in ependymoma, and 11.6% in low-grade gliomas. Detailed characterization confirmed their replication of the histopathological and genetic abnormalities of the original patient tumors. Conclusions: The protocol is easy to follow, without a sterotactic frame, in order to generate large cohorts of tumor-bearing mice to meet the needs of biological studies and preclinical drug testing.

The Association Between Relative Deprivation, Depression, and Youth Suicide: Evidence From a Psychological Autopsy Study.

OBJECTIVE: Suicide is a serious public health concern in China. In the present study, we investigated the specific mechanisms underlying relative deprivation and suicide in rural China. METHODS: A large psychological autopsy study was conducted in rural China, in which 392 suicides and 416 community-living controls were consecutively recruited. Multiple logistic regression analysis was used to assess the relationship between relative deprivation and suicide, with depression as a potential mediator. RESULTS: Young people who experienced relative deprivation were at a greater risk of suicide and depression. Depression plays a mediating role in the relationship between relative deprivation and suicide. LIMITATIONS: Due to the limitations of the data, we cannot know whether there is mutual causation between relative deprivation and depression. The self-reported relative deprivation may also produce some influence on the results. CONCLUSIONS: The current findings demonstrate the importance of relative deprivation as one of the four sources of psychological strain to explain how relative status is associated with suicide. The findings also can be translated into the clinical and preventive practice for suicide.

Correction: Long-term Pu-erh tea consumption improves blue light-induced depression-like behaviors.

Correction for 'Long-term Pu-erh tea consumption improves blue light-induced depression-like behaviors' by Sibo Zhao et al., Food Funct., 2023, https://doi.org/10.1039/d2fo02780a.

Long-term Pu-erh tea consumption improves blue light-induced depression-like behaviors.

Blue light emitted by smartphones and tablets at night increases the risk of depression. Pu-erh tea has been reported to reduce the risk of depression by regulating tryptophan metabolism, but its underlying protective mechanism on depression induced by blue light at night (BLAN) remains unclear. In this work, two groups of C57BL6/J mice were given water or 0.25% (w/v) Pu-erh tea for 120 days, followed by a 45-day BLAN treatment (400 lux blue light between 21:00 and 23:00) to simulate blue light emitted from electronic equipment. Our results indicated that BLAN induced depression-like behaviors and gut microbiota disorders in healthy mice. Pu-erh tea intake significantly reshaped the gut microbiome (especially Bifidobacterium) and regulated the metabolism of short-chain fatty acids (SCFAs) which protected the integrity of the intestinal barrier. This improvement further reduced blood-brain barrier (BBB) damage and alleviated neuroinflammation by inhibiting MyD88/NF-κB pathways which finally regulated neurotransmitters such as brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT). Collectively, 0.25% (w/v) Pu-erh tea has the potential to prevent BLAN-induced depression-like behaviors by reshaping the gut microbiota and increasing the generation of SCFAs via the gut-brain axis.

Pu-erh tea alleviated colitis-mediated brain dysfunction by promoting butyric acid production.

Brain inflammation develops with increased colitis. Pu-erh tea is considered a potential dietary intervention to improve colitis. However, it's unclear whether Pu-erh tea helps alleviate colitis-mediated brain dysfunction. Here, we found that colitis triggered brain dysfunction and increased the risk of depression. Pu-erh tea improved gut-brain barrier function (increased ZO-1 and Occludin) and restored short-chain fatty acids (SCFAs) as well as neurotransmitter release (γ-GABA, 5-HT, and dopamine), which stemmed from the production of butyric acid (BA). Pu-erh tea and BA promoted the production of SCFAs by reshaping the gut microbes (increased Lactobacillus, Akkermansia, Faecalibaculum), thereby downregulating gut inflammatory protein expression (PI3K/AKT/NF-κB). SCFAs, especially BA, intervened directly in the blood-brain barrier via the gut-brain axis to restore neurotransmitter release. Collectively, our results highlighted that increasing BA through Pu-erh tea consumption may be a key mechanism for improving colitis-mediated brain dysfunction by lowering gut inflammation and balancing gut microbe-gut-brain axis homeostasis. These results provide a promising step that might encourage further investigations of Pu-erh tea as a protective agent for brain function in colitis patients.

Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas.

Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs (CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and potential booster DMRs (PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies.

Pu-erh tea increases the metabolite Cinnabarinic acid to improve circadian rhythm disorder-induced obesity.

Obesity is one of the circadian rhythm disorders (CRD)-mediated metabolic disorder syndromes. Pu-erh tea is a viable dietary intervention for CRD, however its effect on CRD-induced obesity is unclear. Here, we found that Pu-erh tea improved obesity in CRD-induced mice, which stemmed from the production of Cinnabarinic acid (CA). CA promoted adipose tissue lipolysis and thermogenic response (HSL, ATGL, Pparα, CKB, UCP1) and increased adipocyte sensitivity to hormones and neurotransmitters by targeting the expression of adipose tissue receptor proteins (Q6KAT8, P51655, A2AKQ0, M0QWX7, Q6ZQ33, and mGluR4). This improved mitochondrial activity and facilitated adipose tissue metabolic processes, thereby accelerating glucolipid metabolism. Also, CA-induced alterations in gut microbes and short-chain fatty acids further improved CRD-mediated lipid accumulation. These results suggest that the increase of CA caused by Pu-erh tea, targeted to adipose tissue via the metabolite-blood circulation-adipose tissue axis, maybe a key mechanism for reducing the development of CRD-induced obesity.

Conditionally designed luminescent DNA crystals doped by Ln3+(Eu3+/Tb3+) complexes or fluorescent proteins with smart drug sensing property.

In this work, a designed porous DNA crystal with high intrinsic biocompatibility was used as the scaffold material to load fluorescent guest molecules to detect anti-cancer drugs. It is shown here that the synthesized crystals have the characteristics consistent with the designed large solvent channels, and can therefore accommodate guest molecules such as fluorescent proteins that cannot be accommodated by less porous crystals. Eu(TTA)3phen and Tb(acac)3phen lanthanide complexes were individually noncovalently loaded into the porous crystals, resulting in hybrid luminescent DNA crystals. Emodin, an anti-cancer, anti-tumor, anti-inflammatory drug, was found to quench lanthanide complexes in solution or in crystals. Notably, emodin is the active ingredient of Lianhua Qingwen Capsule, an anti-COVID-19 drug candidate. Therefore, the porous DNA crystals reported here have potential applications as a biocompatible and theranostic delivery biomaterial for functional macromolecules.

The role of the extension region on the structural and physicochemical characteristics of the α-subunit of ß-conglycinin: implications of pH value and ionic strength.

BACKGROUND: To clarify the role of the extension region on the structure-functional relationship of the α-subunit of ß-conglycinin, α-subunit and its segment of the core region (αc-subunit) were expressed via an Escherichia coli system. Their physicochemical properties were compared under acid, neutral or alkaline conditions (pH 4.0, 7.0, and 8.0) and high or low ionic strength (µ = 0.05 and 0.5), respectively. RESULTS: The results showed that the extension region contributed to increasing thermal stability, especially at low ionic strength under acidic and neutral conditions. The extension region stabilized the α-subunit with high solubility, low turbidity, and small particle size under neutral and alkaline conditions, whereas these impacts were suppressed at a high ionic strength and acidic conditions. Surface hydrophobicity of the α-subunit decreased under acidic and alkaline conditions without being interfered with by ionic strength. CONCLUSION: It can be concluded that the extension region played different roles under different pH and ionic strength conditions. These factors should be specified carefully and speculated individually to explore the more detailed and profound nature of ß-conglycinin at the submolecular level. The results could benefit a better understanding of the relationship between domain structure and functions of soybean protein. © 2022 Society of Chemical Industry.

Pu-erh Tea Restored Circadian Rhythm Disruption by Regulating Tryptophan Metabolism.

Pu-erh tea is a healthy beverage rich in phytochemicals, and its effect on the risk of inducing circadian rhythm disorders (CRD) is unclear. In this study, healthy mice were given water or 0.25% (w/v) Pu-erh tea for 7 weeks, followed by a 40 day disruption of the light/dark cycle. CRD caused dysregulation of neurotransmitter secretion and clock gene oscillations, intestinal inflammation, and disruption of intestinal microbes and metabolites. Pu-erh tea boosted the indole and 5-hydroxytryptamine pathways of tryptophan metabolism via the gut-liver-brain axis. Furthermore, its metabolites (e.g., IAA, Indole, 5-HT) enhanced hepatic glycolipid metabolism and down-regulated intestinal oxidative stress by improving the brain hormone release. Tryptophan metabolites and bile acids also promoted liver lipid metabolism and inhibited intestinal inflammation (MyD88/NF-κB) via the enterohepatic circulation. Collectively, 0.25% (w/v) Pu-erh tea has the potential to prevent CRD by promoting indole and 5-HT pathways of tryptophan metabolism and signaling interactions in the gut-liver-brain axis.

Synergistic anti-tumor efficacy of mutant isocitrate dehydrogenase 1 inhibitor SYC-435 with standard therapy in patient-derived xenograft mouse models of glioma.

Clinical outcomes in patients with WHO grade II/III astrocytoma, oligodendroglioma or secondary glioblastoma remain poor. Isocitrate dehydrogenase 1 (IDH1) is mutated in > 70% of these tumors, making it an attractive therapeutic target. To determine the efficacy of our newly developed mutant IDH1 inhibitor, SYC-435 (1-hydroxypyridin-2-one), we treated orthotopic glioma xenograft model (IC-BT142AOA) carrying R132H mutation and our newly established orthotopic patient-derived xenograft (PDX) model of recurrent anaplastic oligoastrocytoma (IC-V0914AOA) bearing R132C mutation. In addition to suppressing IDH1 mutant cell proliferation in vitro, SYC-435 (15 mg/kg, daily x 28 days) synergistically prolonged animal survival times with standard therapies (Temozolomide + fractionated radiation) mediated by reduction of H3K4/H3K9 methylation and expression of mitochondrial DNA (mtDNA)-encoded molecules. Furthermore, RNA-seq of the remnant tumors identified genes (MYO1F, CTC1 and BCL9) and pathways (base excision repair, TCA cycle II, sirtuin signaling, protein kinase A, eukaryotic initiation factor 2 and α-adrenergic signaling) as mediators of therapy resistance. Our data demonstrated the efficacy SYC-435 in targeting IDH1 mutant gliomas when combined with standard therapy and identified a novel set of genes that should be prioritized for future studies to overcome SYC-435 resistance.

Religion, Psychological Strain, and Suicidality in China: A Preliminary Study.

BACKGROUND: There is a lack of religiosity studies in China especially in relation to mental health and suicidality. In this research, we focus our studies on medical workers of which some studies reported to have higher stress, and to pilot our studies in this adult age-group. DATA AND METHODOLOGY: Data were obtained by a questionnaire survey in a large public hospital in a big metropolitan city of China. The final sample consisted of 1012 respondents with 237 (23.4%) being male and 775 (76.6%) being female. The respondents were of three groups: (1) Believers (n = 34; 3.5%); (2) Non-Believers or Atheists (n = 547; 55.8%); and (3) Agnostics or Fence-Sitters (n = 400; 40.8%). Suicidality was measured by the NCS-Suicidality Scale, and standard measures were employed for other major variables. FINDINGS: In line with other recent studies in China, the religion rate among the urban adults remained low (3.5%). However, about 40.8% of the respondents chose "don't know" and could be fence-sitters on the issue of religious belief. Many of them are involved in various folk beliefs which may not be considered as religious. The religious believers were at higher risk of suicidality and depression than the atheists and the fence-sitters. However, the fence-sitters were higher than the believers and atheists on psychological strains, and they were higher on depression compared to the atheists. CONCLUSION: The religious believers and religious fence-sitters have higher psychopathologic risks and suicidal risk than the atheist group. Religion as of low prevalence in Chinese societies is a social value deviant from the norm and its practitioners are likely to be marginalized or stigmatized. The Strain Theory of Suicide is used for detailed explanations.

Ubiquitous Topological States of Phonons in Solids: Silicon as a Model Material.

Research on topological physics of phonons has attracted enormous interest but demands appropriate model materials. Our ab initio calculations identify silicon as an ideal candidate material containing extraordinarily rich topological phonon states. In silicon, we identify various topological nodal lines characterized by quantized Berry phase π, which gives drumhead surface states observable from any surface orientations. Remarkably, a novel type of topological nexus phonon is discovered which is featured by double Fermi-arc-like surface states but requires neither inversion nor time-reversal symmetry breaking. Versatile topological states can be created from the nexus phonons, such as Hopf nodal links by strain. Furthermore, we generalize the symmetry analysis to other centrosymmetric systems and find numerous candidate materials, demonstrating the ubiquitous existence of topological phonons in solids. These findings open up new opportunities for studying topological phonons in realistic materials and their influence on surface physics.

One-pot conversion of wheat straw into biobased chemicals in methanol/water medium using cheap mixed acid catalyst.

BACKGROUND: Environmental concerns and the diminishing availability of unrenewable resources have spurred research into the use of agricultural waste as a feedstock for industrial applications. Efficient conversion of wheat straw into biobased chemicals is an important way to realize the potential value of renewable agricultural biomass. This study investigated one-pot conversion of wheat straw into two notable platform chemicals, levulinic acid (LA) and methyl levulinate (ML). RESULTS: A mixed acid catalyst system, including 1% H2 SO4 and 0.015 mol L-1 Al2 (SO4 )3 , was an efficient catalyst for the conversion of wheat straw due to the combination of Brønsted acid and Lewis acid. A ratio of wheat straw to methanol of 5 g/50 mL was identified as the preferred solid/liquid ratio, and a methanol/H2 O medium with 25% water content aided the simultaneous production of LA and ML from wheat straw. Under optimum conditions, the maximum total yield of LA and ML reached 23.01% at 220 °C and 3 h. The kinetics of biobased chemical formation and the reaction pathways in methanol/water were investigated. CONCLUSION: The presence of water in the methanol/H2 O medium affected the distribution of products and promoted hydrolysis reactions. The methanol/H2 O medium not only inhibited the side reactions but also promoted the degradation of wheat straw and increased the total yield of LA and ML. This study provides a feasible method for the conversion of wheat straw to prepare biobased chemicals. © 2021 Society of Chemical Industry.

Evaluation of an EZH2 inhibitor in patient-derived orthotopic xenograft models of pediatric brain tumors alone and in combination with chemo- and radiation therapies.

Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mg/kg, gavaged, twice daily) alone and in combination with cisplatin (5 mg/kg, i.p., twice) and/or radiation (2 Gy/day × 5 days). Compared with the untreated controls, tazemetostat significantly (Pcorrected < 0.05) prolonged survival times in IC-L1115ATRT (101% at 400 mg/kg) and IC-2305GBM (32% at 250 mg/kg, 45% at 400 mg/kg) in a dose-dependent manner. The addition of tazemetostat with radiation was evaluated in 3 models, with only one [IC-1078MB (group 4)] showing a substantial, though not statistically significant, prolongation in survival compared to radiation treatment alone. Combining tazemetostat (250 mg/kg) with cisplatin was not superior to cisplatin alone in any model. Analysis of in vivo drug resistance detected predominance of EZH2-negative cells in the remnant PDOX tumors accompanied by decreased H3K27me2 and H3K27me3 expressions. These data supported the use of tazemetostat in a subset of pediatric brain tumors and suggests that EZH2-negative tumor cells may have caused therapy resistance and should be prioritized for the search of new therapeutic targets.

Mental Health Outcomes among Chinese College Students over a Decade.

BACKGROUND: Economic growth in China has brought about significant social and psychological changes in society. OBJECTIVE: This study aims to explore how the mental and psychological health of college students has changed over the past decade. METHODS: We observed several cohort samples in a Chinese university over a decade and looked at five mental health outcomes, including suicidal ideation, depression, optimism, self-esteem, and perceived social support, throughout each year of testing. RESULTS: Our study highlights the declining rates of suicidal ideation and depression, combined with relative stability and even small increases in optimism, self-esteem, and perceived social support across a range of demographic variables. CONCLUSIONS: The findings of this study imply that in the context of economic growth, stabilizing and improving positive mental health states can help prevent and reduce the risk of depression and suicidal ideation among college students. The study also highlighted the need for more public health campaigns and interventions in universities to help students cope with mental health problems.

Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion.

Diffuse invasion is the primary cause of treatment failure of glioblastoma (GBM). Previous studies on GBM invasion have long been forced to use the resected tumor mass cells. Here, a strategy to reliably isolate matching pairs of invasive (GBMINV ) and tumor core (GBMTC ) cells from the brains of 6 highly invasive patient-derived orthotopic models is described. Direct comparison of these GBMINV and GBMTC cells reveals a significantly elevated invasion capacity in GBMINV cells, detects 23/768 miRNAs over-expressed in the GBMINV cells (miRNAINV ) and 22/768 in the GBMTC cells (miRNATC ), respectively. Silencing the top 3 miRNAsINV (miR-126, miR-369-5p, miR-487b) successfully blocks invasion of GBMINV cells in vitro and in mouse brains. Integrated analysis with mRNA expression identifies miRNAINV target genes and discovers KCNA1 as the sole common computational target gene of which 3 inhibitors significantly suppress invasion in vitro. Furthermore, in vivo treatment with 4-aminopyridine (4-AP) effectively eliminates GBM invasion and significantly prolongs animal survival times (P = 0.035). The results highlight the power of spatial dissection of functionally accurate GBMINV and GBMTC cells in identifying novel drivers of GBM invasion and provide strong rationale to support the use of biologically accurate starting materials in understanding cancer invasion and metastasis.

Ripened Pu-Erh Tea Improved the Enterohepatic Circulation in a Circadian Rhythm Disorder Mice Model.

Glucolipid metabolism, nitrogen metabolism, and inflammation are closely related to circadian rhythm disorder (CRD). Ripened Pu-erh tea (RPT) shows significant antidyslipidemic, antihyperurecemic, and anti-inflammatory effects. However, it is unclear whether healthy population are affected by CRD and whether long-term consumption of RPT can alleviate it. To investigate this problem, healthy mice were pretreated with RPT (0.25%, w/v) for 60 days and then subjected to CRD for 40 days. Our results indicated that healthy mice showed obesity, and the intestinal and liver inflammation increased after CRD, which were associated with the development of a metabolic disorder syndrome. RPT effectively reversed this trend by increasing the production and excretion rates of bile acid. RPT reshaped the disorder of gut microbiota caused by CRD and promoted the change of archaeal intestinal types from Firmicutes-dominant type to Bacteroidota-dominant type. In addition, by repairing the intestinal barrier function, RPT inhibited the infiltration of harmful microorganisms or metabolites through enterohepatic circulation, thus reducing the risk of chronic liver inflammation. In conclusion, RPT may reduce the risk of CRD-induced obesity in mice by increasing bile acid metabolism. The change of bile acid pool contributes to the reshaping of gut microflora, thus reducing intestinal inflammation and oxidative stress induced by CRD. Therefore, we speculated that the weakening of CRD damage caused by RPT is due to the improvement of bile acid-mediated enterohepatic circulation. It was found that 0.25% RPT (a human equivalent dose of 7 g/60 kg/day) has potential for regulating CRD.