Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity.

MiRNAs are regulatory molecules that can be packaged into exosomes and secreted from cells. Here, we show that adipose tissue macrophages (ATMs) in obese mice secrete miRNA-containing exosomes (Exos), which cause glucose intolerance and insulin resistance when administered to lean mice. Conversely, ATM Exos obtained from lean mice improve glucose tolerance and insulin sensitivity when administered to obese recipients. miR-155 is one of the miRNAs overexpressed in obese ATM Exos, and earlier studies have shown that PPARγ is a miR-155 target. Our results show that miR-155KO animals are insulin sensitive and glucose tolerant compared to controls. Furthermore, transplantation of WT bone marrow into miR-155KO mice mitigated this phenotype. Taken together, these studies show that ATMs secrete exosomes containing miRNA cargo. These miRNAs can be transferred to insulin target cell types through mechanisms of paracrine or endocrine regulation with robust effects on cellular insulin action, in vivo insulin sensitivity, and overall glucose homeostasis.

Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer.

Fibroblasts and macrophages are present in all tissues, and mounting evidence supports that these cells engage in direct communication to influence the overall tissue microenvironment and affect disease outcomes. Here, we review the current understanding of the molecular mechanisms that underlie fibroblast-macrophage interactions in health, fibrosis, and cancer. We present an integrated view of fibroblast-macrophage interactions that is centered on the CSF1-CSF1R axis and discuss how additional molecular programs linking these cell types can underpin disease onset, progression, and resolution. These programs may be tissue and context dependent, affected also by macrophage and fibroblast origin and state, as seen most clearly in cancer. Continued efforts to understand these cells and the means by which they interact may provide therapeutic approaches for the treatment of fibrosis and cancer.

Early window of diabetes determinism in NOD mice, dependent on the complement receptor CRIg, identified by noninvasive imaging.

All juvenile mice of the nonobese diabetic (NOD) strain develop insulitis, but there is considerable variation in their progression to diabetes. Here we used a strategy based on magnetic resonance imaging (MRI) of magnetic nanoparticles to noninvasively visualize local effects of pancreatic-islet inflammation to predict the onset of diabetes in NOD mice. MRI signals acquired during a narrow early time window allowed us to sort mice into groups that would progress to clinical disease or not and to estimate the time to diabetes development. We exploited this approach to identify previously unknown molecular and cellular elements correlated with disease protection, including the complement receptor of the immunoglobulin superfamily (CRIg), which marked a subset of macrophages associated with diabetes resistance. Administration of a fusion of CRIg and the Fc portion of immunoglobulin resulted in lower MRI signals and diabetes incidence. In addition to identifying regulators of disease progression, we show here that diabetes is set at an early age in NOD mice.

A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells.

The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3(+)CD4(+) regulatory T cells (T(reg) cells) but is neither strictly necessary nor sufficient to determine the characteristic T(reg) cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T(reg) cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T(reg) cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T(reg) cell phenotype, a model that would account for several aspects of T(reg) cell physiology, differentiation and stability.

Relationship between borderline personality features, emotion regulation, and non-suicidal self-injury in depressed adolescents: a cross-sectional study.

OBJECTIVE: Non-suicidal self-injury (NSSI) is common among adolescents and has been linked to mental disorders and suicide in addition to physical injuries. According to the empirical avoidance model, adolescents with NSSI have stronger emotional affect and poorer emotional regulation than those without NSSI, and these constitute core features of borderline personality disorder (BPD). The relationship between borderline personality features, emotional regulation, and NSSI in the population is unclear. This study explored these associations to provide a theoretical basis for the treatment of NSSI in the future. METHODS: Depressed adolescents (n = 1192) were evaluated using Chinese versions of the Function Assessment of Self-mutilation Scale, Emotional Regulation Questionnaire for Children and Adolescents, and Borderline Personality Features Scale for Children. RESULTS: The majority of depressed adolescents (71.3%, 850/1192) had demonstrated NSSI in the past year, with cutting or scratching being the most common form (57.4%). Pearson correlation analysis with NSSI as a fixed factor (NSSI = 1, no NSSI = 2) revealed a negative correlation between NSSI and borderline personality features (r = -0.314, P < 0.01) but a positive correlation between NSSI and emotional regulation capacity (r = 0.159, P < 0.01), which was positively correlated with the expression suppression dimension (r = 0.079, p < 0.01); however, there was no significant correlation between the cognitive reappraisal dimension and expression suppression (r = 0.022, p > 0.05). The occurrence of NSSI was also positively correlated with borderline personality features in general (r = 0.314, p < 0.01). These results were statistically significant. Emotional regulation played a mediating role between borderline personality traits and NSSI in adolescents with depression (effect value = 0.151). CONCLUSION: Borderline personality features and emotional regulation ability were significantly correlated with NSSI in depressed adolescents. Borderline personality symptoms not only directly influenced NSSI risk in adolescents with depression, but also indirectly influenced NSSI risk through emotional regulation.

Transcriptional regulation of Treg homeostasis and functional specification.

CD4+Foxp3+ regulatory T (Treg) cells are key players in keeping excessive inflammation in check. Mounting evidence has shown that Treg cells exert much more diverse functions in both immunological and non-immunological processes. The development, maintenance and functional specification of Treg cells are regulated by multilayered factors, including antigens and TCR signaling, cytokines, epigenetic modifiers and transcription factors (TFs). In the review, we will focus on TFs by summarizing their unique and redundant roles in Treg cells under physiological and pathophysiological conditions. We will also discuss the recent advances of Treg trajectories between lymphoid organs and non-lymphoid tissues. This review will provide an updated view of the newly identified TFs and new functions of known TFs in Treg biology.

ß Cell GHS-R Regulates Insulin Secretion and Sensitivity.

Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in ß and α cells. We then generated ß-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic ß and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, ß cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.

A Novel miR-24-TCF1 Axis in Modulating Effector T Cell Responses.

miR-23∼27∼24 was recently implicated in restricting Th2 immunity, as well as the differentiation and function of other effector T cell lineages. Interestingly, miR-24, unlike other family members, actually promotes Th1 and Th17 responses. In this article, we show that miR-24 drives the production of IFN-γ and IL-17 in T cells at least in part through targeting TCF1, a transcription factor known for its role in limiting Th1 and Th17 immunity. Surprisingly, whereas TCF1 was previously shown to promote Th2 responses through inducing GATA3, enforced TCF1 expression in miR-24-overexpressing T cells led to further downregulation of IL-4 and GATA3 expression, suggesting miR-24-mediated inhibition of Th2 immunity cannot be attributed to TCF1 repression by miR-24. Together, our data demonstrate a novel miR-24-TCF1 pathway in controlling effector cytokine production by T cells and further suggest miR-24 could function as a key upstream molecule regulating TCF1-mediated immune responses.

Distinct gene signatures predict insulin resistance in young mice with high fat diet-induced obesity.

Highly inbred C57BL/6 mice show wide variation in their degree of insulin resistance in response to diet-induced obesity even though they are almost genetically identical. Here we employed transcriptional profiling by RNA sequencing (RNA-Seq) of visceral adipose tissue (VAT) and liver in young mice to determine how gene expression patterns correlate with the later development of high-fat diet (HFD)-induced insulin resistance in adulthood. To accomplish this goal, we partially removed and banked tissues from pubertal mice. Mice subsequently received HFD followed by metabolic phenotyping to identify two well-defined groups of mice with either severe or mild insulin resistance. The remaining tissues were collected at study termination. We then applied RNA-Seq to generate transcriptome profiles associated with worsened insulin resistance before and after the initiation of HFD. We found 244 up- and 109 downregulated genes in VAT of the most insulin-resistant mice even before HFD exposure. Downregulated genes included serine protease inhibitor, major urinary protein, and complement genes; upregulated genes represented mostly muscle constituents. These gene families were also differentially expressed in VAT of mice with high or low insulin resistance after HFD. Inflammatory genes predicted insulin resistance in liver, but not in VAT. In contrast, when we compared VAT of all mice before and after HFD, differentially expressed genes were predominantly composed of immune response genes. These data show a distinct set of gene transcripts in young mice correlates with the severity of insulin resistance in adulthood, providing insight into the pathogenesis of insulin resistance in early life.

The Relationship Between Childhood Trauma and Non-Suicidal Self-Injury Behavior in Adolescents with Depression: The Mediating Role of Rumination.

Objective: Non-suicidal self-injury (NSSI) behavior is very common in adolescents with depression, and childhood trauma is considered one of the distal risk factors for its exacerbation. Rumination caused by adverse traumatic experiences, which can be transferred through NSSI behavior, can alleviate symptoms of depression in adolescents. The current research focuses on the relationship between the three, further exploring whether rumination is a mediator in the relationship between childhood trauma and NSSI behavior on the basis of previous studies, and provides some suggestions for future early intervention for adolescents with depression. Methods: A total of 833 adolescent patients with depression who met the DSM-5 criteria for depressive episode were recruited from 12 hospitals in China. The Chinese version of the Function Assessment of Self-mutilation, Childhood Trauma Questionnaire, and Rumination Inventory were used as research tools. Results: The scores of childhood trauma and rumination in adolescents with depression in the NSSI group were higher than those in the non-NSSI group. A Pearson's correlation analysis showed that childhood trauma was positively correlated with rumination (r=0.165, P<0.01), different types of childhood trauma were significantly positively correlated with rumination and its three factors, and these results were statistically significant. Rumination partially mediated the relationship between childhood trauma and NSSI behavior in depressed adolescent patients (effect size=0.002), and the effect in female participants (effect size=0.003), was greater than that in male participants (effect size=0.002). Conclusion: Childhood trauma and rumination were key factors for NSSI behavior in adolescents with depression. Childhood trauma not only has a direct effect on NSSI behavior in adolescent depression, but also plays an indirect effect on NSSI behavior through rumination.

Enhanced degradation of bisphenol A: Influence of optimization of removal, kinetic model studies, application of machine learning and microalgae-bacteria consortia.

Bisphenol A (BPA), a typical endocrine disruptor and a contaminant of emerging concern (CECs), has detrimental impacts not only on the environment and ecosystems, but also on human health. Therefore, it is essential to investigate the degrading processes of BPA in order to diminish its persistent effects on ecological environmental safety. With this objective, the present study reports on the effectiveness of biotic/abiotic factors in optimizing BPA removal and evaluates the kinetic models of the biodegradation processes. The results showed that BPA affected chlorophyll a, superoxide dismutase (SOD) and peroxidase (POD) activities, malondialdehyde (MDA) content, and photosystem intrinsic PSII efficiency (Fv/Fm) in the microalga Chlorella pyrenoidosa, which degraded 43.0 % of BPA (8.0 mg L-1) under general experimental conditions. The bacteria consortium AEF21 could remove 55.4 % of BPA (20 mg L-1) under orthogonal test optimization (temperature was 32 °C, pH was 8.0, inoculum was 6.0 %) and the prediction of artificial neural network (ANN) of machine learning (R2 equal to 0.99 in training, test, and validation phase). The microalgae-bacteria consortia have a high removal rate of 57.5 % of BPA (20.0 mg L-1). The kinetic study revealed that the removal processes of BPA by microalgae, bacteria, and microalgae-bacteria consortia all followed the Monod's kinetic model. This work provided a new perspective to apply artificial intelligence to predict the degradation of BPA and to understand the kinetic processes of BPA biodegradation by integrated biological approaches, as well as a novel research strategy to achieve environmental CECs elimination for long-term ecosystem health.

Combined PD-L1/TGFß blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors.

TGFß signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFß signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFß and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFß/PD-L1 blockade IFNγhi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFß therapy efficacy. Our data suggest that TGFß works with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.

Growth performance, antioxidant response, biodegradation and transcriptome analysis of Chlorella pyrenoidosa after nonylphenol exposure.

Chlorella pyrenoidosa was exposed to nonylphenol (NP) to investigate the tolerance, antioxidant response, removal efficiency, and biodegradation mechanism. We conducted studies on algal biomass, chlorophyll a content, and photosynthetic activity, and found that C. pyrenoidosa exhibited a high tolerance even at 8 mg L-1 of NP. Changes in peroxidase (POD) and superoxide dismutase (SOD) activities indicated that the NP-induced oxidative stress caused oxidant damage, which increased the malondialdehyde (MDA) content. After culturing for 120 h, the NP removal efficiency of C. pyrenoidosa was 89%, 59%, 49%, and 48% in the 2, 4, 6, and 8 mg L-1 treatment groups, respectively. Degradation intermediates determined by GC-MS suggested that the biodegradation of NP in C. pyrenoidosa originated from the long alkyl chain. In addition, transcriptome analysis indicated that NP affected photosynthesis, antioxidase, and oxidoreductase activity-related genes. In summary, our results indicated that C. pyrenoidosa is a species that exhibits high tolerance and biodegradation capacity toward NP.

Synergetic effects of microbial-phytoremediation reshape microbial communities and improve degradation of petroleum contaminants.

Microbial-phytoremediation is an effective bioremediation technology that introduces petroleum-degrading bacteria and oil-tolerant plants into oil-contaminated soils in order to achieve effective degradation of total petroleum hydrocarbons (TPH). In this work, natural attenuation (NA), microbial remediation (MR, using Acinetobacter sp. Tust-DM21), phytoremediation (PR, using Suaeda glauca), and microbial-phytoremediation (MPR, using both species) were utilized to degrade petroleum hydrocarbons. We evaluated four different biological treatments, assessing TPH degradation rates, soil enzyme activities, and the structure of microbial community in the petroleum-contaminated soil. This finding revealed that the roots of Suaeda glauca adsorbed small amounts of polycyclic aromatic hydrocarbons, causing the structure of soil microbiota community to reshape. The abundance of petroleum-degrading bacteria and plant growth-promoting rhizobacteria (PGPR) has increased, as has microbial diversity. According to correlation research, these genera increased soil enzyme activity, boosted the number of degradation-functional genes in the petroleum hydrocarbon degradation pathway, and accelerated the dissipation and degradation of TPH in petroleum-contaminated soil. This evidence contributes to a better understanding of the mechanisms involved in the combined microbial-phytoremediation strategies for contaminated soil, specifically the interaction between microflora and plants in co-remediation and the effects on the structural reshaping of rhizosphere microbial communities.

Effectiveness of mindfulness-based cognitive therapy against suicidal ideation in patients with depression: A systematic review and meta-analysis.

BACKGROUND: Mindfulness-based cognitive therapy (MBCT) can effectively prevent relapse of major depression, but there is currently insufficient evidence for efficacy against suicidal ideation during depressive episodes. We thus conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing MBCT to treatment as usual (TAU) for suppression of suicidal ideation in patients with current depression. METHODS: We systematically searched PubMed, Embase, Cochrane, CNKI, and Wan Fang databases for RCTs published in English or Chinese between January 1, 2000, and August 30, 2021. Pooled data were compared between MBCT and TAU groups using a random-effects model. FINDINGS: Seven RCTs with a total of 479 participants were included. Suicidal ideation and general depression scores were significantly improved following MBCT compared to TAU [Suicidal Ideation: standard mean difference (SMD) = -0.33, 95 % CI, -0.56 to -0.10; Depression: SMD = -0.96, 95%CI, -1.54 to -0.38]. INTERPRETATION: Mindfulness-based cognitive therapy is an effective intervention for reducing depressive symptoms and suicidal ideation in depressed patients. TRIAL REGISTRATION: This meta-analysis was conducted in accordance with PRISMA guidelines and registered at PROSPERO https://www.crd.york.ac.uk/PROSPERO/ (CRD42021285016).

Concurrent Disruption of the Ras/MAPK and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis.

The Ras/Erk and NF-κB pathways play critical roles in cell proliferation and are known to drive oncogenesis when overactivated. Herein we report a gatekeeper function of the two pathways by working in synergy to suppress liver tumorigenesis. Hepatocyte-specific deletion of both Shp2/Ptpn11 and Ikkß in mice, which promote Ras/Erk and NF-κB signaling, respectively, exacerbated chemical carcinogenesis and even triggered spontaneous development of hepatocellular carcinoma (HCC). We show that the unanticipated severe tumor phenotype was contributed collectively by severe cholestasis, metabolic changes, upregulated cell-cycle progression, and disruption of circadian rhythm in mutant hepatocytes. Remarkably, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/Erk and NF-κB signaling and poor prognosis. Together, these data indicate that at the ground state, the two central pathways, previously known as oncogenic, cooperate to sustain tumor-suppressive physiologic homeostasis and to prevent hepatic damage. Disruption of this intricate signaling network is carcinogenic in the liver. IMPLICATIONS: We demonstrate here that basal levels of the Ras/MAPK and NF-κB pathways, while promoting tumorigenesis if overactivated, are required to maintain physiologic homeostasis and regulate circadian rhythm in the liver, which are antitumorigenic.

Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075.

In chronic obesity, hepatocytes become insulin resistant and exert important effects on systemic metabolism. Here we show that in early onset obesity (4 weeks high-fat diet), hepatocytes secrete exosomes that enhance insulin sensitivity both in vitro and in vivo. These beneficial effects were due to exosomal microRNA miR-3075, which is enriched in these hepatocyte exosomes. FA2H is a direct target of miR-3075 and small interfering RNA depletion of FA2H in adipocytes, myocytes and primary hepatocytes leads to increased insulin sensitivity. In chronic obesity (16-18 weeks of a high-fat diet), hepatocyte exosomes promote a state of insulin resistance. These chronic obese hepatocyte exosomes do not directly cause impaired insulin signalling in vitro but do promote proinflammatory activation of macrophages. Taken together, these studies show that in early onset obesity, hepatocytes produce exosomes that express high levels of the insulin-sensitizing miR-3075. In chronic obesity, this compensatory effect is lost and hepatocyte-derived exosomes from chronic obese mice promote insulin resistance.

CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease.

Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.

Immune regulation of islet homeostasis and adaptation.

The islet of Langerhans produces endocrine hormones to regulate glucose homeostasis. The normal function of the islet relies on the homeostatic regulations of cellular composition and cell-cell interactions within the islet microenvironment. Immune cells populate the islet during embryonic development and participate in islet organogenesis and function. In obesity, a low-grade inflammation manifests in multiple organs, including pancreatic islets. Obesity-associated islet inflammation is evident in both animal models and humans, characterized by the accumulation of immune cells and elevated production of inflammatory cytokines/chemokines and metabolic mediators. Myeloid lineage cells (monocytes and macrophages) are the dominant types of immune cells in islet inflammation during the development of obesity and type 2 diabetes mellitus (T2DM). In this review, we will discuss the role of the immune system in islet homeostasis and inflammation and summarize recent findings of the cellular and molecular factors that alter islet microenvironment and ß cell function in obesity and T2DM.

The role of macrophages in obesity-associated islet inflammation and ß-cell abnormalities.

Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to ß-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive ß-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of ß-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the ß-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on ß-cell function and glycaemia.