Long noncoding RNA LRG modulates Drosophila locomotion by sequestering Synaptotagmin 1 protein.

Apparently, the genomes of many organisms are pervasively transcribed, and long noncoding RNAs (lncRNAs) make up the majority of cellular transcripts. LncRNAs have been reported to play important roles in many biological processes; however, their effects on locomotion are poorly understood. Here, we presented a novel lncRNA, Locomotion Regulatory Gene (LRG), which participates in locomotion by sequestering Synaptotagmin 1 (SYT1). LRG deficiency resulted in higher locomotion speed which could be rescued by pan-neuronal overexpression but not by limited ellipsoid body, motoneuron or muscle-expression of LRG. At the molecular level, the synaptic vesicles (SVs) release and movement-related SYT1 protein was recognized as LRG-interacting protein candidate. Furthermore, LRG had no effects on SYT1 expression. Genetically, the behavioral defects in LRG mutant could be rescued by pan-neuronal knock-down of Syt1. Taken together, all the results suggested LRG exerts regulatory effects on locomotion via sequestering SYT1 thereby blocking its function without affecting its expression. Our work displays a new function of lncRNA and provides insights for revealing the pathogenesis of neurological diseases with motor disorders.

Immune checkpoint inhibitors or anti-claudin 18.2 antibodies? A network meta-analysis for the optimized first-line therapy of HER2-negative gastric cancer.

Background: Multiple anti-programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors and zolbetuximab, an anti-claudin 18.2 antibody, have shown efficacy in the first-line treatment of HER2-negative gastric cancers. How to choose the best regimen remains an unsolved question. Objectives: We aimed to conduct a comparative analysis of the therapeutic advantages between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers. Design: Network meta-analysis was employed to systematically compare efficacy and safety data derived from various clinical trials. Data sources and methods: We included phase III randomized controlled trials in PubMed, Embase, Web of Science, Cochrane Library, and major conference abstracts. Network meta-analysis was used to compare the efficacy of each first-line therapeutic agent and to indirectly compare immunotherapy with anti-claudin-18.2-targeted therapy. Results: Eight trials comprising a total of 6455 patients were included. For the overall survival (OS) analysis, no statistically significant differences were observed between pembrolizumab [hazard ratios (HR) = 1.00, 95% CI: 0.94-1.07], sintilimab (HR = 0.99, 95% CI: 0.89-1.09), sugemalimab (HR = 0.98, 95% CI: 0.87-1.10), tislelizumab (HR = 0.97, 95% CI: 0.87-1.09), zolbetuximab (HR = 0.98, 95% CI: 0.91-1.07), and nivolumab (HR = 1.00). For the progression-free survival (PFS) analysis, no statistically significant differences were observed between pembrolizumab (HR = 1.00, 95% CI: 0.93-1.06), sintilimab (HR = 0.91, 95% CI: 0.83-1.00), sugemalimab (HR = 0.92, 95% CI: 0.84-1.02), tislelizumab (HR = 0.93, 95% CI: 0.84-1.03), zolbetuximab (HR = 0.96, 95% CI: 0.88-1.05), and nivolumab (HR = 1.00). For the overall response rate analysis, all regimens presented similar effects on ORR. In addition, anti-claudin-18.2-targeted therapies presented similar OS (HR = 0.99, 95% CI: 0.95-1.04) and PFS (HR = 1.01, 95% CI: 0.91-1.12) compared to immunotherapy, although their toxicity profiles were distinct. Conclusions: Our network meta-analysis showed no significant difference in PFS, OS, or ORR between different checkpoint inhibitors or between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers.

Application of Radiomics in the Efficacy Evaluation of Transarterial Chemoembolization for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

RATIONALE AND OBJECTIVES: This meta-analysis was aimed at evaluating the predictive value of radiomics in the context of transarterial chemoembolization (TACE) therapeutic response (TR) for hepatocellular carcinoma (HCC) and patients' survival status (SS) and providing favorable evidence for clinical application. MATERIALS AND METHODS: We searched for literature in which radiomics was applied to assess the TR of TACE for HCC and the affected patients' survival status across PubMed, Embase, Cochrane Library and Web of Science until Jul 12, 2023. The quality of included literature was evaluated using a radiomics quality score (RQS) approach, and a meta-analysis was conducted using Stata15.0. RESULTS: Twenty-four studies were included in the analysis. The meta-analysis revealed that the overall concordance-index (C-index) based on radiomics for predicting the TR and SS with TACE was 0.85 and 0.78, respectively. The combined radiomics-clinical model provided the best performance in evaluating the TR and SS associated with TACE. The C-index was 0.93 and 0.88 for TR and 0.84 and 0.80 for SS, in the training and validation sets, respectively. These values were higher than the 0.87 and 0.79 for TR and 0.79 and 0.70 for SS, respectively with the radiomics model, and 0.71 and 0.66 for TR and 0.72 and 0.66 for SS, respectively with the clinical model. CONCLUSION: The radiomics prediction model for the efficacy of TACE in HCC showed a satisfactory prediction performance. The combined radiomics-clinic prediction model had the best performance.

Histological Correlates of Auditory Nerve Injury from Kainic Acid in the Budgerigar (Melopsittacus undulatus).

PURPOSE: Loss of auditory nerve afferent synapses with cochlear hair cells, called cochlear synaptopathy, is a common pathology in humans caused by aging and noise overexposure. The perceptual consequences of synaptopathy in isolation from other cochlear pathologies are still unclear. Animal models provide an effective approach to resolve uncertainty regarding the physiological and perceptual consequences of auditory nerve loss, because neural lesions can be induced and readily quantified. The budgerigar, a parakeet species, has recently emerged as an animal model for synaptopathy studies based on its capacity for vocal learning and ability to behaviorally discriminate simple and complex sounds with acuity similar to humans. Kainic acid infusions in the budgerigar produce a profound reduction of compound auditory nerve responses, including wave I of the auditory brainstem response, without impacting physiological hair cell measures. These results suggest selective auditory nerve damage. However, histological correlates of neural injury from kainic acid are still lacking. METHODS: We quantified the histological effects caused by intracochlear infusion of kainic acid (1 mM; 2.5 µL), and evaluated correlations between the histological and physiological assessments of auditory nerve status. RESULTS: Kainic acid infusion in budgerigars produced pronounced loss of neural auditory nerve soma (60% on average) in the cochlear ganglion, and of peripheral axons, at time points 2 or more months following injury. The hair cell epithelium was unaffected by kainic acid. Neural loss was significantly correlated with reduction of compound auditory nerve responses and auditory brainstem response wave I. CONCLUSION: Compound auditory nerve responses and wave I provide a useful index of cochlear synaptopathy in this animal model.

A scoping review of implementation science theories, models, and frameworks - an appraisal of purpose, characteristics, usability, applicability, and testability.

BACKGROUND: A proliferation of theories, models, and frameworks (TMFs) have been developed in the implementation science field to facilitate the implementation process. The basic features of these TMFs have been identified by several reviews. However, systematic appraisals on the quality of these TMFs are inadequate. To fill this gap, this study aimed to assess the usability, applicability, and testability of the current TMFs in a structured way. METHODS: A scoping review method was employed. Electronic databases were searched to locate English and Chinese articles published between January 2000 and April 2022. Search terms were specific to implementation science. Additionally, hand searches were administered to identify articles from related reviews. Purpose and characteristics such as the type of TMF, analytical level, and observation unit were extracted. Structured appraisal criteria were adapted from Birken et al.'s Theory Comparison and Selection Tool (T-CaST) to conduct an in-depth analysis of the TMFs' usability, applicability, and testability. RESULTS: A total of 143 TMFs were included in this analysis. Among them, the most common purpose was to identify barriers and facilitators. Most TMFs applied the descriptive method to summarize the included constructs or the prescriptive method to propose courses of implementation actions. TMFs were mainly mid-range theories built on existing conceptual frameworks or demonstrated grand theories. The usability of the TMFs needs to be improved in terms of the provision of conceptually matched strategies to barriers and facilitators and instructions on the TMFs usage. Regarding the applicability, little attention was paid to the constructs of macro-level context, stages of scale-up and sustainability, and implementation outcomes like feasibility, cost, and penetration. Also, fewer TMFs could propose recommended research and measurement methods to apply the TMFs. Lastly, explicit hypotheses or propositions were lacking in most of the TMFs, and empirical evidence was lacking to support the claimed mechanisms between framework elements in testability. CONCLUSIONS: Common limitations were found in the usability, application, and testability of the current TMFs. The findings of this review could provide insights for developers of TMFs for future theoretical advancements.

Mechanisms of masking by Schroeder-phase harmonic tone complexes in the budgerigar (Melopsittacus undulatus).

Schroeder-phase harmonic tone complexes can have a flat temporal envelope and rising or falling instantaneous-frequency sweeps within F0 periods, depending on the phase-scaling parameter C. Human tone-detection thresholds in a concurrent Schroeder masker are 10-15 dB lower for positive C values (rising frequency sweeps) compared to negative (falling sweeps), potentially due to cochlear mechanics, though this hypothesis remains controversial. Birds provide an interesting model for studies of Schroeder masking because many species produce vocalizations containing frequency sweeps. Prior behavioral studies in birds suggest less behavioral threshold difference between maskers with opposite C values than in humans, but focused on low masker F0s and did not explore neural mechanisms. We performed behavioral Schroeder-masking experiments in budgerigars (Melopsittacus undulatus) using a wide range of masker F0 and C values. Signal frequency was 2800 Hz. Neural recordings from the midbrain characterized encoding of behavioral stimuli in awake animals. Behavioral thresholds increased with increasing masker F0 and showed minimal difference between opposite C values, consistent with prior budgerigar studies. Midbrain recordings showed prominent temporal and rate-based encoding of Schroeder F0, and in many cases, marked asymmetry in Schroeder responses between C polarities. Neural thresholds for Schroeder-masked tone detection were often based on a response decrement compared to the masker alone, consistent with prominent modulation tuning in midbrain neurons, and were generally similar between opposite C values. The results highlight the likely importance of envelope cues in Schroeder masking and show that differences in supra-threshold Schroeder responses do not necessarily result in neural threshold differences.

The relationship between psychiatric nurses' perceived organizational support and job burnout: Mediating role of psychological capital.

Background: Psychiatric nurses need to keep close contact with patients suffering from mental illness. Because of the special nature of their profession, there is an increasing incidence of job burnout among psychiatric nurses. Aim: This study examined the relationship between psychiatric nurses' perceived organizational support, job burnout, and psychological capital. It also investigated the mediating role of psychological capital in the relationship between their perceived organizational support and job burnout. Methods: A total of 916 psychiatric nurses were recruited from 6 grade-III mental facilities in Shandong Province using the stratified sampling approach. Their data were collected and examined using a general demographic data questionnaire, The Maslach Burnout Inventory, the Perceived Organizational Support Scale, and the Psychological Capital Questionnaire. Results: The total score of job burnout was 53.71 ± 16.37. Specifically, 73.69% of the nurses had moderate to severe emotional exhaustion, 76.75% had moderate to severe job burnout pertaining to depersonalization, and 98.80% had moderate to severe job burnout pertaining to personal accomplishment. Spearman's correlation analysis showed that both psychological capital (r = -0.35, p < 0.01) and perceived organizational support (r = -0.31, p < 0.01) were adversely related to job burnout. Additionally, psychological capital somewhat mediated the relationship between perceived organizational support and job burnout. Its mediating impact accounted for 33.20% of the overall effect. Conclusion: This study's participants had a moderate to severe level of job burnout. However, organizational support and psychological capital can be crucial in alleviating this problem among psychiatric nurses. Therefore, nursing managers and medical institutions should undertake timely and positive interventions to improve psychiatric nurses' mental health and prevent job burnout. While exploring the impact of organizational support and psychological capital on job burnout, future studies should consider other effective influencing factors, and the relationship between the different factors should be explored in depth. This would provide a basis for developing a job burnout prevention mechanism.

Nexus Between Economic Efficiency, Healthcare, and Environmental Expenditures: A Perspective of BRI Countries.

Public health and the environment are the most essential pillars, and play a vital role in the economy. In order to better public health, the economic and environmental atmosphere must be stable and clean, respectively. Thus, this paper emphasizes on nexus between economic, public health, and the environment. Therefore, the objective of this paper is whether healthcare and environmental expenditures affect economic efficiency and vice versa. So, this study evaluates the performance of the country's economic efficiency and investigates the effect of healthcare and environmental expenditures for 62 Belt and Road Initiative countries for the period from 1996 to 2020. Suitable input-output variables are employed under the framework of DEA-window and Malmquist Index Productivity, and Stochastic Frontier Analysis (SFA). In addition, this study estimates the relationship between economic efficiency, healthcare, and environmental expenditures by fixed and random effects models. Therefore, the analytical outcomes reveal that countries are economically efficient. On the contrary, SFA estimation concludes that countries are found to be inefficient, because higher variation is exists in efficiency change compared to technological efficiency change and total factor productivity change on average. In addition, it is worth notable that healthcare and environmental expenditures improve the country's economic efficiency. Furthermore, public health is also influenced by economic efficiency. Thus, this study suggests that countries should better utilize given resources and invest a specific portion of national income in order to improve economic efficiency.

Midbrain-Level Neural Correlates of Behavioral Tone-in-Noise Detection: Dependence on Energy and Envelope Cues.

Hearing in noise is a problem often assumed to depend on encoding of energy level by channels tuned to target frequencies, but few studies have tested this hypothesis. The present study examined neural correlates of behavioral tone-in-noise (TIN) detection in budgerigars (Melopsittacus undulatus, either sex), a parakeet species with human-like behavioral sensitivity to many simple and complex sounds. Behavioral sensitivity to tones in band-limited noise was assessed using operant-conditioning procedures. Neural recordings were made in awake animals from midbrain-level neurons in the inferior colliculus, the first processing stage of the ascending auditory pathway with pronounced rate-based encoding of stimulus amplitude modulation. Budgerigar TIN detection thresholds were similar to human thresholds across the full range of frequencies (0.5-4 kHz) and noise levels (45-85 dB SPL) tested. Also as in humans, thresholds were minimally affected by a challenging roving-level condition with random variation in background-noise level. Many midbrain neurons showed a decreasing response rate as TIN signal-to-noise ratio (SNR) was increased by elevating the tone level, a pattern attributable to amplitude-modulation tuning in these cells and the fact that higher SNR tone-plus-noise stimuli have flatter amplitude envelopes. TIN thresholds of individual neurons were as sensitive as behavioral thresholds under most conditions, perhaps surprisingly even when the unit's characteristic frequency was tuned an octave or more away from the test frequency. A model that combined responses of two cell types enhanced TIN sensitivity in the roving-level condition. These results highlight the importance of midbrain-level envelope encoding and off-frequency neural channels for hearing in noise.SIGNIFICANCE STATEMENT Detection of target sounds in noise is often assumed to depend on energy-level encoding by neural processing channels tuned to the target frequency. In contrast, we found that tone-in-noise sensitivity in budgerigars was often greatest in midbrain neurons not tuned to the test frequency, underscoring the potential importance of off-frequency channels for perception. Furthermore, the results highlight the importance of envelope processing for hearing in noise, especially under challenging conditions with random variation in background noise level over time.

An Actinobacterial Isolate, Streptomyces sp. YX44, Produces Broad-Spectrum Antibiotics That Strongly Inhibit Staphylococcus aureus.

The need for new antibiotics is increasing due to their overuse, and antibiotic resistance has become one of the major threats worldwide to public health, food safety, and clinical treatment. In this study, we describe an actinobacterial isolate, YX44, which belongs to the genus Streptomyces. This Streptomyces was isolated from a drinking pipe located in Osaka, Japan, and has the ability to inhibit Gram-positive bacteria, Gram-negative bacteria, and various fungi. YX44 fermentation broth shows strong activity against Escherichia coli and Staphylococcus aureus, as well as also inhibiting clinical isolates of multidrug-resistant Staphylococcus aureus. The YX44 antibacterial substances in the broth are relatively heat-stable, show high stability from the pH range 1 to 11, and have good solubility in both organic and non-organic solvents. Size-exclusion chromatography revealed that the YX44 antibacterial compounds are less than 1000 Da in size. LC-MS was able to identify three possible candidate molecules with molecular weights of 308, 365, 460, and 653 g/mol; none of these sizes correspond to any well-known antibiotics. Our results show that Streptomyces sp. YX44 seems to produce a number of novel antibiotics with high pH stability and good solubility that have significant activity against S. aureus, including multidrug-resistant strains.

Anti-ATR001 monoclonal antibody ameliorates atherosclerosis through beta-arrestin2 pathway.

BACKGROUND: Our previous study developed ATRQß-001 vaccine, which targets peptide ATR001 from angiotensin Ⅱ (Ang Ⅱ) receptor type 1 (AT1R). The ATRQß-001 vaccine could induce the production of anti-ATR001 monoclonal antibody (McAb-ATR) and inhibit atherosclerosis without feedback activation of the renin-angiotensin system (RAS). This study aims at investigating the underexploited mechanisms of McAb-ATR in ameliorating atherosclerosis. METHODS: AT1R-KO HEK293T cell lines were constructed to identify the specificity of McAb-ATR and key sites of ATRQß-001 vaccine. Beta-arrestin1 knock-out (Arrb1-/-) mice, Beta-arrestin2 knock-out (Arrb2-/-) mice, and low-density lipoprotein receptor knock-out (LDLr-/-) mice were used to detect potential signaling pathways affected by McAb-ATR. The role of McAb-ATR in beta-arrestin and G proteins (Gq or Gi2/i3) signal transduction events was also investigated. RESULTS: McAb-ATR could specifically bind to the Phe182-His183-Tyr184 site of AT1R second extracellular loop (ECL2). The anti-atherosclerotic effect of McAb-ATR disappeared in LDLr-/- mice transplanted with Arrb2-/- mouse bone marrow (BM) and BM-derived macrophages (BMDMs) from Arrb2-/- mice. Furthermore, McAb-ATR inhibited beta-arrestin2-dependent extracellular signal regulated kinase1/2 (ERK1/2) phosphorylation, and promoted beta-arrestin2-mediated nuclear factor kappa B p65 (NFκB p65) inactivity. Compared with conventional AT1R blockers (ARBs), McAb-ATR did not inhibit Ang Ⅱ-induced uncoupling of heterotrimeric G proteins (Gq or Gi2/i3) and Gq-dependent intracellular Ca2+ release, nor cause RAS feedback activation. CONCLUSIONS: Through regulating beta-arrestin2, McAb-ATR ameliorates atherosclerosis without affecting Gq or Gi2/i3 pathways. Due to high selectivity for AT1R and biased interaction with beta-arrestin2, McAb-ATR could serve as a novel strategy for treating atherosclerosis.

PCSK9Qß-003 Vaccine Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice.

PURPOSE: Our group has developed a therapeutic vaccine targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), named PCSK9Qß-003. In this study, we investigated the potential effectiveness of the PCSK9Qß-003 vaccine on atherosclerosis. METHODS: Male ApoE-/- mice were randomly assigned to three groups: a phosphate-buffered saline (PBS) group, Qß virus-like particles (VLP) group, and PCSK9Qß-003 vaccine group. Mice in the PCSK9Qß-003 group were injected with the PCSK9Qß-003 vaccine four times (100 µg/time) over a period of 18 weeks. The effects of the vaccine on atherosclerotic plaque, cholesterol transport, inflammation and apoptosis were investigated. RESULTS: The PCSK9Qß-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in ApoE-/- mice. Compared with the other groups, the PCSK9Qß-003 vaccine significantly reduced the lesion area and promoted the stability of atherosclerotic plaque. The vaccine regulated cholesterol transport in the aorta of ApoE-/- mice by up-regulating the expression level of liver X receptor α and ATP binding cassette transporter A1. Additionally, macrophage infiltration and expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α were significantly decreased in the mice administered the PCSK9Qß-003 vaccine. The vaccine also markedly reduced apoptosis in the lesion area of the aorta in ApoE-/- mice. CONCLUSIONS: The results demonstrated that the PCSK9Qß-003 vaccine attenuated the progression of atherosclerosis by modulating reverse cholesterol transport and inhibiting inflammation infiltration and apoptosis, which may provide a novel therapeutic approach for atherosclerosis and greatly improve treatment compliance among patients.

Effect of long-term growth hormone replacement on glucose metabolism in adults with growth hormone deficiency: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis was performed to summarize the long-term (more than 6 months) effect of growth hormone (GH) replacement therapy (GHRT) on glucose metabolism among adults growth hormone deficiency (AGHD) patients. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library databases from inception till March 2020 for relevant studies evaluating the effect of GHRT on glucose metabolism in AGHD patients. Results were stratified into two periods (6-12 months and more than12 months) according to the length of follow-up. RESULTS: Thirty-three studies including 11 randomized controlled trials (RCTs) and 22 prospective open-label studies (POLs) were included in the meta-analysis. The findings of this meta-analysis showed that GH supplementation with a duration of 6-12 months among adults with growth hormone deficiency (GHD) significantly increased fasting plasma glucose (FPG) (SMD 0.37; 95% CI 0.25 to 0.49; I2 = 0%; P < 0.00001), fasting insulin (FI) (SMD 0.2; 95% CI 0.08 to 0.33; I2 = 9%; P = 0.001), glycated hemoglobin (HbA1c) (SMD 0.31; 95% CI 0.17 to 0.46; I2 = 10%; P < 0.0001) and homeostasis model of assessment-insulin resistance (HOMA-IR) (SMD 0.28; 95% CI 0.08 to 0.47; I2 = 13%; P = 0.006). Notably, GH intervention with a duration of more than 12 months showed no significant effect on FI (SMD 0.14; 95% CI - 0.09 to 0.37; I2 = 0%; P = 0.24), HbA1c (SMD - 0.02; 95% CI - 0.3 to 0.26; I2 = 72%; P = 0.89) and HOMA-IR levels (SMD 0.04; 95% CI - 0.24 to 0.31; I2 = 0%; P = 0.80) in adults with GHD. However, FPG levels in AGHD were still significantly increased with more than one year intervention period (SMD 0.41; 95% CI 0.29 to 0.53; I2 = 0%; P < 0.00001). CONCLUSION: Overall, the current meta-analysis demonstrated that GHRT with a shorter duration (6-12 months) led to a deterioration in glucose metabolism including FPG, FI, HbA1c and HOMA-IR in AGHD patients. However, the negative effects of GH therapy on these glucose homeostasis parameters were not seen in longer duration of GHRT, except for FPG.

Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor-dependent manner.

The angiotensin II type 1 receptor (AT1R) signaling pathway is reported to modulate glucose metabolism. Targeting AT1R, our group invented ATRQß-001 vaccine, a novel immunotherapeutic strategy to block the activation of AT1R. Here, we evaluated the therapeutic efficacy of ATRQß-001 vaccine in insulin resistance, and investigated the mechanism. Our results showed that ATRQß-001 vaccine and specific monoclonal antibody against epitope ATR-001 (McAb-ATR) decreased fasting serum insulin concentration and improved glucose and insulin tolerance in ob/ob mice. These beneficial effects were verified in high-fat diet-induced obese mice. McAb-ATR activated insulin signaling in skeletal muscle and insulin-resistant C2C12 myotubes without affecting liver or white adipose tissue of ob/ob mice. Mechanistically, the favorable impact of McAb-ATR on insulin resistance was abolished in db/db mice and in C2C12 myotubes with leptin receptor knockdown. AT1R knockdown also eradicated the effects of McAb-ATR in C2C12 myotubes. Furthermore, McAb-ATR treatment was able to activate the leptin receptor-mediated JAK2/STAT3 signaling in skeletal muscle of ob/ob mice and C2C12 myotubes. Additionally, angiotensin II downregulated the leptin signaling in skeletal muscle of ob/ob and diet-induced obese mice. We demonstrated that ATRQß-001 vaccine and McAb-ATR improved whole-body insulin resistance and regulated glucose metabolism in skeletal muscle in a leptin receptor-dependent manner. Our data suggest that immunotherapy targeting AT1R is a novel strategy for treating insulin resistance.

The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance.

Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.

Vaccine Against PCSK9 Improved Renal Fibrosis by Regulating Fatty Acid ß-Oxidation.

Background Defects in the renal fatty acid ß-oxidation pathway have been implicated in the development of renal fibrosis. Our group has developed a therapeutic vaccine targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), named PCSK9Qß-003. In this study, we investigated the potential effectiveness of the PCSK9Qß-003 vaccine on hypercholesterolemia with renal fibrosis. Methods and Results The low-density lipoprotein receptor+/- male mice fed with a high-cholesterol (1%) Western diet were randomly assigned into 4 groups: the sham group (or the control group), the phosphate-buffered saline group, the Qß virus-like particles group and the PCSK9Qß-003 vaccine group. Mice of the PCSK9Qß-003 group were injected with the PCSK9Qß-003 vaccine (100 µg/time) every 2 or 4 weeks. The mice were administered with either unilateral ureteral obstruction for 2 weeks or N-nitro-l-arginine methyl ester (50 mg/kg per day) for 6 weeks to establish a renal fibrosis model. Compared with the other 3 groups, the PCSK9Qß-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in low-density lipoprotein receptor+/- mice with hypercholesterolemia. Compared with the phosphate-buffered saline and Qß virus-like particles groups, the PCSK9Qß-003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK9Qß-003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK9Qß-003 vaccine obviously upregulated the expression of low-density lipoprotein receptor, very-low-density lipoprotein receptor, sterol-regulatory element binding protein 2, and fatty acid ß-oxidation-related factors, and ameliorated renal fibrosis-related molecules both in the unilateral ureteral obstruction and N-nitro-l-arginine methyl ester models. Conclusions This study suggested that the PCSK9Qß-003 vaccine improved renal lipid accumulation and renal fibrosis by regulating fatty acid ß-oxidation, which may provide a promising method for treating hypercholesterolemia with renal fibrosis.

ATRQß-001 Vaccine Prevents Experimental Abdominal Aortic Aneurysms.

Background We have developed a peptide vaccine named ATRQß-001, which was proved to retard signal transduction initiated by angiotensin II (Ang II). Ang II was implicated in abdominal aortic aneurysm (AAA) progression, but whether the ATRQß-001 vaccine would prevent AAA is unknown. Methods and Results Ang II-infused ApoE-/- mice and calcium phosphate-induced AAA in C57BL/6 mice were used to verify the efficiency of ATRQß-001 vaccine in AAA. Results demonstrated that the vaccine effectively restrained the aneurysmal dilation and vascular wall destruction of aorta in both animal models, beyond anti-hypertensive effects. In Ang II-induced AAA vascular sections, Immunohistochemical staining showed that the vaccine notably constrained vascular inflammation and vascular smooth muscle cell (VSMC) phenotypic transition, concurrently reduced macrophages infiltration. In cultured VSMC, the anti-ATR-001 antibody inhibited osteopontin secretion induced by Ang II, thereby impeded macrophage migration while co-culture. Furthermore, metalloproteinases and other matrix proteolytic enzymes were also found to be limited by the vaccine in vivo and in vitro. Conclusions ATRQß-001 vaccine prevented AAA initiation and progression in both Ang II and calcium phosphate-induced AAA models. And the beneficial effects were played beyond decrease of blood pressure, which provided a novel and promising method to take precautions against AAA.

Small cell lung cancer starting with diabetes mellitus: Two case reports and literature review.

BACKGROUND: Small-cell lung cancer (SCLC) is a type of fatal tumor that is increasing in prevalence. While these are unpleasant facts to consider, it is vitally important to be informed, and it is important to catch the disease early. Typically, lung cancer does not show severe clinical symptoms in the early stage. Once lung cancer has progressed, patients might present with classical symptoms of respiratory system dysfunction. Thus, the prognosis of SCLC is closely related to the early diagnosis of the disease. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is related to cancer occurrence, especially for SCLC with the presence of Cushing's syndrome, which is dependent on markedly elevated ACTH and cortisol levels. CASE SUMMARY: In the current report, we describe two middle-age patients who were originally diagnosed with diabetes mellitus with no classical symptoms of lung cancer. The patients were eventually diagnosed with SCLC, which was confirmed by bronchoscopic biopsy and histopathology. SCLC-associated diabetes was related to EAS, which was an endogenous ACTH-dependent form of Cushing's syndrome with elevated ACTH and cortisol levels. Multiple organ metastases were found in Patient 1, while Patient 2 retained good health at 2 years follow-up. EAS symptoms including thyroid dysfunction, hypercortisolism and glucose intolerance were all resolved after anticancer treatment. CONCLUSION: In conclusion, SCLC might start with diabetes mellitus and increased cortisol and hypokalemia or other EAS symptoms. These complex clinical features were the most significant factors to deteriorate a patient's condition. Early diagnosis and treatment from clinicians were essential for the anti-cancer treatment for patients with SCLC.

Glucose Metabolism in Turner Syndrome.

Turner syndrome (TS) is one of the most common female chromosomal disorders. The condition is caused by complete or partial loss of a single X chromosome. Adult patients with TS have a high prevalence of diabetes mellitus (DM). Deranged glucose metabolism in this population seems to be genetically triggered. The traditional risk factors for DM in the general population may not play a major role in the pathogenesis of DM in patients with TS. This review focuses on the latest research studies pertaining to abnormalities of glucose metabolism in TS. We extensively review the available evidence pertaining to the influence of insulin secretion and sensitivity, obesity, autoimmunity, lifestyle, growth hormone, and sex hormone replacement therapy on the occurrence of DM in these patients.