Extracorporeal closed-loop respiratory regulation for patients with respiratory difficulty using a soft bionic robot.

OBJECTIVE: Respiratory regulation is critical for patients with respiratory dysfunction. Clinically used ventilators can lead to long-term dependence and injury. Extracorporeal assistance approaches such as iron-lung devices provide a noninvasive alternative, however, artificial actuator counterparts have not achieved marvelous biomimetic ventilation as human respiratory muscles. Here, we propose a bionic soft exoskeleton robot that can achieve extracorporeal closed-loop respiratory regulation by emulating natural human breath. METHODS: For inspiration, a soft vacuum chamber is actuated to produce negative thoracic pressure and thus expand lung volume by pulling the rib cage up and outward through use of external negative pressure. For expiration, a soft origami array under positive pressure pushes the abdominal muscles inward and the diaphragm upward. To achieve in vitro measurement of respiratory profile, we describe a wireless respiratory monitoring device to measure respiratory profiles with high accuracy, validated by quantitative comparisons with spirometer as gold-standard reference. By constructing a human-robot coupled respiratory mechanical model, a model-based proportional controller is designed for continuous tracking of the target respiratory profile. RESULTS: In experiments with ten healthy participants and ten patients with respiratory difficulty, the robot can adjust its assistive forces in real time and drive human-robot coupling respiratory system to track the target profile. CONCLUSION: The biomimetic robot can achieve extracorporeal closed-loop respiratory regulation for a diverse population. SIGNIFICANCE: The soft robot has important potential to assist respiration for people with respiratory difficulty, whether in a hospital or a home setting.

Deciphering the molecular regulatory of RAB32/GPRC5A axis in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a significant public health problem characterized by persistent airflow limitation. Despite previous research into the pathogenesis of COPD, a comprehensive understanding of the cell-type-specific mechanisms in COPD remains lacking. Recent studies have implicated Rab GTPases in regulating chronic immune response and inflammation via multiple pathways. In this study, the molecular regulating mechanism of RAB32 in COPD was investigated by multiple bioinformatics mining and experimental verification. METHODS: We collected lung tissue surgical specimens from Zhongshan Hospital, Fudan University, and RT-qPCR and western blotting were used to detect the expression of Rabs in COPD lung tissues. Four COPD microarray datasets from the Gene Expression Omnibus (GEO) were analyzed. COPD-related epithelial cell scRNA-seq data was obtained from the GSE173896 dataset. Weighted gene co-expression network analysis (WGCNA), mfuzz cluster, and Spearman correlation analysis were combined to obtain the regulatory network of RAB32 in COPD. The slingshot algorithm was used to identify the regulatory molecule, and the co-localization of RAB32 and GPRC5A was observed with immunofluorescence. RESULTS: WGCNA identified 771 key module genes significantly associated with the occurrence of COPD, including five Rab genes. RAB32 was up-regulated in lung tissues from subjects with COPD as contrast to those without COPD on both mRNA and protein levels. Integrating the results of WGCNA, Mfuzz clusters, and Spearman analysis, nine potential interacting genes with RAB32 were identified. Among these genes, GPRC5A exhibited a similar molecular expression pattern to RAB32. Co-expression density analysis at the cell level demonstrated that the co-expression density of RAB32 and GPRC5A was higher in type I alveolar epithelial cells (AT1s) than in type II alveolar epithelial cells (AT2s). The immunofluorescence also confirmed the co-localization of RAB32 and GPRC5A, and the Pearson correlation analysis found the relationship between RAB32 and GPRC5A was significantly stronger in the COPD lungs (r = 0.65) compared to the non-COPD lungs (r = 0.33). CONCLUSIONS: Our study marked endeavor to delineate the molecular regulatory axis of RAB32 in COPD by employing diverse methods and identifying GPRC5A as a potential interacting molecule with RAB32. These findings offered novel perspectives on the mechanism of COPD.

DNA nanoparticles targeting FOXO4 selectively eliminate cigarette smoke-induced senescent lung fibroblasts.

The pathogenesis and development of chronic obstructive pulmonary disease (COPD) are significantly related to cellular senescence. Strategies to eliminate senescent cells have been confirmed to benefit several senescence-related diseases. However, there are few reports of senolytic drugs in COPD management. In this study, we demonstrated elevated FOXO4 expression in cigarette smoke-induced senescent lung fibroblasts both in vitro and in vivo. Additionally, self-assembled DNA nanotubes loaded with single-stranded FOXO4 siRNA (siFOXO4-NT) were designed and synthesized to knockdown FOXO4 in senescent fibroblasts. We found that siFOXO4-NT can concentration- and time-dependently enter human lung fibroblasts (HFL-1 cells), thereby reducing FOXO4 levels in vitro. Most importantly, siFOXO4-NT selectively cleared senescent HFL-1 cells by reducing BCLXL expression and the BCL2/BAX ratio, which were increased in CSE-induced senescent HFL-1 cells. The findings from our work present a novel strategy for senolytic drug development for COPD therapy.

Cleft palate and minor metabolic disturbances in a mouse global Arl15 gene knockout.

ARL15, a small GTPase protein, was linked to metabolic traits in association studies. We aimed to test the Arl15 gene as a functional candidate for metabolic traits in the mouse. CRISPR/Cas9 germline knockout (KO) of Arl15 showed that homozygotes were postnatal lethal and exhibited a complete cleft palate (CP). Also, decreased cell migration was observed from Arl15 KO mouse embryonic fibroblasts (MEFs). Metabolic phenotyping of heterozygotes showed that females had reduced fat mass on a chow diet from 14 weeks of age. Mild body composition phenotypes were also observed in heterozygous mice on a high-fat diet (HFD)/low-fat diet (LFD). Females on a HFD showed reduced body weight, gonadal fat depot weight and brown adipose tissue (BAT) weight. In contrast, in the LFD group, females showed increased bone mineral density (BMD), while males showed a trend toward reduced BMD. Clinical biochemistry analysis of plasma on HFD showed transient lower adiponectin at 20 weeks of age in females. Urinary and plasma Mg2+ concentrations were not significantly different. Our phenotyping data showed that Arl15 is essential for craniofacial development. Adult metabolic phenotyping revealed potential roles in brown adipose tissue and bone development.

Cathepsin B abundance, activity and microglial localisation in Alzheimer's disease-Down syndrome and early onset Alzheimer's disease; the role of elevated cystatin B.

Cathepsin B is a cysteine protease that is implicated in multiple aspects of Alzheimer's disease pathogenesis. The endogenous inhibitor of this enzyme, cystatin B (CSTB) is encoded on chromosome 21. Thus, individuals who have Down syndrome, a genetic condition caused by having an additional copy of chromosome 21, have an extra copy of an endogenous inhibitor of the enzyme. Individuals who have Down syndrome are also at significantly increased risk of developing early-onset Alzheimer's disease (EOAD). The impact of the additional copy of CSTB on Alzheimer's disease development in people who have Down syndrome is not well understood. Here we compared the biology of cathepsin B and CSTB in individuals who had Down syndrome and Alzheimer's disease, with disomic individuals who had Alzheimer's disease or were ageing healthily. We find that the activity of cathepsin B enzyme is decreased in the brain of people who had Down syndrome and Alzheimer's disease compared with disomic individuals who had Alzheimer's disease. This change occurs independently of an alteration in the abundance of the mature enzyme or the number of cathepsin B+ cells. We find that the abundance of CSTB is significantly increased in the brains of individuals who have Down syndrome and Alzheimer's disease compared to disomic individuals both with and without Alzheimer's disease. In mouse and human cellular preclinical models of Down syndrome, three-copies of CSTB increases CSTB protein abundance but this is not sufficient to modulate cathepsin B activity. EOAD and Alzheimer's disease-Down syndrome share many overlapping mechanisms but differences in disease occur in individuals who have trisomy 21. Understanding this biology will ensure that people who have Down syndrome access the most appropriate Alzheimer's disease therapeutics and moreover will provide unique insight into disease pathogenesis more broadly.

ROS induced the Rab26 promoter hypermethylation to promote cigarette smoking-induced airway epithelial inflammation of COPD through activation of MAPK signaling.

Cigarette smoking (CS) exposure-induced airway inflammatory responses drive the occurrence and development of emphysema and chronic obstructive pulmonary disease (COPD). However, its precise mechanisms have not been fully elucidated. In this study, we explore the role of Rab26 in CS exposure modulating the inflammatory response of airway epithelium and the novel mechanism of CS exposure regulation Rab26. These data showed that CS exposure and H2O2 (a type of ROS) suppressed the expression of Rab26 and increased the expression of DNMT3b in vivo and in vitro. GEO data analysis found the level of Rab26 was decreased in the lung tissue of COPD patients. CSE-induced ROS promoted DNA methylation of the Rab26 promoter and inhibited its promoter activity by elevating the DNMT3b level. Antioxidants N-Acetyl-l-cysteine (NAC), 5-Aza-2'-deoxycytidine (5-AZA) (DNA methylation inhibitor) and DNMT3B siRNA alleviated CSE's inhibitory effect on Rab26 expression in vitro. Importantly, NAC alleviated the improved expression of Rab26 and reduced DNMT3B expression, in the airway of smoking exposure as well as attenuated the inflammatory response in vivo. Overexpression of Rab26 attenuated CSE-induced production of inflammatory mediators through part inactivation of p38 and JNK MAPK. On the contrary, silencing Rab26 enhanced p38 and JNK activation and aggravated inflammatory response. These findings suggest that ROS-mediated Rab26 promoter hypermethylation is a critical step in cigarette smoking-induced airway epithelial inflammatory response. Restoring Rab26 in the airway epithelium might be a potential strategy for treating airway inflammation and COPD.

The Clinical Impact of Metagenomic Next-Generation Sequencing (mNGS) Test in Hospitalized Patients with Suspected Sepsis: A Multicenter Prospective Study.

Background: Metagenomic Next Generation Sequencing (mNGS) has the potential to detect pathogens rapidly. We aimed to assess the diagnostic performance of mNGS in hospitalized patients with suspected sepsis and evaluate its role in guiding antimicrobial therapy. Methods: A multicenter, prospective cohort study was performed. We enrolled patients with suspected sepsis, collected clinical characteristics and blood samples, and recorded the 30-day survival. Diagnostic efficacy of mNGS test and blood culture was compared, and the clinical impact of mNGS on antibiotic regimen modification was analyzed. Results: A total of 277 patients were enrolled, and 162 were diagnosed with sepsis. The mortality was 44.8% (121/270). The mNGS test exhibited shorter turn-out time (27.0 (26.0, 29.0) vs. 96.0 (72.0, 140.3) hours, p < 0.001) and higher sensitivity (90.5% vs. 36.0%, p < 0.001) compared with blood culture, especially for fungal infections. The mNGS test showed better performance for patients with mild symptoms, prior antibiotic use, and early stage of infection than blood culture, and was capable of guiding antibiotic regimen modification and improving prognosis. Higher reads of pathogens detected by mNGS were related to 30-day mortality (p = 0.002). Conclusions: Blood mNGS testing might be helpful for early etiological diagnosis of patients with suspected sepsis, guiding the antibiotic regimen modification and improving prognosis.

Prevention of exacerbation in patients with moderate-to-very severe COPD with the intent to modulate respiratory microbiome: a pilot prospective, multi-center, randomized controlled trial.

Introduction: Considering the role of bacteria in the onset of acute exacerbation of COPD (AECOPD), we hypothesized that the use of influenza-Streptococcus pneumoniae vaccination, oral probiotics or inhaled amikacin could prevent AECOPD. Methods: In this pilot prospective, muti-central, randomized trial, moderate-to-very severe COPD subjects with a history of moderate-to-severe exacerbations in the previous year were enrolled and assigned in a ratio of 1:1:1:1 into 4 groups. All participants were managed based on the conventional treatment recommended by GOLD 2019 report for 3 months, with three groups receiving additional treatment of inhaled amikacin (0.4 g twice daily, 5-7 days monthly for 3 months), oral probiotic Lactobacillus rhamnosus GG (1 tablet daily for 3 months), or influenza-S. pneumoniae vaccination. The primary endpoint was time to the next onset of moderate-to-severe AECOPD from enrollment. Secondary endpoints included CAT score, mMRC score, adverse events, and survival in 12 months. Results: Among all 112 analyzed subjects (101 males, 96 smokers or ex-smokers, mean ± SD age 67.19 ± 7.39 years, FEV1 41.06 ± 16.09% predicted), those who were given dual vaccination (239.7 vs. 198.2 days, p = 0.044, 95%CI [0.85, 82.13]) and oral probiotics (248.8 vs. 198.2 days, p = 0.017, 95%CI [7.49, 93.59]) had significantly delayed onset of next moderate-to-severe AECOPD than those received conventional treatment only. For subjects with high symptom burden, the exacerbations were significantly delayed in inhaled amikacin group as compared to the conventional treatment group (237.3 vs. 179.1 days, p = 0.009, 95%CI [12.40,104.04]). The three interventions seemed to be safe and well tolerated for patient with stable COPD. Conclusion: The influenza-S. pneumoniae vaccine and long-term oral probiotic LGG can significantly delay the next moderate-to-severe AECOPD. Periodically amikacin inhalation seems to work in symptomatic patients. The findings in the current study warrants validation in future studies with microbiome investigation.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT03449459.

Genetic evidence on the causality between gut microbiota and various asthma phenotypes: a two-sample Mendelian randomization study.

Introduction: Asthma is a multifarious disease that manifests in various phenotypes. Among the various factors that contribute to the development of asthma, the gut microbiota has recently emerged as a compelling area of investigation. This study aims to investigate the causal relationships between gut microbiota and distinct asthma phenotypes. Methods: The genome-wide association study (GWAS) summary statistics for 211 gut microbial taxa were used as study exposure. Five traits pertaining to various asthma phenotypes (asthma, allergic asthma, childhood asthma, suggestive for eosinophilic asthma and obesity-related asthma) were included as study outcome. We conducted Mendelian randomization (MR) analysis and sensitivity analysis for each bacterial taxa and asthma phenotypes. Result: We discovered a total of 58 associations that exhibited evidence of causality. Out of these, 4 associations remained significant even after applying multiple correction. An increased risk of asthma was causally associated with higher abundance of genus Holdemanella (OR = 1.11; CI: 1.05-1.17; p = 0.027), genus Oxalobacter (OR = 1.09; CI: 1.04-1.15; p = 0.025) and genus Butyricimonas (OR = 1.14; CI: 1.06-1.22; p = 0.027). Order NB1n was causally linked with an increased risk of obesity-related asthma (OR = 1.17; CI: 1.07-1.29; p = 0.015). There was limited overlap among the taxa that exhibited potential causal relationships with distinct asthma phenotypes. Conclusion: Our research has provided genetic evidence that establishes multiple causal relationships between the gut microbiota and distinct asthma phenotypes, supporting the role of the gut microbiota in various asthma phenotypes. It is possible that different taxa play a role in the development of distinct asthma phenotypes. The causal relationships identified in this study require further investigation.

Cell models for Down syndrome-Alzheimer's disease research.

Down syndrome (DS) is the most common chromosomal abnormality and leads to intellectual disability, increased risk of cardiac defects, and an altered immune response. Individuals with DS have an extra full or partial copy of chromosome 21 (trisomy 21) and are more likely to develop early-onset Alzheimer's disease (AD) than the general population. Changes in expression of human chromosome 21 (Hsa21)-encoded genes, such as amyloid precursor protein (APP), play an important role in the pathogenesis of AD in DS (DS-AD). However, the mechanisms of DS-AD remain poorly understood. To date, several mouse models with an extra copy of genes syntenic to Hsa21 have been developed to characterise DS-AD-related phenotypes. Nonetheless, due to genetic and physiological differences between mouse and human, mouse models cannot faithfully recapitulate all features of DS-AD. Cells differentiated from human-induced pluripotent stem cells (iPSCs), isolated from individuals with genetic diseases, can be used to model disease-related cellular and molecular pathologies, including DS. In this review, we will discuss the limitations of mouse models of DS and how these can be addressed using recent advancements in modelling DS using human iPSCs and iPSC-mouse chimeras, and potential applications of iPSCs in preclinical studies for DS-AD.

Palmitoylated small GTPase ARL15 is translocated within Golgi network during adipogenesis.

The small GTPase ARF family member ARL15 gene locus is associated in population studies with increased risk of type 2 diabetes, lower adiponectin and higher fasting insulin levels. Previously, loss of ARL15 was shown to reduce insulin secretion in a human ß-cell line and loss-of-function mutations are found in some lipodystrophy patients. We set out to understand the role of ARL15 in adipogenesis and showed that endogenous ARL15 palmitoylated and localised in the Golgi of mouse liver. Adipocyte overexpression of palmitoylation-deficient ARL15 resulted in redistribution to the cytoplasm and a mild reduction in expression of some adipogenesis-related genes. Further investigation of the localisation of ARL15 during differentiation of a human white adipocyte cell line showed that ARL15 was predominantly co-localised with a marker of the cis face of Golgi at the preadipocyte stage and then translocated to other Golgi compartments after differentiation was induced. Finally, co-immunoprecipitation and mass spectrometry identified potential interacting partners of ARL15, including the ER-localised protein ARL6IP5. Together, these results suggest a palmitoylation dependent trafficking-related role of ARL15 as a regulator of adipocyte differentiation via ARL6IP5 interaction. This article has an associated First Person interview with the first author of the paper.

The effects of Cstb duplication on APP/amyloid-ß pathology and cathepsin B activity in a mouse model.

People with Down syndrome (DS), caused by trisomy of chromosome 21 have a greatly increased risk of developing Alzheimer's disease (AD). This is in part because of triplication of a chromosome 21 gene, APP. This gene encodes amyloid precursor protein, which is cleaved to form amyloid-ß that accumulates in the brains of people who have AD. Recent experimental results demonstrate that a gene or genes on chromosome 21, other than APP, when triplicated significantly accelerate amyloid-ß pathology in a transgenic mouse model of amyloid-ß deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-ß accumulation. Located on human chromosome 21 (Hsa21) is an endogenous inhibitor of cathepsin proteases, CYSTATIN B (CSTB) which is proposed to regulate cysteine cathepsin activity in vivo. Here we determined if three copies of the mouse gene Cstb is sufficient to modulate amyloid-ß accumulation and cathepsin activity in a transgenic APP mouse model. Duplication of Cstb resulted in an increase in transcriptional and translational levels of Cstb in the mouse cortex but had no effect on the deposition of insoluble amyloid-ß plaques or the levels of soluble or insoluble amyloid-ß42, amyloid-ß40, or amyloid-ß38 in 6-month old mice. In addition, the increased CSTB did not alter the activity of cathepsin B enzyme in the cortex of 3-month or 6-month old mice. These results indicate that the single-gene duplication of Cstb is insufficient to elicit a disease-modifying phenotype in the dupCstb x tgAPP mice, underscoring the complexity of the genetic basis of AD-DS and the importance of multiple gene interactions in disease.

A Circulating Exosome RNA Signature Is a Potential Diagnostic Marker for Pancreatic Cancer, a Systematic Study.

Several exosome proteins, miRNAs and KRAS mutations have been investigated in the hope of carrying out the early detection of pancreatic cancer with high sensitivity and specificity, but they have proven to be insufficient. Exosome RNAs, however, have not been extensively evaluated in the diagnosis of pancreatic cancer. The purpose of this study was to investigate the potential of circulating exosome RNAs in pancreatic cancer detection. By retrieving RNA-seq data from publicly accessed databases, differential expression and random-effects meta-analyses were performed. The results showed that pancreatic cancer had a distinct circulating exosome RNA signature in healthy individuals, and that the top 10 candidate exosome RNAs could distinguish patients from healthy individuals with an area under the curve (AUC) of 1.0. Three (HIST2H2AA3, LUZP6 and HLA-DRA) of the 10 genes in exosomes had similar differential patterns to those in tumor tissues based on RNA-seq data. In the validation dataset, the levels of these three genes in exosomes displayed good performance in distinguishing cancer from both chronic pancreatitis (AUC = 0.815) and healthy controls (AUC = 0.8558), whereas a slight difference existed between chronic pancreatitis and healthy controls (AUC = 0.586). Of the three genes, the level of HIST2H2AA3 was positively associated with KRAS status. However, there was no significant difference in the levels of the three genes across the disease stages (stages I-IV). These findings indicate that circulating exosome RNAs have a potential early detection value in pancreatic cancer, and that a distinct exosome RNA signature exists in distinguishing pancreatic cancer from healthy individuals.

Respiratory Aspergillus Colonization Was Associated With Relapse of Acute Exacerbation in Patients With Chronic Obstructive Pulmonary Disease: Analysis of Data From A Retrospective Cohort Study.

Background: Patients with chronic obstructive pulmonary disease (COPD) are more susceptible to Aspergillus colonization or infection. Several studies have demonstrated that invasive pulmonary Aspergillosis (IPA) and Aspergillus hypersensitivity (AH) have a detrimental effect on COPD. However, it remains to be clarified whether Aspergillus colonization is associated with acute exacerbation of COPD (AECOPD). This study aimed to explore the impact of Aspergillus colonization in the lower respiratory tract on AECOPD. Method: Patients with Aspergillus colonization were identified from a retrospective cohort of hospitalized AECOPD from 2011 to 2016 in eight centers in Shanghai, China. The demographic information, conditions of the stable stage, clinical characteristics during hospitalization, and 1-year follow-up information after discharge were collected and compared to participants without fungi colonization. Result: Twenty-six hospitalized AECOPD patients with Aspergillus colonization and 72 controls were included in the final analysis after excluding patients with other fungi isolation and matching. The rates of recurrence of acute exacerbation within 90 days and 180 days after discharge in the patients with Aspergillus colonization were both significantly higher than that in the fungi negative patients (90 days: 19.2 vs. 4.2%, p = 0.029; 180 days: 23.1 vs. 4.2%, p = 0.010), and the all-cause mortality within 1 year was also higher (11.5 vs. 0.0%, p = 0.017). Multivariate logistic regression analysis showed that Aspergillus colonization was an independent risk factor for the recurrence of acute exacerbation within 90 days and 180 days (90 days: OR = 8.661, 95% CI: 1.496-50.159, p = 0.016; 180 days: OR =10.723, 95% CI: 1.936-59.394, p = 0.007). Conclusion: Aspergillus colonization may predict poor prognosis of AECOPD while leading to an increased risk of recurrent AECOPD in a short period.

Syndecan-1 and KRAS Gene Expression Signature Associates With Patient Survival in Pancreatic Cancer.

OBJECTIVES: The purpose of this study was to investigate the association of syndecan-1 (SDC1) and KRAS molecular characteristics with patient survival in pancreatic cancer. METHODS: Both SDC1 mRNA and methylation and KRAS mRNA and somatic mutations, as well as clinical data were retrieved from The Cancer Genome Alta pancreatic cancer data set for survival analyses. Kyoto Encyclopedia of Gene and Genomes pathway analysis for coexpressed genes for either SDC1 or KRAS was performed, respectively. RESULTS: A significantly negative correlation existed between SDC1 mRNA and DNA methylation. Patients with KRAS somatic mutations had a significantly higher SDC1 mRNA but lower methylation than those without the mutations. Compared with patients with KRASSDC1 signature, those with a high level of KRAS and SDC1 alone or both had a significantly elevated mortality. The adjusted hazard ratios (95% confidence interval) were 2.30 (1.16-4.54, P = 0.017) for KRASSDC1, 2.85 (1.48-5.49, P = 0.002) for KRASSDC1, and 2.48 (1.31-4.70, P = 0.005) for KRASSDC1, respectively. Several Kyoto Encyclopedia of Gene and Genomes pathways were shared, whereas there were distinct pathways between KRAS and SDC1 coexpressed genes. CONCLUSIONS: SDC1 interplays with KRAS, and targeting both KRAS and SDC1 in combination may be more beneficial to pancreatic cancer patients.

How Does Diabetes Impair Penile Tissues during Erectile Dysfunction?

BACKGROUND: Erectile dysfunction (ED) is a significant but underestimated complication during diabetes mellitus (DM). Currently, few special treatments are available clinically due to the lack of specific therapeutic targets. Genomic analysis can be helpful to find potential targets. In this study, the gene expression under diabetic ED condition was analyzed using a gene array, and the significance of the outcomes was evaluated through clinical data. METHODS: The expressions of 15923 genes were analyzed using R software. Differential expression genes (DEGs) were identified through the constructed volcano plot. The function enrichment of Gene Ontology (GO) and KEGG was screened with the DAVID online tool. The interaction between these DEGs was revealed through constructing a protein-protein interaction network and the hub genes were uncovered using the STRING and Cytoscape tool. Lastly, the data of diabetic ED patients were applied to verify the bioinformatics findings. RESULTS: The study showed that 75 genes in the rat penile tissues were upregulated, while 97 genes were downregulated on the diabetic ED condition. These genes were mainly involved in extracellular matrix composition, collagen fibril organization, as well as protein digestion & absorption. Additionally, insulin-related signaling pathways were affected. The clinical analysis indicated that insulin resistance was associated with the diabetic ED severity. Notably, the bioinformatics analysis also suggested that ferroptosis pathway was probably activated under the diabetic ED condition. CONCLUSION: The impaired protein synthesis induced by deficient insulin signaling is an important cause of the diabetic ED. The improvement of protein synthesis through restoring insulin function may be potentially useful for diabetic ED therapy.

Nerve Growth Factor Improves the Outcome of Type 2 Diabetes-Induced Hypotestosteronemia and Erectile Dysfunction.

Hypotestosterone and erectile dysfunction (ED) occur frequently in males with type 2 diabetes. It is still clinically challenging to manage diabetes-induced ED. Here, we conducted a 2-arm randomized clinical study and in vitro cell line experiments to investigate the effects of nerve growth factor (NGF) on serum testosterone and ED in diabetic males with sensorimotor polyneuropathy and to identify its underlying mechanisms. The analyses of serum total testosterone (TT) and free testosterone (FT), and 5-item version of the International Index of Erectile Function (IIEF-5) score at baseline and after treatment show increases in TT (3.90 nmol/L, 95% confidence interval [CI]: 3.13-4.66 nmol/L vs 1.21 nmol/L [95% CI: 0.57-1.85 nmol/L]), FT (3.79 pg/mL [95% CI: 3.05-4.54 pg/mL] vs 1.27 pg/mL [95% CI: 0.85-1.70 pg/mL]), and IIEF-5 score (1.84 [95% CI: 1.21-2.47] vs 0.24 [95% CI: -0.24 to 0.73]) in the NGF treatment compared controls ( P < .005). In mouse Leydig cells, NGF significantly ameliorated the hyperglycemia-induced downregulation of steroidogenic acute regulatory protein and cytochrome P450 11A1 ( P < .05). Thus, NGF treatment effectively improves type 2 diabetes-induced hypotestosterone and ED outcome through a mechanism that includes upregulation of key enzymes in testosterone biosynthesis.

Plasma glucose to glycated hemoglobin ratio: Method of differentiating fulminant type 1 diabetes from diabetic ketoacidosis.

OBJECTIVES: In fulminant type 1 diabetes mellitus (fT1DM), plasma glucose (PG) levels are strongly increased, unlike glycated hemoglobin (HbA1C) levels, resulting in a sharply increased PG/HbA1C ratio. We investigated the PG/HbA1C ratio in fT1DM and tested the accuracy of cutoff points to easily and efficiently differentiate fT1DM from diabetic ketoacidosis (DKA). METHODS: We report 41 cases of fT1DM in which PG/HbA1C ratio was studied as a novel clinical parameter to predict fT1DM. Clinical and biochemical characteristics were analyzed in 41 fT1DM and 51 DKA patients in China. Receiver-operating characteristic curve analysis was used to identify PG/HbA1C ratio cutoff points to differentiate fT1DM from DKA. RESULTS: PG/HbA1C ratio was significantly higher in fT1DM patients (7.24±2.49mmol/L/%; i.e., 0.88±0.36L/mol) than in DKA patients (2.60±0.69mmol/L/%; i.e., 0.06±0.01L/mol) (P<0.001). PG/HbA1C ratio exceeded 4.2mmol/L/% (i.e., 0.6 l/mol) in 39 of the 41 fT1DM patients (95.1%), versus only 1 of the 51 DKA patients (1.9%). CONCLUSIONS: PG/HbA1C ratio is a simple tool that may be useful to identify DKA patients at high risk of fT1DM. PG/HbA1C ratio with a threshold of≥4.2mmol/L/% (i.e., 0.6L/mol) can be adopted as a new clinical parameter in predicting fT1DM.