Monitoring the Mitochondrial Viscosity Changes During Cuproptosis with Iridium(III) Complex Probe via In Situ Phosphorescence Lifetime Imaging.

Cuproptosis is a novel copper-dependent form of programmed cell death, displaying important regulatory functions in many human diseases, including cancer. However, the relationship between the changes in mitochondrial viscosity, a key factor associated with cellular malfunction, and cuproptosis is still unclear. Herein, we prepared a phosphorescent iridium (Ir) complex probe for precisely monitoring the changes of mitochondrial viscosity during cuprotosis via phosphorescence lifetime imaging. The Ir complex probe possessed microsecond lifetimes (up to 1 µs), which could be easily distinguished from cellular autofluorescence to improve the imaging contrast and sensitivity. Benefiting from the long phosphorescence lifetime, excellent viscosity selectivity, and mitochondrial targeting abilities, the Ir complex probe could monitor the increase in the mitochondrial viscosity during cuproptosis (from 46.8 to 68.9 cP) in a quantitative manner. Moreover, through in situ fluorescence imaging, the Ir complex probe successfully monitored the increase in viscosity in zebrafish treated with lipopolysaccharides or elescolomol-Cu2+, which were well-known cuproptosis inducers. We anticipate that this new Ir complex probe will be a useful tool for in-depth understanding of the biological effects of mitochondrial viscosity during cuproptosis.

Choroid plexus enlargement in amyotrophic lateral sclerosis patients and its correlation with clinical disability and blood-CSF barrier permeability.

BACKGROUND: Using in vivo neuroimaging techniques, growing evidence has demonstrated that the choroid plexus (CP) volume is enlarged in patients with several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. However, although animal and postmortem findings suggest that CP abnormalities are likely important pathological mechanisms underlying amyotrophic lateral sclerosis (ALS), the third most common neurodegenerative disease, no available study has been conducted to thoroughly assess CP abnormalities and their clinical relevance in vivo in ALS patients to date. Thus, we aimed to determine whether in vivo CP enlargement may occur in ALS patients. We also aimed to identify the relationships of CP volume with clinical disabilities and blood-CSF barrier (BCSFB) permeability in ALS patients. METHODS: In this retrospective study, based on structural MRI data, CP volume was assessed using a Gaussian mixture model and underwent further manual correction in 155 ALS patients and 105 age- and sex-matched HCs from October 2021 to April 2023. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess clinical disability. The CSF/serum albumin quotient (Qalb) was used to assess BCSFB permeability. Moreover, all the ALS patients completed genetic testing, and according to genetic testing, the ALS patients were further divided into genetic ALS subgroup and sporadic ALS subgroup. RESULTS: We found that compared with HCs, ALS patients had a significantly higher CP volume (p < 0.001). Moreover, compared with HCs, CP volume was significantly increased in both ALS patients with and without known genetic mutations after family-wise error correction (p = 0.006 and p < 0.001, respectively), while there were no significant differences between the two ALS groups. Furthermore, the CP volume was significantly correlated with the ALSFRS-r score (r = -0.226; p = 0.005) and the Qalb (r = 0.479; p < 0.001) in ALS patients. CONCLUSION: Our study first demonstrates CP enlargement in vivo in ALS patients, and continues to suggest an important pathogenetic role for CP abnormalities in ALS. Moreover, assessing CP volume is likely a noninvasive and easy-to-implement approach for screening BCSFB dysfunction in ALS patients.

Effects of Aromatherapy Massage Combined with TCM Emotional Release Technique on Maternal and Neonatal Physical and Mental Health and Family Relationship in Patients with Postpartum Depression.

Objective: To explore the effects of aromatherapy massage combined with TCM emotional release technique on maternal and neonatal physical and mental health and family relationships in patients with postpartum depression. Methods: A The total number of participants in the study was 160, who were evenly distributed through random assignment into four groups of 40 in each group. This random assignment process was designed to ensure that each group was similar in terms of demographic characteristics and other potential confounding factors to increase the comparability and internal validity of the study. The 160 patients with postpartum depression admitted to the obstetrics department of the Hebei 3a Hospital were enrolled between April 2021 and May 2022, and they were randomly divided into control group, sweet orange aromatherapy massage group, emotional release technique group and combination group, 40 cases in each group. The negative emotions, stress state, mania, levels of neurotransmitters and family intimacy adaptability were compared in the four groups before and after intervention. Results: After the intervention, scores of a generalized anxiety disorder (GAD-7) and Edinburgh Postpartum Depression Scale (EPDS) in the combination group were higher than those in the other three groups, and were higher in the emotional release technique group and sweet orange aromatherapy massage group than control group (P < .05). After the intervention, scores of PTSD Checklist-Civilian Version (PCL) and 32-item hypomania checklist (HCL-32) were the highest in the control group, followed by the sweet orange aromatherapy massage group, emotional release technique group and combination group (P < .05). After the intervention, levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) were the highest in the combination group, followed by the emotional release technique group, sweet orange aromatherapy massage group, and control group (P < .05), and adaptability level of family intimacy was also in the same order (P < .05). In the combined treatment group, generalized anxiety disorder score (GAD-7) and postpartum depression scale (EPDS) scores were increased compared with the control group, indicating increased symptom severity in these two areas. GAD-7 and EPDS scores also increased significantly in the emotional release technique group and the sweet orange aromatherapy massage group. Although the magnitude of the increase may be different, both interventions seemed to lead to an increase in anxiety and depressive symptoms. As the intervention progressed, the control group had the highest scores on the Post-Traumatic Stress Disorder Checklist-Citizen Version (PCL) and the Hyperactivity Checklist 32 (HCL-32), followed by the Sweet Orange Aromatherapy Massage Group and the Emotional Release Technique group and combined treatment group. This indicates that symptom severity was significantly higher in the control group than in the other intervention groups in both areas. Levels of serotonin (5-HT) and dopamine (DA) increased in different groups, the highest in the combined treatment group, followed by the emotional release technique group, sweet orange aromatherapy massage group and the control group. This may indicate that the combination treatment had a positive effect on modulating the levels of these neurotransmitters. The adaptation level of family intimacy also changed according to the same trend. The highest level was in the combined treatment group, followed by the emotional release technique group, the sweet orange aromatherapy massage group and the control group. This may mean that combined treatment has a positive impact on the adaptability of family relationships. Conclusion: Aromatherapy massage combined with an emotional release technique can reduce negative emotions, stress, and mania, improve positive emotions and family intimacy adaptability of patients. These findings have important clinical implications as they relate to the well-being of women and families in the postpartum period. Reducing negative emotions and stress will improve women's mental health and improve their quality of life. In addition, positive emotional support helps create a healthy family atmosphere and has a positive impact on society as a whole.

Interaction between COVID-19 and epilepsy during the omicron surge: A cross-sectional survey conducted in China tertiary hospital.

Objective: It is unclear whether patients with epilepsy are more susceptible to SARS-CoV-2 infection, whether they experience more severe manifestations of COVID-19, and whether seizures worsen after SARS-CoV-2 infection. Our study aims to explore these points and provide comprehensive and practical guidance for patients with epilepsy. Methods: We designed a questionnaire to collect variables from epilepsy patients. We used the Chi-square test, Fisher's exact test, or Mann-Whitney U test to analyze differences between the two groups. Multiple logistic regressions were employed to determine the risk factors for relevant outcome variables. Results: We identified a total of 181 patients, with 74% (n = 134) reporting COVID-19. The patients' educational level was found to be a risk factor for COVID-19 (OR = 0.33, 95% CI 0.14-0.80, P = 0.013). When comparing seizure frequency changes between epilepsy patients with and without COVID-19, no statistically significant difference was observed (P > 0.05). However, an increase in seizure frequency was significantly associated with higher levels of anxiety (P < 0.001) and depression (P < 0.005). Conclusion: The risk of COVID-19 infection may be increased in patients with epilepsy. COVID-19 infection does not seem to worsen seizures in epilepsy patients. Patients with epilepsy rarely develop more severe clinical manifestations of COVID-19 after SARS-CoV-2 infection. During the COVID-19 pandemic, patients with epilepsy who also suffer from anxiety and depression may experience an increase in the frequency of their seizures.

The relationship between the number of CAG repeats and clinical manifestations: a survey of Chinese DRPLA family.

OBJECTIVE: To describe the clinical, radiological, and genetic characteristics of a Chinese family with dentatorubropallidoluysian atrophy (DRPLA). Explore the distribution of CAG repeat size to the clinical features of patients. METHODS: We collected the clinical symptoms and DNA analysis for the DRPLA gene was performed on the family members. DRPLA patients reported in the literature were reviewed to analyze the association between CAG repeat size and clinical features. RESULTS: Six family members were confirmed by genetic analysis. The number of CAG repeat in the proband, her sister, her grandmother, her father, her uncle, and her cousin, was determined respectively as 63, 75, 50, 50, 50, 54. In our family, the sister of the proband had the earliest onset age and the most severe clinical symptoms, followed by the proband, and other family members showed no obvious clinical symptoms. Consistent with the conclusion of previous studies, the more repeats CAG, the earlier the age of onset and the severer phenotypes are. CONCLUSION: We found six family members have CAG repeat expansion in the DRPLA gene on chromosome 12p13. Even in the same family, patients have different clinical presentations. The size of CAG repeats is negatively correlated with the age of onset and positively correlated with symptom severity. When the number of repeats is ≥ 63, the age at onset is < 21 years old, and obvious clinical symptoms generally appear. It seems to say the more repeats CAG, the earlier the age of onset and the severer phenotypes are. LIMITATIONS: With a small number of cases in our family, the conclusion that the more CAG repeats, the earlier the onset and the more severe the clinical symptoms cannot be fully proved.

Predictive role of blood-based indicators in neuromyelitis optica spectrum disorders.

Introduction: This study aimed to assess the predictive role of blood markers in neuromyelitis optica spectrum disorders (NMOSD). Methods: Data from patients with NMOSD, multiple sclerosis (MS), and healthy individuals were retrospectively collected in a 1:1:1 ratio. The expanded disability status scale (EDSS) score was used to assess the severity of the NMOSD upon admission. Receiver operating characteristic (ROC) curve analysis was used to distinguish NMOSD patients from healthy individuals, and active NMOSD from remitting NMOSD patients. Binary logistic regression analysis was used to evaluate risk factors that could be used to predict disease recurrence. Finally, Wilcoxon signed-rank test or matched-sample t-test was used to analyze the differences between the indicators in the remission and active phases in the same NMOSD patient. Results: Among the 54 NMOSD patients, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) (platelet × NLR) were significantly higher than those of MS patients and healthy individuals and positively correlated with the EDSS score of NMOSD patients at admission. PLR can be used to simultaneously distinguish between NMOSD patients in the active and remission phase. Eleven (20.4%) of the 54 patients had recurrence within 12 months. We found that monocyte-to-lymphocyte ratio (MLR) (AUC = 0.76, cut-off value = 0.34) could effectively predict NMOSD recurrence. Binary logistic regression analysis showed that a higher MLR at first admission was the only risk factor for recurrence (p = 0.027; OR = 1.173; 95% CI = 1.018-1.351). In patients in the relapsing phase, no significant changes in monocyte and lymphocyte count was observed from the first admission, whereas patients in remission had significantly higher levels than when they were first admitted. Conclusion: High PLR is a characteristic marker of active NMOSD, while high MLR is a risk factor for disease recurrence. These inexpensive indicators should be widely used in the diagnosis, prognosis, and judgment of treatment efficacy in NMOSD.

Efficacy, tolerability and safety of perampanel in children and adolescents with epilepsy: Systematic review and meta-analysis.

OBJECTIVE: Perampanel (PER) is a novel antiepileptic drug. The efficacy, tolerability and safety of PER in children and adolescents with epilepsy are still unclear. We aimed to study the efficacy and safety of PER in children and adolescents with epilepsy. METHODS: We searched PubMed, Embase and Cochrane Library for relevant literature up to November 2022. Then we extracted the relevant data from eligible literature for systematic review and meta-analysis. RESULT: Twenty-one studies involving 1968 children and adolescent patients were included. A reduction in seizure frequency of at least 50 percent occurred in 51.5% (95% confidence interval [CI] [47.1%, 55.9%]) of patients. Complete seizure cessation occurred in 20.6% (95%CI [16.7%, 25.4%]). The incidence of adverse events was 40.8% (95%CI [33.8%, 48.2%]). The most common adverse events were drowsiness 15.3% (95% CI [13.7%, 16.9%]), irritability 9.3% (95%CI [8.0%, 10.6%]), dizziness 8.4% (95% CI [7.2%, 9.7%]). The incidence of drug discontinuation due to adverse events was 9.2% (95% CI [7.0%, 11.5%]). CONCLUSION: PER is generally well tolerated and effective in the treatment of epilepsy in children and adolescents. Larger studies are still needed to explore the application of PER in children and adolescents. RISK OF BIAS AND LIMITATION: The funnel plot suggests that there may be publication bias in our meta-analysis, and most of the included studies were Asian, so there may be some racial differences.

Effect of Multimodal Health Education Combined with the Feedback Method in Perioperative Patients with Lung Cancer: A Randomised Controlled Study.

Objective: To explore the effect of multimodal health education combined with a feedback method in perioperative patients with lung cancer. Methods: A total of 200 lung cancer patients were divided into the observation group and the control group. The observation group adopted the multimodal health education combined with the feedback method, and the control group adopted the conventional health education model. The postoperative extubation time, length of hospital stay, time to first leaving the bed, postoperative exercise compliance, emotional-distress index and patient satisfaction were compared between the two groups. Results: The postoperative extubation time (2.80 ± 1.03 days), the emotional-distress index (8.26 ± 3.01) and the time to first leaving the bed (23.74 ± 11.87 h) were all lower in the observation group than in the control group, with a statistically significant difference (P < 0.05). The postoperative exercise compliance (49.69 ± 3.60) and patient satisfaction (98.32 ± 1.66) values were higher in the observation group than in the control group, with statistically significant differences (P < 0.05). Conclusion: Multimodal health education combined with the feedback method can improve the postoperative exercise compliance of lung cancer patients, reduce their postoperative rehabilitation time and improve their postoperative psychological state and satisfaction, which is in line with the concept of promoting the enhanced recovery of lung cancer patients.

An Evidence-Based Nursing Intervention Decreases Anxiety, Depression, Sleep Quality and Somatic Symptoms of Patients with Acute Ischemic Stroke.

Purpose: This study aimed to explore the effects of evidence-based nursing (EBN) intervention on anxiety, depression, sleep quality and somatic symptoms of patients with acute ischemic stroke (AIS). Methods: The eligible AIS patients were randomized into the intervention group and control group in a 1:1 ratio. Patients in both groups received routine nursing care. On the basis of routine nursing, patients in the intervention group also received EBN. Self-rating anxiety scale (SAS), self-rating depression scale (SDS), Pittsburgh Sleep Quality Index (PSQI), and the Patient Health Questionnaire-15 (PHQ-15) were used to assess patients' anxiety, depression, sleep quality, and somatic symptoms at baseline (T0) and 6 months after intervention (T1), respectively. Results: There was no difference in SAS, SDS, PSQI, and PHQ-15 scores at T0 between the 2 groups (all P > 0.05). Comparing to the control group, the intervention group had significantly lower SAS and SDS scores at T1 (P = 0.002, P < 0.001, respectively). The SAS and SDS score changes (T1-T0) were more evident in the intervention group than in the control group (all P < 0.001). No difference of PSQI or PHQ-15 score between the 2 groups was observed at T1. However, the PSQI and PHQ-15 score changes were more evident in the intervention group than in the control group (P = 0.044 and P = 0.007, respectively). Conclusion: EBN invention significantly improved anxiety, depression, sleep quality and somatic symptoms of patients with AIS.

Diphenyl Diselenide Alleviates Tert-Butyl Hydrogen Peroxide-Induced Oxidative Stress and Lipopolysaccharide-Induced Inflammation in Rat Glomerular Mesangial Cells.

Hyperglycemia, oxidative stress, and inflammation play key roles in the onset and development of diabetic complications such as diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple organic selenium compound with anti-hyperglycemic, anti-inflammatory, and anti-oxidative activities. Nevertheless, in vitro, the role and molecular mechanism of DPDS on DN remains unknown. Therefore, we investigated the effects of DPDS on tert-butyl hydrogen peroxide (t-BHP)-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation in rat glomerular mesangial (HBZY-1) cells and explored the underlying mechanisms. DPDS attenuated t-BHP-induced cytotoxicity, concurrent with decreased intracellular ROS and MDA contents and increased SOD activity and GSH content. Moreover, DPDS augmented the protein and mRNA expression of Nrf2, HO-1, NQO1, and GCLC in t-BHP-stimulated HBZY-1 cells. In addition, DPDS suppressed LPS-induced elevations of intracellular content and mRNA expression of interleukin (IL)-6, IL-1ß and TNF-α. Furthermore, LPS-induced NFκB activation and high phosphorylation of JNK and ERK1/2 were markedly suppressed by DPDS in HBZY-1 cells. In summary, these data demonstrated that DPDS improves t-BHP-induced oxidative stress by activating the Nrf2/Keap1 pathway, and also improves LPS-induced inflammation via inhibition of the NFκB/MAPK pathways in HBZY-1 cells, suggesting that DPDS has the potential to be developed as a candidate for the prevention and treatment of DN.

O-GlcNAc Transferase (OGT) Protects Cerebral Neurons from Death During Ischemia/Reperfusion (I/R) Injury by Modulating Drp1 in Mice.

Previous studies have demonstrated that increased O-linked N-acetylglucosamine (O-GlcNAc) level could promote cell survival following environmental stresses. This study aimed to explore the role of O-GlcNAc transferase (OGT) during cerebral ischemia/reperfusion (I/R) injury. The mouse model with cerebral I/R injury was induced by middle cerebral artery occlusion/reperfusion (MCAO/R). The expression of ogt in brain tissues was detected by qRT-PCR, Western blot, and immunohistochemistry (IHC) staining assay. Neurological deficit was evaluated using a modified scoring system. The infarct volume was assessed by TTC staining assay. Neuronal apoptosis in brain tissues was evaluated by TUNEL staining assay. The level of cleaved caspase-3 in brain tissues was detected by Western blot and IHC staining assay. The expression of critical proteins involved in mitochondrial fission, including OPA1, Mfn1, and Mfn2, as well as Mff and Drp1 was detected by Western blot and IHC, respectively. The expression of ogt during cerebral I/R injury was significantly upregulated. Ogt knockdown significantly increased neurological score and infarct volume in I/R-induced mice. Meanwhile, ogt knockdown significantly enhanced neuronal apoptosis and cleaved caspase-3 level in brain tissues of I/R-induced mice. In addition, ogt knockdown markedly decreased serine 637 phosphorylation level of mitochondrial fission protein dynamin-related protein 1 (Drp1) and promoted Drp1 translocation from the cytosol to the mitochondria. Moreover, the specific Drp1 inhibitor mdivi-1 effectively attenuated ogt knockdown-induced brain injury of I/R-stimulated mice in vivo. Our study revealed that OGT protects against cerebral I/R injury by inhibiting the function of Drp1 in mice, suggesting that ogt may be a potential therapeutic target for cerebral I/R injury.

Berberine combined with stachyose improves glycometabolism and gut microbiota through regulating colonic microRNA and gene expression in diabetic rats.

AIMS: Berberine is effective for type 2 diabetes mellitus (T2DM), but has limited use in clinic. This study aims to evaluate the effect of berberine combined with stachyose on glycolipid metabolism and gut microbiota and to explore the underlying mechanisms in diabetic rats. MAIN METHODS: Zucker diabetic fatty (ZDF) rats were orally administered berberine, stachyose and berberine combined with stachyose once daily for 69 days. The oral glucose tolerance and levels of blood glucose, insulin, triglyceride and total cholesterol were determined. The gut microbial profile, colonic miRNA and gene expression were assayed using Illumina sequencing. The quantitative polymerase chain reaction was used to verify the expression of differentially expressed miRNAs and genes. KEY FINDINGS: Repeated treatments with berberine alone and combined with stachyose significantly reduced the blood glucose, improved the impaired glucose tolerance, and increased the abundance of beneficial Akkermansiaceae, decreased that of pathogenic Enterobacteriaceae in ZDF rats. Furthermore, combined treatment remarkably decreased the abundances of Desulfovibrionaceae and Proteobacteria in comparison to berberine. Combined treatment evidently decreased the expression of intestinal early growth response protein 1 (Egr1) and heparin-binding EGF-like growth factor (Hbegf), and significantly increased the expression of miR-10a-5p, but berberine alone not. SIGNIFICANCE: Berberine combined with stachyose significantly improved glucose metabolism and reshaped gut microbiota in ZDF rats, especially decreased the abundance of pathogenic Desulfovibrionaceae and Proteobacteria compared to berberine alone, providing a novel strategy for treating T2DM. The underlying mechanisms may be associated with regulating the expression of intestinal Egr1, Hbegf and miR-10a-5p, but remains further elucidation.

Colorimetric and fluorometric dual-readout protein kinase assay by tuning the active surface of nanoceria.

Herein, we demonstrate that the active surface of nanoceria can be fine-tuned by phosphorylated peptides. Accordingly, a colorimetric and fluorometric dual-readout strategy is rationally developed for assaying protein kinase activity. This feature not only enables the versatile monitoring of peptide phosphorylation but also broadens the application scope of nanoceria.

Diphenyl diselenide ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats via suppressing oxidative stress and inflammation.

Oxidative stress and inflammation are implicated in the occurrence and progression of diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple diaryl diselenide with anti-hyperglycemic, anti-inflammatory, and antioxidant activities. However, the effects of DPDS on DN are still unclear to date. Herein, we aimed to explore whether DPDS could improve renal dysfunction in streptozotocin (STZ)-induced diabetic rats and its underlying mechanisms. STZ-induced DN rats were administered with DPDS (5 or 15 mg/kg) or metformin (200 mg/kg) once daily by intragastric gavage for 12 weeks. DPDS supplementation significantly improved hyperglycemia, glucose intolerance, dyslipidemia, and the renal pathological abnormalities, concurrent with significantly reduced serum levels of creatinine, urea nitrogen, urine volume, and urinary levels of micro-albumin, ß2-microglobulin and N-acetyl-glucosaminidase activities. Moreover, DPDS effectively promoted the activities of antioxidant enzymes, and reduced the levels of MDA and pro-inflammatory factors in serum and the kidney. Furthermore, DPDS supplementation activated the renal Nrf2/Keap1 signaling pathway, but attenuated the high phosphorylation levels of NFκB, JNK, p38 and ERK1/2. Altogether, the current study indicated for the first time that DPDS ameliorated STZ-induced renal dysfunction in rats, and its mechanism of action may be attributable to suppressing oxidative stress via activating the renal Nrf2/Keap1 signaling pathway and mitigating inflammation by suppressing the renal NFκB/MAPK signaling pathways, suggesting a potential therapeutic approach for DN.

Applications of Micro/Nanotechnology in Ultrasound-based Drug Delivery and Therapy for Tumor.

Ultrasound has been broadly used in biomedicine for both tumor diagnosis as well as therapy. The applications of recent developments in micro/nanotechnology promote the development of ultrasound-based biomedicine, especially in the field of ultrasound-based drug delivery and tumor therapy. Ultrasound can activate nano-sized drug delivery systems by different mechanisms for ultrasound- triggered on-demand drug release targeted only at the tumor sites. Ultrasound Targeted Microbubble Destruction (UTMD) technology can not only increase the permeability of vasculature and cell membrane via sonoporation effect but also achieve in situ conversion of microbubbles into nanoparticles to promote cellular uptake and therapeutic efficacy. Furthermore, High Intensity Focused Ultrasound (HIFU), or Sonodynamic Therapy (SDT), is considered to be one of the most promising and representative non-invasive treatment for cancer. However, their application in the treatment process is still limited due to their critical treatment efficiency issues. Fortunately, recently developed micro/nanotechnology offer an opportunity to solve these problems, thus improving the therapeutic effect of cancer. This review summarizes and discusses the recent developments in the design of micro- and nano- materials for ultrasound-based biomedicine applications.

The Chinese patent medicine, Jin-tang-ning, ameliorates hyperglycemia through improving ß cell function in pre-diabetic KKAy mice.

Jin-tang-ning (JTN), a Chinese patent medicine, mainly comprised of Bombyx moriL., has been proved to show α-glucosidase inhibitory efficacy and clinically effective for the treatment of type 2 diabetes (T2DM). Recently, we have reported that JTN could ameliorate postprandial hyperglycemia and improved ß cell function in monosodium glutamate (MSG)-induced obese mice, suggesting that JTN might play a potential role in preventing the conversion of impaired glucose tolerance (IGT) to T2DM. In this study, we evaluated the effect of JTN on the progression of T2DM in the pre-diabetic KKAy mice. During the 10 weeks of treatment, blood biochemical analysis and oral glucose tolerance tests were performed to evaluate glucose and lipid profiles. The ß cell function was quantified using hyperglycemic clamp at the end of the study. JTN-treated groups exhibited slowly raised fasting and postprandial blood glucose levels, and also ameliorated lipid profile. JTN improved glucose intolerance after 8 weeks of treatment. Meanwhile, JTN restored glucose-stimulated first-phase of insulin secretion and induced higher maximum insulin levels in the hyperglycemic clamp. Thus, to investigate the underlying mechanisms of JTN in protecting ß cell function, the morphologic changes of the pancreatic islets were observed by optical microscope and immunofluorescence of hormones (insulin and glucagon). Pancreatic protein expression levels of key factors involving in insulin secretion-related pathway and ER stress were also detected by Western blot. Pre-diabetic KKAy mice exhibited a compensatory augment in ß cell mass and abnormal α cell distribution. Long-term treatment of JTN recovered islet morphology accompanied by reducing α cell area in KKAy mice. JTN upregulated expression levels of glucokinase (GCK), pyruvate carboxylase (PCB) and pancreas duodenum homeobox-1 (PDX-1), while down-regulating C/EBP homologous protein (Chop) expression in pancreas of the hyperglycemic clamp, which indicated the improvement of mitochondrial metabolism and relief of endoplasmic reticulum (ER) stress of ß cells after JTN treatment. These results will provide a new insight into exploring a novel strategy of JTN for protecting ß cell function and preventing the onset of pre-diabetes to T2DM.

Dual-Product Synergistically Enhanced Colorimetric Assay for Sensitive Detection of Lipid Transferase Activity.

Lipid transferase-catalyzed protein lipidation plays critical roles in many physiological processes and it has been an increasingly attractive therapeutic target from cancer to neurodegeneration, while sensitive detection of lipid transferase activity in biological samples remains challenging. Here, we presented an AuNP-based colorimetric method with dual-product synergistically enhanced sensitivity for convenient detection of lipid transferase activity. Homo sapiens N-myristoyltransferase 1 (HsNMT1), a key lipid transferase, was selected as the model. Accordingly, positively charged substrate peptides (Pep) of HsNMT1 can induce the aggregation of AuNPs through disrupting their electrostatic repulsion, while the HsNMT1-catalyzed lipid modification generates aggregated lipidated peptides (C14-Pep) and negatively charged HS-CoA, which will eliminate the disruption and stabilize the AuNPs by the formation of Au-S bonds, respectively. Consequently, charge reversal of the biomolecules and the formation of Au-S bonds synergistically contribute to the stability of AuNPs in the presence of HsNMT1. Therefore, the HsNMT1 activity can be visually detected by the naked eye through the color change of the AuNPs originated from the change in their distance-dependent surface plasmon resonance absorptions. Here, the A520/A610 ratio can sensitively reflect the activity of HsNMT1 in the linear range of 2-75 nM with a low detection limit of 0.56 nM. Moreover, the method was successfully applied for probing the HsNMT1 activities in different cell lysates and inhibitor screening. Furthermore, given the replaceability of the substrate peptide, the proposed assay is promising for universal application to other lipid transferases and exhibits great potential in lipid transferase-targeted drug development.

Stachyose Improves the Effects of Berberine on Glucose Metabolism by Regulating Intestinal Microbiota and Short-Chain Fatty Acids in Spontaneous Type 2 Diabetic KKAy Mice.

Berberine (BBR) has the beneficial effects of anti-inflammation, anti-bacteria, and anti-diabetes. The clinical application of BBR has been hindered by its poor gastrointestinal absorption. Stachyose (Sta), a prebiotic agent, improves the composition of gut microbiota and benefits for diabetes. We therefore investigated whether Sta improves the anti-diabetic actions of BBR using KKAy mice. Here, we find that the combination of BBR and Sta is more effective than BBR alone in blood glucose control, improvement of insulin resistance and islet functions, inflammatory mediators decrease, and maintenance of intestinal barrier integrity. Gut microbiota analysis demonstrates that both BBR and combined administration enhance the abundance of Bacteroidaceae and Akkermansiaceae and decrease Lachnospiraceae levels, whereas Akkermansiaceae elevation due to the administration of BBR with Sta is more significant than BBR alone. Interestingly, the proportion of Lactobacillaceae increases with combination treatment, but is diminished by BBR. Additionally, BBR with Sta significantly reduces the concentrations of fecal short-chain fatty acids compared to BBR. Collectively, these results indicate that the combination of BBR and Sta imparts better effects on the maintenance of glycemia and intestinal homeostasis than BBR alone by modulating gut microbiota and short-chain fatty acids, thereby providing a novel approach for the treatment of type 2 diabetes mellitus.

Diphenyl diselenide alleviates diabetic peripheral neuropathy in rats with streptozotocin-induced diabetes by modulating oxidative stress.

Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications occurring in both type 1 and type 2 diabetes mellitus patients. Oxidative stress (OS) plays a key role in the pathogenesis of DPN; thus, antioxidant therapy is considered a promising strategy for treating DPN. Diphenyl diselenide (DPDs) is an organic selenium compound with antioxidant pharmacological activities. This study aimed to evaluate its preventive and therapeutic effects on DPN in rats with streptozotocin (STZ)-induced diabetes and explore the underlying mechanisms. In vitro, RSC96 cells were exposed to high glucose (100 mM) and then treated with different concentrations of DPDs (1, 10, 25 and 50 µM). Notably, DPDs markedly suppressed high glucose-induced cytotoxicity and oxidative stress in Schwann cells by decreasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Furthermore, the DPDs treatment effectively activated Nrf2 signaling and inhibited Keap1 expression. An in vivo DPN model was established in Sprague-Dawley (SD) rats injected with STZ (60 mg·kg-1, ip) and orally administered either different doses of DPDs (5 and 15 mg· kg-1· d-1) for 12 weeks or alpha lipoic acid (ALA, 100 mg kg-1·d-1) as a positive control. The administration of DPDs significantly increased the motor nerve conduction velocity (MNCV), improved thermal and mechanical hyperalgesia and the sciatic nerve morphology, and ameliorated oxidative stress in the serum and the sciatic nerve of rats with DPN. Mechanistically, DPDs reduced the level of Keap1 and stimulated Nrf2 signaling in the sciatic nerve. Taken together, the results of this study indicate that DPDs ameliorates experimental DPN as an antioxidant by activating the Nrf2/Keap1 signaling pathway. DPDs may represent a new alternative treatment for DPN.

Effects of a ready-to-eat cereal formula powder on glucose metabolism, inflammation, and gut microbiota in diabetic db/db mice.

The cereal formula powder, Zhengda Jingshan (ZDJS), comprises dietary fiber, multivitamins, fine protein, and various cereal ingredients. The present study evaluated the effects of ZDJS on glucose metabolism and explored the corresponding mechanisms in terms of modulating gut microbiota and the fecal metabolome. Type 2 diabetic db/db mice were given ZDJS (1 g/kg) orally twice daily for 55 days, after which glucose metabolism, inflammation, gut microbiota, and fecal metabolomics were assayed. Repeated administration of ZDJS was associated with a trend toward decreasing fasting blood glucose and a 0.12% decrease in hemoglobin A1c (HbA1c), as well as statistically significant increases in the insulin sensitivity index and decreases in serum levels of tumor necrosis factor (TNF-α) and ileum expression of mucin-2. ZDJS also ameliorated the compensatory enlargement of islets and decreased the ratio of the α-cell area to total islet area; however, this amelioration of impaired oral glucose tolerance became less pronounced as treatment continued. In addition, ZDJS remarkably decreased the abundance of phylum Proteobacteria and the phylum ratio of Firmicutes to Bacteroidetes, as well as altered the fecal metabolic profile. Taken together, our findings demonstrate that ZDJS improved glucose metabolism and reduced inflammation in type 2 diabetic db/db mice, which may be associated with a reshaping of the gut microbiome and fecal metabolome in db/db mice. Thus, our study suggests that ZDJS may represent a complementary therapy for patients with type 2 diabetes.