Activation of mitophagy improves cognitive dysfunction in diabetic mice with recurrent non-severe hypoglycemia.

Recurrent non-severe hypoglycemia (RH) in patients with diabetes might be associated with cognitive impairment. Previously, we found that mitochondrial dysfunction plays an important role in this pathological process; however, the mechanism remains unclear. The objective of this study was to determine the molecular mechanisms of mitochondrial damage associated with RH in diabetes mellitus (DM). We found that RH is associated with reduced hippocampal mitophagy in diabetic mice, mainly manifested by reduced autophagosome formation and impaired recognition of impaired mitochondria, mediated by the PINK1/Parkin pathway. The same impaired mitophagy initiation was observed in an in vitro high-glucose cultured astrocyte model with recurrent low-glucose interventions. Promoting autophagosome formation and activating PINK1/Parkin-mediated mitophagy protected mitochondrial function and cognitive function in mice. The results showed that impaired mitophagy is involved in the occurrence of mitochondrial dysfunction, mediating the neurological impairment associated with recurrent low glucose under high glucose conditions.

Potential risk factors for mild cognitive impairment among patients with type 2 diabetes experiencing hypoglycemia.

AIMS: This study examined the association between hypoglycemia and mild cognitive impairment (MCI) among patients with type 2 diabetes mellitus (T2DM) and identified risk factors for MCI in patients with hypoglycemia. METHODS: In this retrospective study, 328 patients with T2DM were screened in 2019 and followed up in 2022. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). The diagnosis of MCI was based on established criteria. Risk ratio (RR) with 95 % confidence intervals (CI) was calculated to estimate the risk of MCI. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for MCI in those with hypoglycemia. RESULTS: Patients with hypoglycemia had lower cognitive performance 3 years later. The RR of MCI was 2.221 (95 % CI 1.269-3.885). Multivariate logistic analysis showed that low grip strength, existing diabetic retinopathy (DR), and multiple hypoglycemia episodes were associated with higher odds of MCI in patients with hypoglycemia (adjusted odds ratio [OR] 0.909 [95 % CI 0.859-0.963]), 3.078 [95 % CI 1.158-12.358], and 4.642 [95 % CI 1.284-16.776], respectively, all P < 0.05). CONCLUSIONS: Hypoglycemia increased MCI risk among patients with T2DM. Low grip strength, DR, and multiple hypoglycemia episodes may be potential risk factors for hypoglycemia-associated MCI.

Clouclip combined with a questionnaire on the influence factors of myopia in children.

Purpose: To evaluate eye use behavior in myopic and non-myopic children objectively using Clouclip M2 device and subjectively using questionnaire and compare the results. The study also aimed to assess the relationships between ocular biometric parameters and refractive status. Methods: Clouclip M2 was used in monitoring eye use behavior and visual environment in children aged 9-11 years. The participants were monitored for 7 days. On the eighth day, data stored in the device were collected, relevant eye examination were conducted and survey questionnaire was administered. The paired sample t-test was used to compare the eye use behavior obtained objectively and subjectively. The relationships between ocular biometric parameters and refractive status were assessed using the Pearson's Correlation analysis. Results: Spherical equivalent refraction was significantly correlated with axial length, axial length to corneal radius, anterior chamber depth, lens thickness, and corneal radius (P < 0.05). The average time per day spent on near work, the maximum time for single near work, and the average near working distance were significantly lower, and the average total time spent on outdoor activities was significantly longer as determined by questionnaire method than that found using Clouclip M2. Logistic regression analysis revealed that prolonged near work, shorter working distance, presence of parental myopia, and lesser outdoor activities were significant risk factors for myopia. Conclusions: The childhood myopia is influenced by eye use behavior, eye use environment, and parental myopia. Results from this study further support that biometric and optical parameters of the eye determine refractive status. Being an objective method, Clouclip M2 provides an independent eye use behavior data which potentially are more reliable than obtained from subjective method. Our study provided a theoretical basis for myopia prevention and control in clinical practice.

Mitophagy disorder mediates cardiac deterioration induced by severe hypoglycemia in diabetic mice.

Severe hypoglycemia is closely related to adverse cardiovascular outcomes in patients with diabetes; however, the specific mechanism remains unclear. We previously found that severe hypoglycemia aggravated myocardial injury and cardiac dysfunction in diabetic mice, and that the mechanism of damage was related to mitochondrial oxidative stress and dysfunction. Based on the key regulatory role of mitophagy in mitochondrial quality control, this study aimed to further explore whether the myocardial damage caused by severe hypoglycemia is related to insufficient mitophagy and to clarify their underlying regulatory relationship. After severe hypoglycemia, mitochondrial reactive oxygen species increased, mitochondrial membrane potential and ATP content decreased, and pathological mitochondrial damage was aggravated in the myocardium of diabetic mice. This was accompanied by decreased mitochondrial biosynthesis, increased fusion, and downregulated PTEN-induced kinase 1 (PINK1)/Parkin-dependent mitophagy. Treating diabetic mice with the mitophagy activator and polyphenol metabolite urolithin A activated PINK1/Parkin-dependent mitophagy, reduced myocardial oxidative stress and mitochondrial damage associated with severe hypoglycemia, improved mitochondrial function, alleviated myocardial damage, and ultimately improved cardiac function. Thus, we provide insight into the prevention and treatment of diabetic myocardial injury caused by hypoglycemia to reduce adverse cardiovascular outcomes in patients with diabetes.

SIRT3 alleviates mitochondrial dysfunction induced by recurrent low glucose and improves the supportive function of astrocytes to neurons.

Hypoglycemia is an independent risk factor of cognitive impairment in patients with diabetes. Our previous study indicated that dysfunction of astrocytic mitochondria induced by recurrent low glucose (RLG) may account for hypoglycemia-associated neuronal injury and cognitive decline. Sirtuin 3 (SIRT3) is a key deacetylase for mitochondrial proteins and has recently been demonstrated to be an important regulator of mitochondrial function. However, whether mitochondrial dysfunction due to hypoglycemia is associated with astrocytic SIRT3 remains unclear, and few studies have focused on the impact of astrocytic SIRT3 on neuronal survival. In the present work, primary mouse cortical astrocytes cultured in normal glucose (5.5 mM) and high glucose (16.5 mM) were treated with five rounds of RLG (0.1 mM). The results showed that RLG suppressed SIRT3 expression in a glucose-dependent manner. High-glucose culture considerably increased the vulnerability of SIRT3 to RLG, leading to disrupted mitochondrial morphology in astrocytes. Overexpression of SIRT3 markedly improved astrocytic mitochondrial function and reduced RLG-induced oxidative stress. Moreover, SIRT3 suppressed a shift towards a neuroinflammatory A1-like reactive phenotype of astrocytes in response to RLG with reduced IL-1ß, IL-6, and TNFα levels. Furthermore, it elevated brain-derived neurotrophic factor (BDNF) levels and promoted neurite growth by activating BDNF/TrkB signaling in the co-cultured neurons. The present study reveals the probable crosstalk between neurons and astrocytes after hypoglycemic exposure and provides a potential target in treating hypoglycemia-associated neuronal injury.

Microwave ablation therapy assisted by artificial pneumothorax and artificial hydrothorax for lung cancer adjacent to the vital organs.

Objectives: This study aimed to investigate the technical methods and safety of artificial pneumothorax and artificial hydrothorax in the treatment of lung cancer adjacent to vital organs by CT-guided microwave ablation. Subjects and Methods: Three of the six patients were men and three were women, with a mean age of 66.0 years (range 47-78 years). There patients had primary pulmonary adenocarcinoma, one had lung metastasis from liver cancer, one had lung metastasis from colon cancer, and one had lung metastasis from bladder cancer. There were four patients with a single lesion, one with two lesions, and one with three lesions. The nine lesions had a mean diameter of 1.1 cm (range 0.4-1.9). In three patients, the lung cancer was adjacent to the heart, and in the remaining three, it was close to the superior mediastinum. Six patients were diagnosed with lung cancers or lung metastases and received radical treatment with microwave ablation (MWA) assisted by artificial pneumothorax and artificial hydrothorax in our hospital. Postoperative complications were observed and recorded; follow-up was followed to evaluate the therapeutic effect. Results: The artificial pneumothorax and artificial hydrothorax were successfully created in all six patients. A suitable path for ablation needle insertion was also successfully established, and microwave ablation therapy was carried out. 2 patients developed pneumothorax after operation; no serious complications such as operation-related death, hemothorax, air embolism and infection occurred.Moreover, 4-6 weeks later, an enhanced CT re-examination revealed no local recurrence or metastasis, and the rate of complete ablation was 100%. Conclusions: Microwave ablation, assisted by artificial pneumothorax, artificial hydrothorax, is a safe and effective minimally invasive method for treating lung cancer adjacent to the vital organs, and optimizing the path of the ablation needle and broadening the indications of the ablation therapy.

Liraglutide reduces oxidative stress and improves energy metabolism in methylglyoxal-induced SH-SY5Y cells.

Diabetes mellitus can result in severe complications, such as neurodegenerative diseases including cognitive impairment and dementia. The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, is a novel antidiabetic drug with neuroprotective effects against neurodegenerative diseases. In this study, we explored the protective effect of liraglutide on SH-SY5Y cells exposed to methylglyoxal (MG), a byproduct of glucose metabolism that plays a key role in the development of diabetic encephalopathy. We found that liraglutide reduced the MG-induced oxidative stress, increased the activity of superoxide dismutase (SOD) and expression levels of P22phox, Gp91phox, and Xdh genes, and reduced reactive oxygen species (ROS) content. Metabolomics analysis based on 1H nuclear magnetic resonance showed that liraglutide induced alterations in metabolites involved in energy metabolism，including promotion of gluconeogenesis. Moreover, we found that liraglutide promoted oxidative phosphorylation and inhibited glycolysis in SH-SY5Y cells. This study revealed that liraglutide improved diabetes-related neuropathy damage by reducing the level of oxidative stress and maintaining the balance of energy metabolism, thus offering new insights into the potential mechanism of liraglutide in neuronal protection.

Development of Refractive Parameters in 3- to 6-Year-Old Children and Its Application in Myopia Prediction and Intervention Guidance.

OBJECTIVE: To investigate refractive development and prevalence of myopia in children aged 3-6 years in Hebei Province, China, and to explore the developmental law of refraction, so as to clinically guide the prediction and intervention of myopia. METHODS: In May 2019, a total of 6120 people were inspected in 68 kindergartens in 11 cities in Hebei Province. Child refractive refraction was checked under noncycloplegia using a handheld binocular vision screener (SW-800, SUOER, Tianjin, China). Axial length (AL) and corneal radius of curvature (CR) were measured using an ocular biometry (IOLMaster 500, Carl Zeiss, Germany). Myopia was defined as spherical equivalent (SE) ≤ -0.75 D. RESULTS: A total of 5506 children aged 3-6 years met the criteria and were included in the statistical analysis. The prevalence of myopia was 3.49% (1.93% at age 3, 2.90% at age 4, 3.78% at age 5, and 3.88% at age 6). Overall, the mean SE was +0.67 ± 1.05 D (+0.81 ± 1.00 D at age 3, +0.79 ± 1.05 D at age 4, +0.67 ± 1.08 D at age 5, and +0.13 ± 1.01 D at age 6); the mean CR was 7.76 ± 0.26 mm (7.78 ± 0.26 mm at age3, 7.75 ± 0.25 mm at age 4, 7.77 ± 0.26 mm at age 5, and 7.76 ± 0.25 mm at age 6); the mean AL was 22.31 ± 0.73 mm (21.98 ± 0.63 mm at age 3, 22.12 ± 0.69 mm at age 4, 22.34 ± 0.73 mm at age 5, and 22.49 ± 0.73 mm at age 6). CONCLUSIONS: Prevalence of myopia increases with age in children aged 3-6 years in Hebei, China. With the increase of age, CR is basically stable, and AL increases gradually. AL/CR, which is closely related to SE, can be used as an indicator to predict myopia and guide clinical work.

GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer's disease.

OBJECTIVE: Astrocytes actively participate in energy metabolism in the brain, and astrocytic aerobic glycolysis disorder is associated with the pathology of Alzheimer's disease (AD). GLP-1 has been shown to improve cognition in AD; however, the mechanism remains unclear. The objectives of this study were to assess GLP-1's glycolytic regulation effects in AD and reveal its neuroprotective mechanisms. METHODS: The Morris water maze test was used to evaluate the effects of liraglutide (an analog of GLP-1) on the cognition of 4-month-old 5×FAD mice, and a proteomic analysis and Western blotting were used to assess the proteomic profile changes. We constructed an astrocytic model of AD by treating primary astrocytes with Aß1-42. The levels of NAD+ and lactate were examined, and the oxidative levels were assessed by a Seahorse examination. Astrocyte-neuron co-culture was performed to evaluate the effects of GLP-1 on astrocytes' neuronal support. RESULTS: GLP-1 improved cognition in 4-month-old 5×FAD mice by enhancing aerobic glycolysis and reducing oxidative phosphorylation (OXPHOS) levels and oxidative stress in the brain. GLP-1 also alleviated Aß-induced glycolysis declines in astrocytes, which resulted in reduced OXPHOS levels and reactive oxygen species (ROS) production. The mechanism involved the activation of the PI3K/Akt pathway by GLP-1. Elevation in astrocytic glycolysis improved astrocyte cells' support of neurons and promoted neuronal survival and axon growth. CONCLUSIONS: Taken together, we revealed GLP-1's capacity to regulate astrocytic glycolysis, providing mechanistic insight into one of its neuroprotective roles in AD and support for the feasibility of energy regulation treatments for AD.

Effects of Immunocytokine Combined with Cattle Encephalon Glycoside and Ignotin on CTGF, HO-1 and NT-3 in Patients with Type 2 Diabetic Peripheral Neuropathy.

BACKGROUND: This study was designed to explore the correlation of connective tissue growth factor (CTGF), heme oxygenase (HO-1), neurotrophic factors (NT-3) with type 2 diabetic peripheral neuropathy, as well as the changes after immune cytokine alone and combined with cattleencephalon glycoside and ignotin treatment. METHODS: Seventy-six patients with type 2 diabetes and peripheral neuropathy charged into People's Hospital of Rizhaolanshan, China from 2014-2016 were selected. The severity of neuropathy was evaluated by TCSS. Pearson analysis was used to analyze the correlation between the degree of neuropathy and CTGF, HO-1 and NT-3. The patients were randomly divided into control group and observation group, n=38. The control group accepted TGF-ß1 treatment on the basis of controlling diet and blood sugar, while the observation group was treated with cattle encephalon glycoside and ignotin injection on the basis of control group. CTGF, HO-1, NT-3 concentration in the blood and nerve conductive velocity (NCV) were detected and analyzed before and after treatment. RESULTS: CTGF(r=-0.865), HO-1(r=-0.706), NT-3(r=-0.587) was negatively correlated with TCSS scores. After treatment, the concentrations of CTGF, HO-1and NT-3 in the observation group were higher than the control group (P<0.05). In moderate and severe lesions, the concentrations of CTGF, HO-1and NT-3 in the observation group were higher than the control group (P<0.05). The conduction velocity of nerve increased with the increase of CTGF, HO-1 and NT-3 concentrations. The obvious effective rate and total effective rate of observation group were both higher than the control group. CONCLUSION: Immune cytokine TGF-ß1 combined with cattle encephalon glycoside and ignotin injection could improve the contents of CTGF, HO-1 and NT-3, and be better to treat the peripheral neuropathy of type 2 diabetes.

Subcutaneous liraglutide ameliorates methylglyoxal-induced Alzheimer-like tau pathology and cognitive impairment by modulating tau hyperphosphorylation and glycogen synthase kinase-3ß.

Memory deterioration and synapse damage with accumulation of ß-amyloid and hyperphosphorylated tau are hallmark lesions of Alzheimer's disease (AD). Methylglyoxal (MG), a key intermediate of glucose metabolism, is elevated in AD brains and modifies Aß42, increasing misfolding and leading to the accumulation of senile plaques. Liraglutide, an analog of glucagon-like peptide-1 (GLP-1), is neurotrophic and neuroprotective. However, whether liraglutide can protect against AD-like memory-related deficits and tau hyperphosphorylation caused by MG in vivo is not known. Here, we report that MG induces tau hyperphosphorylation and causes ultrastructural hippocampal damage and cognitive impairment in C57BL/6J mice. Liraglutide reduced these effects via activation of the protein kinase B and glycogen synthase kinase-3ß pathways. Our data reveal that liraglutide may alleviate AD-like cognitive impairment by decreasing the phosphorylation of tau.

Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3ß pathway in an amyloid ß protein induced alzheimer disease mouse model.

Type 2 diabetes mellitus is a risk factor for Alzheimer's disease (AD). The glucagon-like peptide-1 analog liraglutide, a novel long-lasting incretin hormone, has been used to treat type 2 diabetes mellitus. In addition, liraglutide has been shown to be neurotrophic and neuroprotective. Here, we investigated the effects of liraglutide on amyloid ß protein (Aß)-induced AD in mice and explored its mechanism of action. The results showed that subcutaneous administration of liraglutide (25nmol/day), once daily for 8 weeks, prevented memory impairments in the Y Maze and Morris Water Maze following Aß1-42 intracerebroventricular injection, and alleviated the ultra-structural changes of pyramidal neurons and chemical synapses in the hippocampal CA1 region. Furthermore, liraglutide reduced Aß1-42-induced tau phosphorylation via the protein kinase B and glycogen synthase kinase-3ß pathways. Thus liraglutide may alleviate cognitive impairment in AD by at least decreasing the phosphorylation of tau.