Plasmalogen Improves Memory Function by Regulating Neurogenesis in a Mouse Model of Alzheimer's Diseases.

Adult hippocampal neurogenesis (AHN) is associated with hippocampus-dependent cognitive function, and its initiation is attributed to neural stem cells (NSCs). Dysregulated AHN has been identified in Alzheimer's disease (AD) and may underlie impaired cognitive function in AD. Modulating the function of NSCs and stimulating AHN are potential ways to manipulate AD. Plasmalogen (PLA) are a class of cell membrane glycerophospholipids which exhibit neuroprotective properties. However, the effect of PLA on altered AHN in AD has not been investigated. In our study, PLA(10µg/mL) -attenuated Aß (1-42) (5µM) induced a decrease in NSC viability and neuronal differentiation of NSCs, partially through regulating the Wnt/ß-catenin pathway. Additionally, AD mice were supplemented with PLA (67mg/kg/day) for 6 weeks. PLA treatment improved the impaired AHN in AD mice, including increasing the number of neural stem cells (NSCs) and newly generated neurons. The memory function of AD mice was also enhanced after PLA administration. Therefore, it was summarized that PLA could regulate NSC differentiation by activating the Wnt/ß-catenin pathway and ameliorate AD-related memory impairment through up-regulating AHN.

Nobiletin Mitigates D-Galactose-Induced Memory Impairment via Improving Hippocampal Neurogenesis in Mice.

Memory impairment is a characteristic of brain aging, and it is associated with a decrease in neurogenesis. Therefore, enhancing neurogenesis is a potential method for mitigating brain aging. Nobiletin (NOB) is a natural polymethoxylated flavonoid derived from citrus peels. It acts as an antioxidant, enhances anti-inflammation, and displays neuroprotective properties. However, the mechanism of NOB on brain aging has not been elucidated. In this study, D-galactose-induced aging mice were treated with NOB (100 mg/kg/day) for 10 weeks. NOB administration attenuated D-galactose-induced memory impairment and restored hippocampal neurogenesis, including the number of newborn neurons and neural stem cells in mice. Furthermore, it downregulated the pro-inflammatory mediators IL-1 ß, IL-6, and pP65 (by 42.2%, 22.9%, and 46.4% of those in the D-galactose treated group, respectively) in the hippocampus and blocked microglia and astrocyte activation. In vitro, NOB inhibited D-galactose-induced inflammatory responses in BV2 cells, and the conditioned medium prepared from NOB- and D-galactose-co-treated BV2 cells elevated the viability (90.3% of control) and differential ability (94.9% of control) of C17.2 cells, compared to the D-galactose-treated group alone. It was concluded that NOB could restore memory impairment via the improvement of neurogenesis by ameliorating neuroinflammation in the hippocampus. Overall, NOB is a potential candidate neurogenesis enhancer for improving brain function.

Comparison of clinical efficacy and safety of transvaginal natural endoscopic surgery and transumbilical single port laparoscopy surgery for endometrial cancer.

OBJECTIVE: To explore the difference in clinical efficacy and safety of transvaginal and transumbilical single port laparoscopy for endometrial cancer. METHODS: We retrospectively included 100 endometrial cancer patients who were admitted to the Fuzhou Second Hospital for surgical treatment from September 2020 to September 2021 and divided them into two groups according to different surgical treatment options. Patients in Group A (48 cases) were treated with transvaginal natural endoscopic surgery (TNES), and those in Group B (52 cases) were with transumbilical single port laparoscopic surgery (TSPLS). The operation time, intraoperative blood loss, time to postoperative exhaust, length of hospital stay, pelvic lymph node dissection, and incision infection rate of two groups were compared. The white blood cell count (WBC), hemoglobin (Hb), hematocrit (Hct) of the two groups of patients before and after the surgery were compared between the two groups, as well as th VAS score of 24 hours after the operation, rate of complications during hospitalization, satisfaction with surgery and quality of life 3 months after surgery. RESULTS: Compared with Group B, the operation time and intraoperative blood loss of Group A patients were markedly increased. The time to postoperative exhaust, length of hospital stay, incision infection rate, VAS score at postoperative 24 h, and complication rate of Group A were significantly lower than that of Group B. In addition, Group A had higher performance on the number of pelvic lymph node dissections, surgical satisfaction and quality of life 3 months after surgery. CONCLUSION: Transvaginal natural cavity endoscopy had better surgical results with faster postoperative recovery and higher safety compared with TSPLS, making it valuable in clinical application and worthy of further popularization.

Effects of Genistein and Exercise Training on Brain Damage Induced by a High-Fat High-Sucrose Diet in Female C57BL/6 Mice.

In recent decades, a shift in the nutritional landscape to the Western-style diet has led to an unprecedented rise in the prevalence of obesity and neurodegenerative diseases. Consumption of a healthy diet and engaging in regular physical activity represents safe and affordable approaches known to mitigate the adverse consequences of the Western diet. We examined whether genistein treatment, exercise training, and a combination treatment (genistein and exercise training) mitigated the effects of a Western diet-induced by high-fat, high-sugar (HFHS) in brain of female mice. HFHS increased the amyloid-beta (Aß) load and phosphorylation of tau, apoptosis, and decreased brain-derived neurotrophic factor (BDNF) levels. Exercise training and genistein each afforded modest protection on Aß accumulation and apoptosis, and both increased BDNF. The greatest neuroprotective effect occurred with combination treatment. BDNF and all markers of Aß accumulation, phosphorylation of tau, and apoptosis were improved with combined treatment. In a separate series of experiments, PC12 cells were exposed to high glucose (HG) and palmitate (PA) to determine cell viability with genistein as well as in the presence of tamoxifen, an estrogen receptor antagonist, to assess a mechanism of action of genistein on cell apoptosis. Genistein prevented the neurotoxic effects of HG and PA in PC12 cells and tamoxifen blocked the beneficial effects of genistein on apoptosis. Our results indicate the beneficial effects of genistein and exercise training on HFHS-induced brain damage. The benefits of genistein may occur via estrogen receptor-mediated pathways.

Genistein: A focus on several neurodegenerative diseases.

Neurodegenerative diseases are caused by the progressive loss of function or structure of nerve cells in the central nervous system. The most common neurodegenerative diseases include Alzheimer's disease, Huntington's disease, motor neuron disease, and Parkinson's disease. Although the physical or mental symptoms of neurodegenerative disease may be relieved by various treatment combinations, there are currently no strategies to directly slow or prevent neurodegeneration. Given the demographic evidence of a rapidly growing aging population and the associated prevalence of these common neurodegenerative diseases, it is paramount to develop safe and effective ways to protect against neurodegenerative diseases. Most neurodegenerative diseases share some common etiologies such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. Genistein is an isoflavone found in soy products that have been shown to exhibit antioxidant, anti-inflammation, and estrogenic properties. Increasing evidence indicates the protective potential of genistein in neurodegenerative disorders. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disease. PRACTICAL APPLICATIONS: Genistein is a naturally occurring isoflavone found mainly in soybean, but also green peas, legumes, and peanuts. Genistein is found to pass through the blood-brain barrier and possess a neuroprotective effect. In this review, we discuss studies in support of these actions and the underlying biological mechanisms. Together, these data indicate that genistein may hold neuroprotective effects in either delaying the onset or relieving the symptoms of neurodegenerative disease.

Mitochondrial dysfunction and beneficial effects of mitochondria-targeted small peptide SS-31 in Diabetes Mellitus and Alzheimer's disease.

Diabetes and Alzheimer's disease are common chronic illnesses in the United States and lack clearly demonstrated therapeutics. Mitochondria, the "powerhouse of the cell", is involved in the homeostatic regulation of glucose, energy, and reduction/oxidation reactions. The mitochondria has been associated with the etiology of metabolic and neurological disorders through a dysfunction of regulation of reactive oxygen species. Mitochondria-targeted chemicals, such as the Szeto-Schiller-31 peptide, have advanced therapeutic potential through the inhibition of oxidative stress and the restoration of normal mitochondrial function as compared to traditional antioxidants, such as vitamin E. In this article, we summarize the pathophysiological relevance of the mitochondria and the beneficial effects of Szeto-Schiller-31 peptide in the treatment of Diabetes and Alzheimer's disease.

Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer's Disease.

To date, there is no cure or effective treatment for Alzheimer's disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aß) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aß and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aß oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aß oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

Beneficial Effect of Genistein on Diabetes-Induced Brain Damage in the ob/ob Mouse Model.

PURPOSE: Diabetes mellitus (DM)-induced brain damage is characterized by cellular, molecular and functional changes. The mechanisms include oxidative stress, neuroinflammation, reduction of neurotrophic factors, insulin resistance, excessive amyloid beta (Aß) deposition and Tau phosphorylation. Both antidiabetic and neuroprotective effects of the phytoestrogen genistein have been reported. However, the beneficial effect of genistein in brain of the ob/ob mouse model of severe obesity and diabetes remains to be determined. METHODS: In this study, female ob/ob mice and lean control mice were fed with either a standard diet or a diet containing genistein (600mg/kg) for a period of 4 weeks. Body weight was monitored weekly. Blood was collected for the measurement of glucose, insulin and common cytokines. Mice brains were isolated for Western immunoblotting analyses. RESULTS: Treatment with genistein reduced weight gain of ob/ob mice and decreased hyperglycemia compared to ob/ob mice fed the standard diet. The main findings show that genistein treatment increased insulin sensitivity and the expression levels of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factors (BDNF). In these mice, genistein also reduced Aß deposition and the level of hyper-phosphorylated Tau protein. CONCLUSION: The results of our study indicate the beneficial effects of genistein in the obese diabetic mouse brain, including improving brain insulin signaling, increasing neurotrophic support, and alleviating Alzheimer's disease-related pathology.

Nerve growth factor in metabolic complications and Alzheimer's disease: Physiology and therapeutic potential.

As the population ages, obesity and metabolic complications as well as neurological disorders are becoming more prevalent, with huge economic burdens on both societies and families. New therapeutics are urgently needed. Nerve growth factor (NGF), first discovered in 1950s, is a neurotrophic factor involved in regulating cell proliferation, growth, survival, and apoptosis in both central and peripheral nervous systems. NGF and its precursor, proNGF, bind to TrkA and p75 receptors and initiate protein phosphorylation cascades, resulting in changes of cellular functions, and are associated with obesity, diabetes and its complications, and Alzheimer's disease. In this article, we summarize changes in NGF levels in metabolic and neuronal disorders, the signal transduction initiated by NGF and proNGF, the physiological and pathophysiological relevance, and therapeutic potential in treating chronic metabolic diseases and cognitive decline.

Nerve growth factor receptor TrkA signaling in streptozotocin-induced type 1 diabetes rat brain.

Previous work from our lab demonstrated a new role of TrkA in the insulin signaling pathway. The kinase activity of TrkA is essential for its interaction with the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) and activation of Akt and Erk5 in PC12 cells. Here we show in brain from streptozotocin (STZ)-induced type 1 diabetic rats that the expression of the inactive proNGF is elevated, whereas the expression of mature NGF is reduced. In addition, tyrosine phosphorylation of TrkA is decreased in STZ-induced diabetes compared to control. Results of the co-immunoprecipitation experiments indicate that the interaction of TrkA with the IR and IRS-1 is also reduced in the brain of diabetic rats. Moreover, tyrosine phosphorylation of the IR and IRS-1, and Akt activation is decreased in STZ diabetes compared to control. Our results suggest that the NGF-TrkA receptor is involved in insulin signaling and is impaired in the brain of STZ-induced diabetic rats.

Effects and Underlying Mechanisms of Bioactive Compounds on Type 2 Diabetes Mellitus and Alzheimer's Disease.

Type 2 diabetes mellitus is a complicated metabolic disorder characterized by hyperglycemia and glucose intolerance. Alzheimer's disease is a progressive brain disorder characterized by a chronic loss of cognitive and behavioral function. Considering the shared characteristics of both diseases, common therapeutic and preventive agents may be effective. Bioactive compounds such as polyphenols, vitamins, and carotenoids found in vegetables and fruits can have antioxidant and anti-inflammatory effects. These effects make them suitable candidates for the prevention or treatment of diabetes and Alzheimer's disease. Increasing evidence from cell or animal models suggest that bioactive compounds may have direct effects on decreasing hyperglycemia, enhancing insulin secretion, and preventing formation of amyloid plaques. The possible underlying molecular mechanisms are described in this review. More studies are needed to establish the clinical effects of bioactive compounds.

Human and mouse microarrays-guided expression analysis of membrane protein trafficking-related genes in MDCK cells, a canine epithelial model for apical and basolateral differential protein targeting.

MDCK cells are widely used to study the differential targeting of membrane transporters to apical and basolateral membrane but its canine origin limited the commercial tools available for the analysis of protein trafficking machinery. Because apical and basolateral membranes are only found in differentiated epithelial cells, genes critical for differential targeting may be specifically up-regulated upon MDCK cell differentiation. To search for these genes, a cross-species screening strategy was used. We first analyzed the human microarray data for protein trafficking-related genes that were up-regulated in colon carcinoma Caco2 cells upon differentiation. The results of mouse 44K gene expression microarray analysis were then used to extract additional candidate genes that showed higher expression in normal colon epithelium compared to primary embryonic fibroblasts. Finally, NCBI genomic sequence information was used to design RT-PCR primers for 13 candidate and 10 negative control genes and used to analyze MDCK cells at 2, 13 and 17 days after seeding. To determine whether the gene up-regulation was specific in epithelial differentiation, we also performed RT-PCR on rat non-differentiating intestinal IEC-6 cells and mouse C2C12 cells, a differentiating myoblast model. Of the 13 candidate genes, 3 genes, SDCBP2, KIF12, KIF27, met all criteria of specific up-regulation in differentiated MDCK cells. In addition, KIF13A showed up-regulation in differentiated MDCK and C2C12 cells but not in IEC-6 cells cultured for the same duration. The functions of these genes need to be analyzed in the future. This cross-species screening strategy may be useful for other non-human, non-rodent cell models.

[Clinical evaluation of radiofrequency ablation therapy in patients with hepatic cavernous hemangiomas].

OBJECTIVE: To evaluate the feasibility, safety and efficacy of radiofrequency ablation (RFA) therapy in patients with hepatic cavernous hemangioma (HCH) and investigate its optimal operative approach. METHODS: Between March 2001 and June 2004, a total of 68 patients, 18 males and 50 females, age 43.1 (30-64), with 104 HCHs 2.5-11 cm in diameter with the mean size of 5.6 cm, were treated by ultrasound-guided RFA, via percutaneous (n = 19), laparoscopic (n = 29), or open surgical (n = 20) approach. In 7 patients with hepatic lesions larger than 7 cm in diameter, Pringle maneuver was used to occlude the hepatic blood flow during the laparoscopic and open RFA therapy. All patients were followed up with helical computed tomographic (CT) scans and ultrasonography for 19 months (6-36 months). RESULTS: Additional intrahepatic lesions not detected preoperatively were found in 2 patients (with 2 new lesions) via laparoscopy and 3 patients (with 4 new lesions) via celiotomy. All patients were treated with RFA successfully. The mean blood loss in the Pringle group (90.0 ml +/- 22.4 ml) was significantly fewer than that in the non-Pringle group (249 ml +/- 56 ml) (P < 0.01). The mean RFA time per lesion in the Pringle group (29.0 min +/- 7.5 min) was shorter markedly compared to the non-Pringle group (55.4 min +/- 12.4 min) (P < 0.01). In the laparoscopic RFA group, laparoscopic cholecystectomy was performed simultaneously in 15 patients with chronic calculous cholecystitis and in another 2 patients because of tumors abutting the gallbladders, and laparoscopic fenestration with intraperitoneal drainage was performed in 3 patients with simple hepatic cysts. In the open RFA group, cholecystectomy was performed in 5 patients with gallbladder diseases, partial cystectomy was performed in one patient with a hepatic cyst, and choledochotomy was performed in 3 patients with common bile duct stones. Postoperative fever and abnormal serum transaminase (ALT and AST) levels were observed in 29 patients (42.6%). A transient hematuria occurred in one patient after open RFA. No specific complications developed during or after RFA. The follow-up showed a complete lesion necrosis rate of 99% (103/104). One patient showed an incomplete lesion necrosis in the margin of RFA site 6 months after percutaneous RFA therapy and obtained retreatment with percutaneous RFA. CONCLUSION: RFA therapy is a safe, feasible and effective treatment options for patients with HCHs. This procedure can be performed via percutaneous, laparoscopic, or open approach. To prevent the RFA-related complications and to increase the therapeutic efficacy of RFA, the choice of optimal operative approach should be based on the lesion size, number, and location and on the patient's clinical status. Hepatic inflow occlusion by Pringle maneuver during laparoscopic or open RFA therapy can reduce the blood loss and increase the therapeutic efficacy significantly.