Pituitary Suppression with Gonadotropin-Releasing Hormone Agonist Prior to Artificial Endometrial Preparation in Frozen-Thawed Embryo Transfer Cycles: A Systematic Review and Meta-Analysis of Different Protocols and Infertile Populations.

This study investigates the effect of GnRHa pretreatment on pregnancy outcomes in artificial endometrial preparation for frozen-thawed embryo transfer (AC-FET) cycles. A systematic review of English language studies published before 1 September 2022, was conducted, excluding conference papers and preprints. Forty-one studies involving 43,021 participants were analyzed using meta-analysis, with a sensitivity analysis ensuring result robustness. The study found that GnRHa pretreatment generally improved the clinical pregnancy rate (CPR), implantation rate (IR), and live birth rate (LBR). However, discrepancies existed between randomized controlled trials (RCTs) and observational studies; RCTs showed no significant differences in outcomes for GnRHa-treated cycles. Depot GnRHa protocols outperformed daily regimens in LBR. Extended GnRHa pretreatment (two to five cycles) significantly improved CPR and IR compared to shorter treatment. Women with polycystic ovary syndrome (PCOS) saw substantial benefits from GnRHa pretreatment, including improved CPR and LBR and reduced miscarriage rates. In contrast, no significant benefits were observed in women with regular menstruation. More rigorous research is needed to solidify these findings.

Acrolein adducts and responding autoantibodies correlate with metabolic disturbance in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is caused by many intertwining pathologies involving metabolic aberrations. Patients with metabolic syndrome (MetS) generally show hyperglycemia and dyslipidemia, which can lead to the formation of aldehydic adducts such as acrolein on peptides in the brain and blood. However, the pathogenesis from MetS to AD remains elusive. METHODS: An AD cell model expressing Swedish and Indiana amyloid precursor protein (APP-Swe/Ind) in neuro-2a cells and a 3xTg-AD mouse model were used. Human serum samples (142 control and 117 AD) and related clinical data were collected. Due to the involvement of MetS in AD, human samples were grouped into healthy control (HC), MetS-like, AD with normal metabolism (AD-N), and AD with metabolic disturbance (AD-M). APP, amyloid-beta (Aß), and acrolein adducts in the samples were analyzed using immunofluorescent microscopy, histochemistry, immunoprecipitation, immunoblotting, and/or ELISA. Synthetic Aß1-16 and Aß17-28 peptides were modified with acrolein in vitro and verified using LC-MS/MS. Native and acrolein-modified Aß peptides were used to measure the levels of specific autoantibodies IgG and IgM in the serum. The correlations and diagnostic power of potential biomarkers were evaluated. RESULTS: An increased level of acrolein adducts was detected in the AD model cells. Furthermore, acrolein adducts were observed on APP C-terminal fragments (APP-CTFs) containing Aß in 3xTg-AD mouse serum, brain lysates, and human serum. The level of acrolein adducts was correlated positively with fasting glucose and triglycerides and negatively with high-density lipoprotein-cholesterol, which correspond with MetS conditions. Among the four groups of human samples, the level of acrolein adducts was largely increased only in AD-M compared to all other groups. Notably, anti-acrolein-Aß autoantibodies, especially IgM, were largely reduced in AD-M compared to the MetS group, suggesting that the specific antibodies against acrolein adducts may be depleted during pathogenesis from MetS to AD. CONCLUSIONS: Metabolic disturbance may induce acrolein adduction, however, neutralized by responding autoantibodies. AD may be developed from MetS when these autoantibodies are depleted. Acrolein adducts and the responding autoantibodies may be potential biomarkers for not only diagnosis but also immunotherapy of AD, especially in complication with MetS.

Osteopontin Splicing Isoforms Contribute to Endometriotic Proliferation, Migration, and Epithelial-Mesenchymal Transition in Endometrial Epithelial Cells.

Osteopontin (OPN) isoforms, including OPNb and OPNc, promote malignancy and may contribute to the pathogenesis of endometriosis, a benign disorder with multiple characteristics resembling malignant tumors. In our experiments, OPNb and OPNc were significantly overexpressed in both endometriosis and adenomyosis compared to the normal endometrium. Upregulation of CD44v and the epithelial-mesenchymal transition (EMT) process was also present in endometriotic lesions. Overexpression of OPNb and OPNc splicing variants in endometriotic cells evoked morphological changes, actin remodeling, cell proliferation, cell migration, and EMT through binding OPN ligand receptors CD44 and αvß3, subsequently activating the PI3K and NF-ĸB pathways. We elucidated the causal role of OPN splice variants in regulating endometriotic cell growth, which may promote the development of OPN-targeted therapies for patients suffering from endometriotic disorders.

Serum levels of 4-hydroxynonenal adducts and responding autoantibodies correlate with the pathogenesis from hyperglycemia to Alzheimer's disease.

OBJECTIVE: Hyperglycemia leads to lipid peroxidation, producing 4-hydroxynonenal (HNE) adducts which correlate with the production of amyloid-beta (Aß), one of the hallmarks of Alzheimer's disease (AD). This study is to investigate the interactions of Aß, HNE adducts and responding autoantibodies during the pathogenesis from hyperglycemia to AD. METHODS: A total of 239 Taiwanese serum samples from a healthy control group and patients with hyperglycemia, and AD with and without hyperglycemia were analyzed. Aß was immunoprecipitated from randomly pooled serum in each group and immunoblotted. Synthetic Aß1-16 and Aß17-28 peptides were modified with HNE in vitro and verified with LC-MS/MS. The levels of Aß, HNE adducts, and autoantibody isotypes IgG and IgM against either native or HNE-modified Aß were determined with ELISA. The diagnostic power of potential biomarkers was evaluated. RESULTS: Increased fasting glucose and decreased high-density-lipoprotein cholesterol in AD groups indicated abnormal metabolism in the pathogenesis progression from hyperglycemia to AD. Indeed, serum Aß, HNE adducts and most of the autoantibodies recognizing either native or HNE-modified Aß were increased in the diseased groups. However, HNE adducts had better diagnostic performances than Aß for both hyperglycemia and AD. Additionally, HNE-Aß peptide levels were increased, and the responding autoantibodies (most notably IgM) were decreased in hyperglycemic AD group compared to the hyperglycemia only group, suggesting an immunity disturbance in the pathogenesis progression from hyperglycemia to AD. CONCLUSION: Hyperglycemia increases the level of HNE adducts which may be neutralized by responding autoantibodies. Depletion of these autoantibodies promotes AD-like pathogenesis. Thus, levels of a patient's HNE adducts and associated responding autoantibodies are potential biomarkers for AD with diabetes.

Pdia4 regulates ß-cell pathogenesis in diabetes: molecular mechanism and targeted therapy.

Loss of ß-cell number and function is a hallmark of diabetes. ß-cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily expressed in ß-cells. This expression was up-regulated in ß-cells and blood of mice in response to excess nutrients. Ablation of Pdia4 alleviated diabetes as shown by reduced islet destruction, blood glucose and HbA1c, reactive oxygen species (ROS), and increased insulin secretion in diabetic mice. Strikingly, this ablation alone or in combination with food reduction could fully reverse diabetes. Conversely, overexpression of Pdia4 had the opposite pathophysiological outcomes in the mice. In addition, Pdia4 positively regulated ß-cell death, dysfunction, and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in ß-cells via its action on the pathway of Ndufs3 and p22phox . Finally, we found that 2-ß-D-glucopyranosyloxy1-hydroxytrideca 5,7,9,11-tetrayne (GHTT), a Pdia4 inhibitor, suppressed diabetic development in diabetic mice. These findings characterize Pdia4 as a crucial regulator of ß-cell pathogenesis and diabetes, suggesting Pdia4 is a novel therapeutic and diagnostic target of diabetes.

Genetic Association in the Maintenance of the Mitochondrial Microenvironment and Sperm Capacity.

Sperm motility is one of the major determinants of male fertility. Since sperm need a great deal of energy to support their fast movement by active metabolism, they are thus extremely vulnerable to oxidative damage by the reactive oxygen species (ROS) and other free radicals generated as byproducts in the electron transport chain. The present study is aimed at understanding the impact of a mitochondrial oxidizing/reducing microenvironment in the etiopathology of male infertility. We detected the mitochondrial DNA (mtDNA) 4,977 bp deletion in human sperm. We examined the gene mutation of ATP synthase 6 (ATPase6 m.T8993G) in ATP generation, the gene polymorphisms of uncoupling protein 2 (UCP2, G-866A) in the uncoupling of oxidative phosphorylation, the role of genes such as manganese superoxide dismutase (MnSOD, C47T) and catalase (CAT, C-262T) in the scavenging system in neutralizing reactive oxygen species, and the role of human 8-oxoguanine DNA glycosylase (hOGG1, C1245G) in 8-hydroxy-2'-deoxyguanosine (8-OHdG) repair. We found that the sperm with higher motility were found to have a higher mitochondrial membrane potential and mitochondrial bioenergetics. The genotype frequencies of UCP2 G-866A, MnSOD C47T, and CAT C-262T were found to be significantly different among the fertile subjects, the infertile subjects with more than 50% motility, and the infertile subjects with less than 50% motility. A higher prevalence of the mtDNA 4,977 bp deletion was found in the subjects with impaired sperm motility and fertility. Furthermore, we found that there were significant differences between the occurrences of the mtDNA 4,977 bp deletion and MnSOD (C47T) and hOGG1 (C1245G). In conclusion, the maintenance of the mitochondrial redox microenvironment and genome integrity is an important issue in sperm motility and fertility.

The Inflammatory Cytokine Profile of Patients with Malignant Pleural Effusion Treated with Pleurodesis.

Patients with malignant pleural effusion (MPE) who underwent successful pleurodesis survive longer than those for whom it fails. We hypothesize that the therapy-induced inflammatory responses inhibit the cancer progression, and thereby lead to a longer survival. Thirty-three consecutive patients with MPE that were eligible for bleomycin pleurodesis between September 2015 and December 2017 were recruited prospectively. Nineteen patients (57.6%) achieved fully or partially successful pleurodesis, while 14 patients either failed or survived less than 30 days after pleurodesis. Two patients without successful pleurodesis were excluded because of missing data. Interleukin (IL)-1 beta, IL-6, IL-10, transforming growth factor beta, tumor necrosis factor alpha (TNF-α), and vascular endothelial growth factor in the pleural fluid were measured before, and after 3 and 24 h of pleurodesis. Their pleurodesis outcome and survival were monitored and analyzed. Patients who underwent successful pleurodesis had a longer survival rate. Patients without successful pleurodesis had significantly higher TNF-α and IL-10 levels in their pleural fluid than in the successful patients before pleurodesis. Following pleurodesis, there was a significant increment of IL-10 in the first three hours in the successful patients. In contrast, significant increments of TNF-α and IL-10 were found in the unsuccessful patients between 3 and 24 h after pleurodesis. The ability to produce specific cytokines in the pleural space following pleurodesis may be decisive for the patient's outcome and survival. Serial measurement of cytokines can help allocate the patients to adequate treatment strategies. Further study of the underlying mechanism may shed light on cytokine therapies as novel approaches.

Mitochondrial Function in Modulating Human Granulosa Cell Steroidogenesis and Female Fertility.

Ovarian follicle steroidogenesis associated with embryo quality results in a successful pregnancy. Each follicle consists of an oocyte surrounded by granulosa cells, which secrete several steroid and peptide hormones. Follicles harvested from women who conceived after assisted reproductive therapy (ART) had significantly higher estradiol levels in follicular fluids than the follicles from women who failed to conceive after ART. The higher follicular estradiol levels correlate well with successful fertilization following ART. Mitochondria are the central sites for steroid hormone biosynthesis. The first and rate-limiting step in the biosynthesis of steroid hormones occurs in the mitochondria of granulosa cells. In the present study, we hypothesized that the mitochondria in granulosa cells are critical for maintaining oocyte quality and fertility capacity. This study aims to clarify the relationship between mitochondrial function and granulosa cell steroidogenesis, and the relationship between hormone levels and fertility capacity. Sera, follicular fluids and granulosa cells were obtained from individuals undergoing IVF-ET treatment. The oocyte numbers, oocyte quality, fertilization rate, and pregnancy rate were also recorded. The patients who provided the granulosa cells were further classified into four groups: endometriosis, ovarian endometrioma, endometriosis without ovarian endometrioma, and polycystic ovary syndrome (PCOS); patients with other female factor infertility and male factor infertility were used as controls. We measured the levels of estradiol (E2) by radioimmunoassay. Concurrently, we analyzed the mitochondrial mass and membrane potential, and apoptosis by flow cytometry using nonyl acridine orange, TMRE, Annexin V-FITC and PI. Mitochondrial morphology was visualized by transfection with pLV-mitoDsRed. In addition, we assessed the protein levels of steroidogenic enzymes, steroidogenic acute regulatory protein (StAR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) by Western blot. The results showed significantly decreased serum E2 and follicular E2 levels, and decreased IVF outcomes, in the patients with endometriosis. Reduced mitochondrial mass and decreased mitochondrial membrane potential were correlated with lower E2. Furthermore, a significant decrease in StAR and 3ß-HSD was found in patients with ovarian endometrioma. The enzyme levels of StAR and 3ß-HSD were highly correlated with E2 levels. Finally, elevated cumulus cell apoptosis was found in the patient group with ovarian endometrioma and PCOS. In conclusion, mitochondrial dysfunction of human granulosa cells may contribute to the decline of steroidogenesis, decreased fertilization rate, oocyte maturation rate, and oocyte quality, and it can ultimately jeopardize fertility.

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy.

Targeted therapy is an efficient treatment for patients with epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Therapeutic resistance invariably occurs in NSCLC patients. Many studies have focused on drug resistance mechanisms, but only a few have addressed the metabolic flexibility in drug-resistant NSCLC. In the present study, we found that during the developing resistance to tyrosine kinase inhibitor (TKI), TKI-resistant NSCLC cells acquired metabolic flexibility in that they switched from dependence on glycolysis to oxidative phosphorylation by substantially increasing the activity of the mitochondria. Concurrently, we found the predominant expression of monocarboxylate transporter 1 (MCT-1) in the TKI-resistant NSCLC cells was strongly increased in those cells that oxidized lactate. Thus, we hypothesized that inhibiting MCT-1 could represent a novel treatment strategy. We treated cells with the MCT-1 inhibitor AZD3965. We found a significant decrease in cell proliferation and cell motility in TKI-sensitive and TKI-resistant cells. Taken together, these results demonstrated that gefitinib-resistant NSCLC cells harbored higher mitochondrial bioenergetics and MCT-1 expression. These results implied that targeting mitochondrial oxidative phosphorylation proteins or MCT-1 could serve as potential treatments for both TKI-sensitive and -resistant non-small cell lung cancer.

Reduction of AHI1 in the serum of Taiwanese with probable Alzheimer's disease.

OBJECTIVE: The development of blood-based biomarkers for early diagnosis and treatment of Alzheimer's disease (AD) is desirable. In AD model mouse brain and neuronal cells, Abelson helper integration site-1 (AHI1) protein is reduced. AHI1 facilitates intracellular amyloid precursor protein (APP) translocation to inhibit amyloidogenic pathology of AD, and thus may be an AD biomarker. METHODS: This study was conducted among 32 AD patients and 54 healthy control (HC) subjects. AHI1-related protein levels from initially collected serum samples in each group were screened using Western blotting. The protein concentrations of AHI1 and amyloid-ß (Aß), peptide(s) derived from APP, from all serum samples were analyzed using ELISA. RESULTS: In AD serum, AHI1 and a large truncated C-terminal APP fragment were significantly reduced. The average concentrations of serum AHI1 and Aß in AD were significantly lower than those in HC. Notably, AHI1 concentration in HC serum was decreased in an age-dependent manner, while it was consistently low in AD serum and had no correlation with Aß or mini-mental state examination score. The receiver operating characteristic analysis on all subjects demonstrated an area under curve (AUC) value of 0.7 for AHI1 on AD diagnosis, while the AUC increased to 0.82 on the subjects younger than 77 years old, suggesting a good diagnostic performance of serum AHI1 for AD especially at relatively young age. CONCLUSION: An early event of AHI1 reduction in the body of AD patients was observed. Serum AHI1 may be valuable for early diagnosis of AD.

Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer's Disease Model Cells.

A hallmark of Alzheimer's disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-ß (Aß) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aß production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as Ahi1-knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-ß (CTFß) and Aß42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFß in the total lysates of AD model cells as well as Aß in the culture media. Consequently, AHI1-APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.

Clinical outcomes of chemical pleurodesis using a minocycline.

BACKGROUND: Pleurodesis is often used to prevent the re-accumulation of a malignant pleural effusion (MPE). Intrapleural urokinase (IPUK) therapy facilitates lung re-expansion for patients with loculated MPE or a trapped lung that allows subsequent pleurodesis. MPE management has been traditionally regarded as a symptomatic treatment. We tried to evaluate their impact on patient survival. METHODS: There were 314 consecutive patients with symptomatic MPE that underwent minocycline pleurodesis with ( n = 109) and without ( n = 205) the antecedent IPUK therapy between September 2005 and August 2015, who were recruited for the pleurodesis outcome and survival analysis. RESULTS: The rate of successful pleurodesis was similar between the simple pleurodesis group and the IPUK therapy group followed by the pleurodesis group (69.0% versus 70.5%; p = 0.804). The patients who succeeded pleurodesis had a longer survival rate than those who failed in either the simple pleurodesis group (median, 414 versus 100 days; p < 0.001) or the IPUK therapy followed by pleurodesis group (259 versus 102 days; p < 0.001). The survival differences remained when the lung and breast cancer patients were studied separately. CONCLUSION: Successful pleurodesis translated into a better survival rate that promotes performing pleurodesis on lung re-expansion. The apparent shorter survival of the patients with loculated MPE or trapped lung, and those that did not respond to the IPUK therapy, lowered the probability of the survival benefit through the simple physical barrier by the fibrin formation to prevent the tumor spreading. The successfully induced inflammatory response by minocycline is supposed to prohibit the tumor invasion and metastasis. Further studies are warranted to clarify the mechanism and provide opportunities to develop novel therapeutic strategies.

ETF-QO Mutants Uncoupled Fatty Acid ß-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology.

The electron-transfer flavoprotein dehydrogenase gene (ETFDH) that encodes the ETF-ubiquinone oxidoreductase (ETF-QO) has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). ETF-QO is an electron carrier that mainly functions in mitochondrial fatty acid ß-oxidation and the delivery of electrons to the ubiquinone pool in the mitochondrial respiratory chain. A high frequency of c.250G>A has been found in Taiwanese patients with late-onset MADD. We postulated that the ETFDH c.250G>A mutation may concomitantly impair fatty acid ß-oxidation and mitochondrial function. Using MADD patient-derived lymphoblastoid cells and specifically overexpressed ETFDH c.92C>T, c.250G>A, or coexisted c.92C>T and c.250G>A (c.92C>T + c.250G>A) mutated lymphoblastoid cells, we addressed the genotype-phenotype relationship of ETFDH variation in the pathogenesis of MADD. The decreased adenosine triphosphate synthesis, dissipated mitochondrial membrane potentials, reduced mitochondrial bioenergetics, and increased neutral lipid droplets and lipid peroxides were found in the MADD patient-derived lymphoblastoid cells. Riboflavin and/or coenzyme Q10 supplementation rescued cells from lipid droplet accumulation. All three mutant types, c.92C>T, c.250G>A, or c.92C>T + c.250G>A, had increased lipid droplet accumulation after treatment with palmitic acid. These results help to clarify the molecular pathogenesis of MADD as a result of the high frequency of the ETFDH c.250G>A and c.92C>T mutations.

Mitochondrial translocation of estrogen receptor ß affords resistance to oxidative insult-induced apoptosis and contributes to the pathogenesis of endometriosis.

Endometriosis is the major cause of female infertility and has been linked to the action of estrogen and estrogen receptor (ER). A new pool of ERß locates within mitochondria, which regulates the endometriotic cell withstanding external insults, but its effect remains controversial. We hypothesize that mitochondrial estrogen receptor ERß (mtERß) is a pivotal regulator in estradiol-mediated cell protection leading to the endometriotic progression. We observed elevated levels of ERß in the endometriotic tissues. A dramatic increase of ERß in mitochondria (mtERß) was found in the ectopic endometriotic tissues, or the estradiol-primed primary endometriotic cells. We analyzed the mtERß-specific overexpressing clone (mtsERß), which exhibited higher mitochondrial bioenergetics and lower reactive oxygen species (ROS) generation. The mtsERß-overexpressed endometriotic cells displayed an enhanced migration phenotype, whereas significantly attenuated migration by mitochondrial respiratory inhibitor (oligomycin) or ERß deficiency by shERß. Further investigations revealed that ERß directly modulated mitochondrial DNA (mtDNA) gene expression by interacting with mtDNA D-loop and polymerase γ. The mtsERß afforded a resistance to oxidative insult-induced apoptosis through the induction of the ROS scavenger enzyme Mn-superoxide dismutase and anti-apoptotic protein Bcl-2. Collectively, the demonstration of mtERß responses in restoration of mitochondrial bioenergetics and inhibition of mitochondria-dependent apoptotic events provides insight into the pathogenesis of endometriosis, suggesting ERß-selective estrogen receptor modulator may serve as novel therapeutics of endometriosis in the future.

G-Protein Coupled Estrogen Receptor in Breast Cancer.

The G-protein coupled estrogen receptor (GPER), an alternate estrogen receptor (ER) with a structure distinct from the two canonical ERs, being ERα, and ERß, is expressed in 50% to 60% of breast cancer tissues and has been presumed to be associated with the development of tamoxifen resistance in ERα positive breast cancer. On the other hand, triple-negative breast cancer (TNBC) constitutes 15% to 20% of breast cancers and frequently displays a more aggressive behavior. GPER is prevalent and involved in TNBC and can be a therapeutic target. However, contradictory results exist regarding the function of GPER in breast cancer, proliferative or pro-apoptotic. A better understanding of the GPER, its role in breast cancer, and the interactions with the ER and epidermal growth factor receptor will be beneficial for the disease management and prevention in the future.

Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer's Disease Model Cells.

Alzheimer's disease (AD) is characterized by extracellular deposition of amyloid plaques, which are predominantly composed of amyloid-ß (Aß) peptide derived from amyloid precursor protein (APP) cleavage. APP interacts with tropomyosin receptor kinase A, a neurotrophic receptor associated with gangliosides and mediating neuronal survival and differentiation through the extracellular signal-regulated protein kinase (ERK) pathway. The ganglioside Hp-s1's analogue Hp-s1A exerts neuritogenic activity; however, its effect on AD pathology remains unknown. To test the hypothesis that Hp-s1A is a potential candidate to treat AD, we established the AD-modeled cell line by expressing human Swedish and Indiana APP gene (APP-Swe/Ind) in N2a mouse neuroblastoma cells. The cells were treated with Hp-s1A or monosialoganglioside GM1 for comparison. The AD model cells expressing APP-Swe/Ind exhibited a significant reduction in viability, as well as neurite outgrowth rate, in comparison to the control cells expressing APP-695. APP C-terminal fragment-ß (CTFß) and Aß42 were increased in the AD cell lysates and the culture media, respectively. With the treatment of either Hp-s1A or GM1 at 1 µM, the AD model cells showed a significant increase in viability; however, only Hp-s1A reduced CTFß levels in these cells. Further analysis of the culture media revealed that Hp-s1A also reduced Aß42 production from AD model cells. The phosphorylation of ERK was elevated and the neurite outgrowth rate was restored with Hp-s1A treatment. In conclusion, the ganglioside analogue Hp-s1A inhibited amyloidogenic processing of APP and promoted neurotrophic activity and survival of AD model cells. Hp-s1A has great potential in AD therapeutic development.

Coenzyme Q10 serves to couple mitochondrial oxidative phosphorylation and fatty acid ß-oxidation, and attenuates NLRP3 inflammasome activation.

Multiple acyl-CoA dehydrogenase deficiency (MADD), an autosomal recessive metabolic disorder of fatty acid metabolism, is mostly caused by mutations in the ETFA, ETFB or ETFDH genes that result in dysfunctions in electron transfer flavoprotein (ETF) or electron transfer flavoprotein-ubiquinone dehydrogenase (ETFDH). In ß-oxidation, fatty acids are processed to generate acyl-CoA, which is oxidised by flavin adenine dinucleotide and transfers an electron to ETF and, through ETFDH, to mitochondrial respiratory complex III to trigger ATP synthesis. Coenzyme Q10 (CoQ10) is believed to be a potential treatment that produces symptom relief in some MADD patients. CoQ10 acts as a key regulator linking ETFDH and mitochondrial respiratory complex III. Our aim is to investigate the effectiveness of CoQ10 in serving in the ETF/ETFDH system to improve mitochondrial function and to reduce lipotoxicity. In this study, we used lymphoblastoid cells with an ETFDH mutation from MADD patients. ETFDH dysfunction caused insufficient ß-oxidation, leading to increasing lipid droplet and lipid peroxide accumulation. In contrast, supplementation with CoQ10 significantly recovered mitochondrial function and concurrently decreased the generation of reactive oxygen species and lipid peroxides, inhibited the accumulation of lipid droplets and the formation of the NOD-like receptor family pyrin domain-containing three (NLRP3) inflammasome, and reduced interleukin-1ß release and cell death. These results clarify the causal role of CoQ10 in coupling the electron transport chain with ß-oxidation, which may promote the development of CoQ10-directed therapies for MADD patients.

Elevated IgM against Nε-(Carboxyethyl)lysine-modified Apolipoprotein A1 peptide 141-147 in Taiwanese with Alzheimer's disease.

OBJECTIVE: Advanced glycation end products (AGEs) are involved in the pathogenesis of Alzheimer's disease (AD). Specific AGEs and related autoantibodies may be early AD markers. Apolipoprotein A1 (ApoA1) and its post-translational modifications (PTMs) are associated with neurodegeneration and thus selected to test the hypothesis. METHODS: Serum samples from totally 64 AD or health control (HC) Taiwanese were analyzed. ApoA1 was isolated from the serum and examined through LC-MS/MS and PTM analyses. A specific AGE and its autoantibodies were determined using Western blotting or ELISA. RESULTS: Nε-(Carboxyethyl)lysine (CEL) modification, a kind of AGEs, was identified on ApoA1 peptide 141-QKVEPLR-147 (ApoA1141-147) from AD serum. Total CEL adducts and autoantibodies against CEL on ApoA1141-147 were significantly increased in AD samples. The area under the receiver operating characteristic curve was 0.965 for anti-CEL-ApoA1141-147 IgM. Mini Mental State Examination scores of the AD patients were positively correlated with anti-CEL-ApoA1141-147 IgM, suggesting that the IgM level is high in early AD pathology and decreased with disease progression. CONCLUSION: CEL modification was increased on AD serum proteins including ApoA1, leading to an elevated anti-CEL IgM in early disease state. Both CEL and anti-CEL IgM may serve as AD biomarkers.

Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is most commonly caused by the A3243G mutation of mitochondrial DNA. The capacity to utilize fatty acid or glucose as a fuel source and how such dynamic switches of metabolic fuel preferences and transcriptional modulation of adaptive mechanism in response to energy deficiency in MELAS syndrome have not been fully elucidated. The fibroblasts from patients with MELAS syndrome demonstrated a remarkable deficiency of electron transport chain complexes I and IV, an impaired cellular biogenesis under glucose deprivation, and a decreased ATP synthesis. In situ analysis of the bioenergetic properties of MELAS cells demonstrated an attenuated fatty acid oxidation that concomitantly occurred with impaired mitochondrial respiration, while energy production was mostly dependent on glycolysis. Furthermore, the transcriptional modulation was mediated by the AMP-activated protein kinase (AMPK) signaling pathway, which activated its downstream modulators leading to a subsequent increase in glycolytic flux through activation of pyruvate dehydrogenase. In contrast, the activities of carnitine palmitoyltransferase for fatty acid oxidation and acetyl-CoA carboxylase-1 for fatty acid synthesis were reduced and transcriptional regulation factors for biogenesis were not altered. These results provide novel information that MELAS cells lack the adaptive mechanism to switch fuel source from glucose to fatty acid, as glycolysis rates increase in response to energy deficiency. The aberrant secondary cellular responses to disrupted metabolic homeostasis mediated by AMPK signaling pathway may contribute to the development of the clinical phenotype.

Estrogen, Estrogen Receptor and Lung Cancer.

Estrogen has been postulated as a contributor for lung cancer development and progression. We reviewed the current knowledge about the expression and prognostic implications of the estrogen receptors (ER) in lung cancer, the effect and signaling pathway of estrogen on lung cancer, the hormone replacement therapy and lung cancer risk and survival, the mechanistic relationship between the ER and the epidermal growth factor receptor (EGFR), and the relevant clinical trials combining the ER antagonist and the EGFR antagonist, to investigate the role of estrogen in lung cancer. Estrogen and its receptor have the potential to become a prognosticator and a therapeutic target in lung cancer. On the other hand, tobacco smoking aggravates the effect of estrogen and endocrine disruptive chemicals from the environment targeting ER may well contribute to the lung carcinogenesis. They have gradually become important issues in the course of preventive medicine.