Exploring the Potential Role of Oligodendrocyte-Associated PIP4K2A in Alzheimer's Disease Complicated with Type 2 Diabetes Mellitus via Multi-Omic Analysis.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two common diseases that affect the elderly population worldwide. The identification of common genes associated with AD and T2DM holds promise for potential biomarkers and intriguing pathogenesis of these two complicated diseases. This study utilized a comprehensive approach by integrating transcriptome data from multiple cohorts, encompassing both AD and T2DM. The analysis incorporated various data types, including blood and tissue samples as well as single-cell datasets, allowing for a detailed assessment of gene expression patterns. From the brain region-specific single-cell analysis, PIP4K2A, which encodes phosphatidylinositol-5-phosphate 4-kinase type 2 alpha, was found to be expressed mainly in oligodendrocytes compared to other cell types. Elevated levels of PIP4K2A in AD and T2DM patients' blood were found to be associated with key cellular processes such as vesicle-mediated transport, negative regulation of autophagosome assembly, and cytosolic transport. The identification of PIP4K2A's potential roles in the cellular processes of AD and T2DM offers valuable insights into the development of biomarkers for diagnosis and therapy, especially in the complication of these two diseases.

A comprehensive bibliometric analysis of global research on the role of acrolein in Alzheimer's disease pathogenesis: involvement of amyloid-beta.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and behavioral decline. Acrolein, an environmental pollutant and endogenous compound, is implicated in AD development. This research employs bibliometric analysis to assess current trends and key areas concerning acrolein-AD interaction. Methods: The Web of Science was used to extensively review literature on acrolein and AD. Relevant data were systematically gathered and analyzed using VOSviewer, CiteSpace, and an online bibliometric tool. Results: We identified 120 English publications in this specialized field across 19 journals. The Journal of Alzheimer's Disease was the most prominent. The primary contributors, both in terms of scientific output and influence, were the USA, the University of Kentucky, and Ramassamy C, representing countries/regions, institutions, and authors, respectively. In this field, the primary focus was on thoroughly studying acrolein, its roles, and its mechanisms in AD utilizing both in vivo and in vitro approaches. A significant portion of the research was based on proteomics, revealing complex molecular processes. The main focuses in the field were "oxidative stress," "lipid peroxidation," "amyloid-beta," and "cognitive impairment." Anticipated future research trajectories focus on the involvement of the internalization pathway, covering key areas such as synaptic dysfunction, metabolism, mechanisms, associations, neuroinflammation, inhibitors, tau phosphorylation, acrolein toxicity, brain infarction, antioxidants, chemistry, drug delivery, and dementia. Our analysis also supported our previous hypothesis that acrolein can interact with amyloid-beta to form a protein adduct leading to AD-like pathology and altering natural immune responses. Conclusion: This study provides a broad and all-encompassing view of the topic, offering valuable insights and guidance to fellow researchers. These emerging directions underscore the continuous exploration of the complexities associated with AD. The analyses and findings aim to enhance our understanding of the intricate relationship between acrolein and AD for future research.

Aquaporin-8 promotes human dermal fibroblasts to counteract hydrogen peroxide-induced oxidative damage: A novel target for management of skin aging.

The skin is subjected to various external factors that contribute to aging including oxidative stress from hydrogen peroxide (H2O2). This study investigated the distribution of aquaporin-8 (AQP8), a protein that transports H2O2 across biological membranes, in skin cells, and its effects in mitigating H2O2-induced oxidative damage. Human dermal fibroblasts were treated with increasing concentrations of H2O2 to evaluate oxidative damage. Cell viability, reactive oxygen species (ROS) generation, and the expression of specific genes associated with skin aging (IL-10, FPR2, COL1A1, KRT19, and Aggrecan) were evaluated and AQP8 expression was assessed via quantitative polymerase chain reaction and western blotting. Small-interfering RNA was used to silence the AQP8 gene and evaluate its significance. The results show that H2O2 treatment reduces cell viability and increases ROS generation, leading to oxidative damage that affects the expression of target molecules. Interestingly, H2O2-treated cells exhibit high levels of AQP8 expression and gene silencing of AQP8 reverses high levels of ROS and low levels of COL1A1, KRT19, and Aggrecan expression in stressed cells, indicating that AQP8 plays a vital role in preventing oxidative damage and consequent aging. In conclusion, AQP8 is upregulated in human dermal fibroblasts during H2O2-induced oxidative stress and may help prevent oxidative damage and aging. These findings suggest that AQP8 could be a potential therapeutic target for skin aging. Further research is necessary to explore the feasibility of using AQP8 as a preventive or therapeutic strategy for maintaining skin health.

HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-Related HCC with Distinct Features.

Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform. Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC. Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort. Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.

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.

Emergence and Persistent Dominance of SARS-CoV-2 Omicron BA.2.3.7 Variant, Taiwan.

Since April 2022, waves of SARS-CoV-2 Omicron variant cases have surfaced in Taiwan and spread throughout the island. Using high-throughput sequencing of the SARS-CoV-2 genome, we analyzed 2,405 PCR-positive swab samples from 2,339 persons and identified the Omicron BA.2.3.7 variant as a major lineage within recent community outbreaks in Taiwan.

Lymphocyte disturbance and functional assessment of the [Asp521Asn] ZAP70 mutation.

Activated zeta-chain-associated protein kinase 70 (ZAP70) phosphorylates the TCRαß:CD3:zeta complex to diversify and amplify TCR signaling. Patients with ZAP70 mutations can present with phenotypes of immune dysregulation as well as infection. We identified the first Taiwanese boy with the [Asp521Asn] ZAP70 mutation who presented with recurrent pneumonia, inflammatory bowel disease-like diarrhea, transient hematuria and autoimmune hepatitis. He had isolated CD8 lymphopenia, eosinophilia, hypogammaglobulinemia, and impaired lymphocyte proliferation. Downstream CD3/CD28 signaling, phosphorylation of AKT, ZAP70 and Ca2+ influx were decreased in [Asp521Asn] ZAP70 lymphocytes. Immunophenotyping analysis revealed expansion of transitional B and CD21-low B cells, Th2-skewing T follicular helper cells, but lower Treg cells. The Asp521Asn-ZAP70 hindered TCR-CD3 downstream phosphorylation and disturbed lymphocyte subgroup "profiles" leading to autoimmunity/autoinflammation. Further large-scale studies are warranted to clarify this lymphocyte disturbance. The prognosis significantly depends on hematopoietic stem cell transplantation, but not the genotype, the presence of opportunistic infections or immune dysregulation.

Genomic profiling with whole-exome sequencing revealed distinct mutations and novel pathways in Asian melanoma.

The clinical characteristics of malignant melanoma are highly variable between patient populations of different ethnicities. To explore the underlining genetic variations, we reviewed the clinical data of 242 malignant melanoma cases from Taiwan and among them submitted formalin-fixed paraffin-embedded tissue samples from 37 patients for whole-exome sequencing to identify the mutational signatures, tumor mutation burden and specific gene mutations. The genomic profiles and clinical outcomes were compared with the information derived from the publicly available TCGA and TGEN databases. Mutation signature 12 was the dominant signature in Taiwanese patients and represented approximately 45% of the mutation signatures observed. In contrast, mutation signature 7 was the most prominent among cases available in the TCGA database. Common gene mutations found in the TCGA melanoma dataset were not frequently found in melanomas from Taiwanese patients. There were a significant number of specific gene mutations that exclusively occurred in acral subtype but not in non-acral subtype melanomas, and vice versa. While certain common mutations form a shared core of genetic features, there appear to be specific genetic pathways that are involved in the occurrence of melanomas that grow in non-UV-exposed areas. Our findings have shed light on the tumorigenesis pathways involved in malignant melanoma.

Elevated alanine aminotransferase is associated with biphasic insulin secretion in the healthy elderly Han Chinese population.

OBJECTIVE: To evaluate the relationship between alanine transaminase (ALT) level and biphasic insulin secretion (BPIS) in healthy elderly Han Chinese individuals. METHODS: This cross-sectional study enrolled healthy elderly participants aged ≥60 years that were part of a health examination programme. In order to explore the correlation and severity of the clinical condition, those with any possible confounding factors known to affect insulin secretion or liver function were excluded from the study. BPIS was calculated using an equation developed previously by this research team. RESULTS: This study enrolled 39 845 healthy elderly individuals (19 058 males and 20 787 females). Participants were stratified into four quartile groups according to their ALT level. In both males and females, the increasing ALT quartiles (ordinal variable) were associated with greater values of log-transformed first-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS). The correlation and the linear regression model showed that increasing ALT level was significantly correlated with higher log-transformed FPIS and SPIS. CONCLUSIONS: ALT was positively correlated with BPIS in a healthy elderly population in both men and women. Elevated ALT may serve as an indicating factor for developing metabolic syndrome and type 2 diabetes mellitus in healthy elderly individuals.

Microtube Array Membrane Encapsulated Cell Therapy: A Novel Platform Technology Solution for Treatment of Alzheimer's Disease.

Alzheimer's disease is the most frequent form of dementia in aging population and is presently the world's sixth largest cause of mortality. With the advancement of therapies, several solutions have been developed such as passive immunotherapy against these misfolded proteins, thereby resulting in the clearance. Within this segment, encapsulated cell therapy (ECT) solutions that utilize antibody releasing cells have been proposed with a multitude of techniques under development. Hence, in this study, we utilized our novel and patented Microtube Array Membranes (MTAMs) as an encapsulating platform system with anti-pTau antibody-secreting hybridoma cells to study the impact of it on Alzheimer's disease. In vivo results revealed that in the water maze, the mice implanted with hybridoma cell MTAMs intracranially (IN) and subcutaneously (SC) showed improvement in the time spent the goal quadrant and escape latency. In passive avoidance, hybridoma cell loaded MTAMs (IN and SC) performed significantly well in step-through latency. At the end of treatment, animals with hybridoma cell loaded MTAMs had lower phosphorylated tau (pTau) expression than empty MTAMs had. Combining both experimental results unveiled that the clearance of phosphorylated tau might rescue the cognitive impairment associated with AD.

A Clinical and Integrated Genetic Study of Isolated and Combined Dystonia in Taiwan.

Dystonia is a clinically and genetically heterogeneous movement disorder. However, genetic causes of dystonia remain largely unknown in Asian subjects. To address this, we applied an integrated two-step approach that included gene dosage analysis and a next-generation sequencing panel containing 72 known genes causative for dystonia and related movement disorders to 318 Taiwanese patients with isolated or combined dystonia. Whole-genome sequencing was performed for one multiplex family with no known causative variant. The panel confirmed the genetic diagnosis in 40 probands (12.6%). A genetic diagnosis was more likely with juvenile onset compared with adult onset (24.2% vs 10.8%; P = 0.03) and those with combined features, especially with myoclonus, compared with isolated dystonia (35.3% vs 10.5%; P = 0.004). The most common causative genes were SGCE followed by GCH1, TH, CACNA1B, PRRT2, MR1, CIZ1, PLA2G6, and PRKN. Genetic causes were identified from single cases in TOR1A, TUBB4A, THAP1, ATP1A3, ANO3, GNAL, KMT2B, SLC6A3, ADCY5, CYP27A1, PANK2, C19orf12, and SPG11. The whole-genome sequencing analysis identified a novel intragenic deletion in OPHN1 in a multiplex family with X-linked dystonia and intellectual delay. Our findings delineate the genetic architecture and clinical spectrum of dystonia-causing pathogenic variants in an Asian population.

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.

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.

Clinical and functional characterization of a novel STUB1 frameshift mutation in autosomal dominant spinocerebellar ataxia type 48 (SCA48).

BACKGROUND: Heterozygous pathogenic variants in STUB1 are implicated in autosomal dominant spinocerebellar ataxia type 48 (SCA48), which is a rare familial ataxia disorder. We investigated the clinical, genetic and functional characteristics of STUB1 mutations identified from a Taiwanese ataxia cohort. METHODS: We performed whole genome sequencing in a genetically undiagnosed family with an autosomal dominant ataxia syndrome. Further Sanger sequencing of all exons and intron-exon boundary junctions of STUB1 in 249 unrelated patients with cerebellar ataxia was performed. The pathogenicity of the identified novel STUB1 variant was investigated. RESULTS: We identified a novel heterozygous frameshift variant, c.832del (p.Glu278fs), in STUB1 in two patients from the same family. This rare mutation is located in the U-box of the carboxyl terminus of the Hsc70-interacting protein (CHIP) protein, which is encoded by STUB1. Further in vitro experiments demonstrated that this novel heterozygous STUB1 frameshift variant impairs the CHIP protein's activity and its interaction with the E2 ubiquitin ligase, UbE2D1, leading to neuronal accumulation of tau and α-synuclein, caspase-3 activation, and promoting cellular apoptosis through a dominant-negative pathogenic effect. The in vivo study revealed the influence of the CHIP expression level on the differentiation and migration of cerebellar granule neuron progenitors during cerebellar development. CONCLUSIONS: Our findings provide clinical, genetic, and a mechanistic insight linking the novel heterozygous STUB1 frameshift mutation at the highly conserved U-box domain of CHIP as the cause of autosomal dominant SCA48. Our results further stress the importance of CHIP activity in neuronal protein homeostasis and cerebellar functions.

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.

Diagnosis of Arboleda-Tham syndrome by whole genome sequencing in an Asian boy with severe developmental delay.

Diagnosis of a 9-month-old boy brought to our genetics clinic with chief complaints of developmental delay (DD), failure to thrive, microcephaly, trunk hypotonia and hypertonia of the extremities. Multiple congenital defects but no significant syndromes or diseases were impressed. The chromosomal analysis and array comparative genomic hybridization (aCGH) revealed no significant pathogenic changes. Whole Genome Sequencing (WGS) identified a p.Glu1139fs de novo mutation of the KAT6A gene. The patient's phenotype was consistent clinically with Arboleda-Tham syndrome (ARTHS). Reviewing the literature showed that this is the first patient in Taiwan detected by WGS and that it involves a novel mutation. Comparing the highly variable clinical presentations of this syndrome with our patient, this boy's features and severe developmental defects seem to be due to a late-truncating mutation at the carboxyl end of the KAT6A protein. Our study demonstrates the power of WGS to confirm a diagnosis within 4 weeks for this rare condition.

Protective Evaluation of Compounds Extracted from Root of Rhodiola rosea L. against Methylglyoxal-Induced Toxicity in a Neuronal Cell Line.

Rhodiola rosea L. (R. rosea) is one of the most beneficial medicinal plants and it is studied as an adaptogen. This study aims to evaluate the neuroprotective activity of compounds extracted from the root of R. rosea against methylglyoxal (MG)-induced apoptosis in neuro-2A (N2A) cells. The root of R. rosea was extracted with ethanol and partitioned with water, ethyl acetate, and n-butanol fractions to evaluate acetylcholinesterase (AChE) inhibitory activity and neuroprotective activity. The ethyl acetate fraction exhibited the highest values of AChE inhibitory activity (49.2% ± 3%) and cell viability (50.7% ± 4.8%) for neuroprotection. The structure identification of the most potential fraction (ethyl acetate fraction) revealed 15 compounds, consisting of three tannins, five flavonoids, and seven phenolics by infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. All compounds were evaluated for their neuroprotective activity. Salidroside had the most potential neuroprotective activity. Gallic acid and methyl gallate had potential cytotoxicity in N2A cells. This study showed that R. rosea might have potential neuroprotective activities.

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.

Alzheimer's Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies.

Alzheimer's (or Alzheimer) disease (AD) is the most prevalent subset of dementia, affecting elderly populations worldwide. The cumulative costs of the AD care are rapidly accelerating as the average lifespan increases. Onset and risk factors for AD and AD-like dementias have been largely unknown until recently. Studies show that chronic type II diabetes mellitus (DM) is closely associated with neurodegeneration, especially AD. Type II DM is characterized by the cells' inability to take up insulin, as well as chronic hyperglycemia. In the central nervous system, insulin has crucial regulatory roles, while chronic hyperglycemia leads to formation and accumulation of advanced glycation end products (AGEs). AGEs are the major contributor to insulin resistance in diabetic cells, due to their regulatory role on sirtuin expression. Insulin activity in the central nervous system is known to interact with key proteins affected in neurodegenerative conditions, such as amyloid-ß precursor protein (AßPP or APP), huntingtin-associated protein-1 (HAP1), Abelson helper integration site-1 (AHI1 or Jouberin), kinesin, and tau. Sirtuins have been theorized to be the mechanism for insulin resistance, and have been found to be affected in neurodegenerative conditions as well. There are hints that all these neuronal proteins may be closely related, although the mechanisms remain unclear. This review will gather existing research on these proteins and highlight the link between neurodegenerative conditions and diabetes mellitus.