Glucometabolic-Related Genes as Diagnostic Biomarkers and Therapeutic Targets for Alzheimer's Disease and Type 2 Diabetes Mellitus: A Bioinformatics Analysis.

Background: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two widespread chronic disorders characterized by shared risk factors and molecular pathways. Glucose metabolism, pivotal for cellular homeostasis and energy supply, plays a critical role in these diseases. Its disturbance has been linked to the pathogenesis of both AD and T2DM. However, a comprehensive investigation into the specific roles of glucometabolic genes in the onset and progression of AD and T2DM has yet to be conducted. Methods: By analyzing microarray datasets from the Gene Expression Omnibus (GEO) repository, we identified differentially expressed glucometabolic genes (DEGs) in AD and T2DM cohorts. A range of bioinformatics tools were employed for functional annotation, pathway enrichment, protein interaction network construction, module analysis, ROC curve assessment, correlation matrix construction, gene set enrichment analysis, and gene-drug interaction mapping of these DEGs. Key genes were further validated using quantitative real-time polymerase chain reaction (qRT-PCR) in AD and T2DM murine models. Results: Our investigation identified 41 glucometabolic-related DEGs, with six prominent genes (G6PD, PKM, ENO3, PFKL, PGD, and TALDO1) being common in both AD and T2DM cohorts. These genes play crucial roles in metabolic pathways including glycolysis, pentose phosphate pathway, and amino sugar metabolism. Their diagnostic potential was highlighted by area under curve (AUC) values exceeding 0.6 for AD and 0.8 for T2DM. Further analysis explored the interactions, pathway enrichments, regulatory mechanisms, and potential drug interactions of these key genes. In the AD murine model, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed significant upregulation of G6pd, Eno3, and Taldo1. Similarly, in the T2DM murine model, elevated expression levels of G6pd, Pfkl, Eno3, and Pgd were observed. Conclusion: Our rigorous research sheds light on the molecular interconnections between AD and T2DM from a glucometabolic perspective, revealing new opportunities for pharmacological innovation and therapeutic approaches. This study appears to be the first to extensively investigate glucometabolic-associated DEGs and key genes in both AD and T2DM, utilizing multiple datasets. These insights are set to enhance our understanding of the complex pathophysiology underlying these widespread chronic diseases.

Mechanism of Hepatocyte Apoptosis.

Hepatocyte apoptosis plays important roles in both the removal of external microorganisms and the occurrence and development of liver diseases. Different conditions, such as virus infection, fatty liver disease, hepatic ischemia reperfusion, and drug-induced liver injury, are accompanied by hepatocyte apoptosis. This review summarizes recent research on the mechanism of hepatocyte apoptosis involving the classical extrinsic and intrinsic apoptotic pathways, endoplasmic reticulum stress, and oxidative stress-induced apoptosis. We emphasized the major causes of apoptosis according to the characteristics of different liver diseases. Several concerns regarding future research and clinical application are also raised.

[The clinical characteristic of 43 cases of neuroendocrine tumors with liver metastases].

OBJECTIVE: To analyze the clinical characteristics of liver metastases of neuroendocrine tumors (NET) and its treatment outcome, so as to further cognition of NET. METHODS: The clinical data of patients with liver metastases of NET diagnosed by Peking Union Medical College Hospital during January 1996 to July 2010 were analyzed retrospectively. RESULTS: The ratio of male to female was 1:1.15 (20:23). The median age at onset of the patients with liver metastases of NET was 47.5 (26 - 70) years. The median duration from onset to diagnosis was 4 (0 - 120) months. The liver metastases were the first manifestation in 69.8% (30/43) cases. The detection rate of primary lesions with routine abdominal imaging (B-type ultrasonography, CT, MRI) was 65.1% (28/43), while increased to 90.7% (39/43) when combined the following one or more special examinations including somatostatin receptor scintigraphy (SRS), PET-CT, endoscopic ultrasound (EUS) (P = 0.004). The definite diagnosis methods mainly depended on surgical specimens (69.8%, 30/43). The ratio of nonfunctional to functional NET with liver metastases was 1.87:1 (28:15). The primary tumors were most commonly located in pancreas [39.3% (11/28) and 73.3% (11/15)], followed by stomach [21.4% (6/28) and 13.3% (2/15)]. Totally 88.4% (38/43) patients received operation, and 9.3% (4/43) patients had reoperation due to missed diagnosis of the primary tumors on earlier operation. Non-surgical treatments included octreotide acetate long-acting release, interventional therapy, chemotherapy and radiotherapy, which were difficult to be evaluated due to less follow-up cases. CONCLUSIONS: Liver metastases of NET are common and even the first manifestation symptom. Primary NET with liver metastases is the most commonly nonfunctional and located in digestive system. The detection rates of primary lesions are increased by special examinations including SRS, PET-CT and EUS. Surgical specimens are helpful to the final diagnosis, but it is necessary to improve the preoperative diagnostic rate of primary tumors to avoid repeat surgeries.

[The diagnostic value of plasma chromogranin A in neuroendocrine tumors].

OBJECTIVE: To investigate the value of plasma chromogranin A (CgA) in the diagnosis of neuroendocrine tumors (NETs), and to evaluate the diagnostic efficacy of plasma CgA in different gastrointestinal pancreatic neuroendocrine tumors (GEP NETs). To investigate the role of monitoring plasma CgA in the progress of GEP NETs. METHODS: ELISA kits were used to measure the CgA plasma level in 56 cases of GEP NETs, 52 cases of pheochromocytoma, and 7 cases of small cell lung cancer (SCLC) and 52 cases of normal controls respectively. The sensitivity and specificity of plasma CgA in diagnosis of gastrointestinal pancreatic endocrine tumor; pheochromocytomas and SCLC were calculated. The group of GEP NETs included 13 cases of gastrointestinal carcinoid tumors, 13 cases of gastrinomas, 12 cases of islet cell tumors and 18 cases of other type tumors of GEP NETs. The differences of plasma CgA levels and various sensitivities were compared in different types tumors of GEP NETs. Meanwhile the value of plasma CgA in the diagnosis of metastatic and nonmetastatic tumors in GEP NETs was determined. RESULTS: The median CgA levels and quartile of the groups of GEP NETs, pheochromocytomas and SCLCs were 84.5 U/L and 38.3 - 175.5 U/L, 154.0 U/L and 53.3 - 243.8 U/L, and 55.0 U/L and 19.0 - 79.0 U/L respectively, which were significantly higher than that of (18.5 U/L and 12.3 - 25.8 U/L) normal controls (P < 0.001). The sensitivities of CgA in diagnosis of GEP NETs, pheochromocytomas and SCLCs were 82.1%, 88.5% and 57.1% respectively, and the specificities were all 96.2%. In the group of GEP NETs, the CgA level of gastrinoma was significant higher than the groups of carcinoid, islet cell tumor, and other type tumors of GEP NETs. The sensitivities of CgA in diagnosis of gastrinoma, carcinoid tumors, and islet cell tumors were 92.3%, 84.6% and 50.0% respectively. In the group of GEP NETs, it showed significant differences in CgA levels in patients with metastatic and non-metastatic tumors. CONCLUSION: The plasma CgA levels were elevated significantly in the GEP NETs, and showed a high sensitivity and specificity particularly in the diagnosis of gastrinoma. CgA also can be used as a marker in monitoring tumor development and evaluating prognosis during the clinical application.

[Study on the chemical constituents of the fruit handles from Schizandra chinensis].

OBJECTIVE: To study the chemical constituents of the fruit handles from Schizandra chinensis. METHODS: Compounds from the 85% ethanol extracts were isolated by silica gel, Sephadex LH-20, recrystal, etc., and their structures were identified by the spectral analysis and chemical evidence. RESULTS: Eight compounds were isolated and identified as wuweizisu C (I), ganwuweizic acid(II), beta-sitosterol(III), gomisin A(IV), schizandrin(V), daucosterol(VI), wuweizisu A(VII), gamma-schizandrin (VIII). CONCLUSION: Compounds I - VIII are isolated from the fruit handles of Schizandra chinensis for the first time.

Evaluation of the diagnostic value of serum tumor markers, and fecal k-ras and p53 gene mutations for pancreatic cancer.

OBJECTIVE: To evaluate the diagnostic value for pancreatic cancer of four serum tumor markers, carbohydrate antigen (CA) 199, CA242, CA50 and carcino-embryonic antigen (CEA), and fecal k-ras and p53 gene mutations. METHODS: From February 2002 to March 2004, 136 patients were consecutively diagnosed with pancreatic cancer in the three participating medical centers. The diagnosis was confirmed by pathology in 53 patients, of whom five were excluded because they did not have measurement of serum tumor marker. The remaining 48 patients comprised the case group in the study. Ninety-six patients with benign digestive diseases diagnosed during the same period were recruited as control subjects. They were matched by sex and age. In both groups, serum CA199, CA242, CA50 and CEA were measured by ELISA, and fecal k-ras and p53 gene mutations were measured by PCR-restriction fragment length polymorphism and PCR-single strand conformational polymorphism, respectively. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to compare their diagnostic value, as well as the sensitivity, specificity and likelihood ratio. Moreover, independent and sensitive tests from these non-invasive approaches were selected to form a parallel test that may have further improved sensitivity for diagnosis of pancreatic cancer. RESULTS: The AUC of serum CA199 and CA242 were 0.821 (95%CI 0.725-0.917) and 0.821 (95%CI 0.723-0.919), respectively. The optimal diagnostic value of serum CA199 for pancreatic cancer was 93 U/mL, with a sensitivity of 73.7% and specificity of 91.4%. The positive likelihood ratio of CA199 was 8.57, and the negative likelihood ratio was 0.29. The optimal diagnostic value of serum CA242 was 25 U/mL, with a sensitivity of 71.1% and specificity of 93.5%. The positive likelihood ratio of CA242 was 10.94, and the negative likelihood ratio was 0.31. The sensitivity of fecal k-ras gene mutation for diagnosis of pancreatic cancer was 77.4%, and the specificity was 81.2%. The positive and negative likelihood ratios of fecal k-ras gene mutation were 4.12 and 0.28, respectively. The sensitivity and specificity of fecal p53 gene mutation were 25.8% and 95.3%, respectively, and its positive and negative likelihood ratios were 5.49 and 0.78. The rate of fecal k-ras mutation was higher in patients with benign pancreatic diseases (57.14%) than that of controls with non-pancreatic disorders. The values of serum tumor markers and fecal k-ras and p53 gene mutation rates were not significantly different in subgroups according to site or stage of pancreatic cancer. The sensitivity and specificity of the parallel test of serum CA199 and fecal k-ras gene mutation were 94.06% and 74.22%, respectively, while the sensitivity and specificity of the parallel test of serum CA242 and fecal k-ras were 93.47% and 75.92%, respectively. CONCLUSIONS: Serum CA199 and CA242 are valuable diagnostic tools for pancreatic cancer. The diagnostic value is further improved when they are combined with fecal k-ras gene mutation measurement.

[The role of fecal elastase-1 in pancreatic diseases].

OBJECTIVE: To determine the average concentration and its ranges of fecal elastase-1 (FE1) in healthy controls; to calculate the sensitivity and specificity of FE1 in the assay of pancreatic insufficiency; and to evaluate the diagnosing and differentiating value of FE1 in pancreatic diseases. METHODS: Used the FE1 ELISA kit to quantitate the concentrations of FE1 in 73 healthy controls with different age groups, and 30 patients with chronic pancreatitis, 17 patients with pancreatic cancer and 24 patients with non-pancreatic digestive diseases. Urine N-benzoyl-tyrosyl-para-aminobenzoic acid (BT-PABA) was measured in those patients as a comparison simultaneously. RESULTS: (1) FE1 concentration in healthy controls ranged from 136 to 1380 (966.93 +/- 256.17) microg/g. There were no statistical significances between the different age groups (P > 0.05). (2) The FE1 of both groups of chronic pancreatitis [(208.80 +/- 197.72) microg/g, ranged from 15 to 900 microg/g] and pancreatic cancer [(175.00 +/- 172.25) microg/g, ranged from 15 to 460 microg/g] compare to that in non-pancreatic digestive diseases [(502.63 +/- 210.28) microg/g] were significantly low (P < 0.05). (3) FE1 concentration of pancreatic diarrhea [(166.11 +/- 192.35) microg/g] was significant lower than that of non-pancreatic diarrhea [(444.50 +/- 212.91) microg/g] (P < 0.01). The sensitivity and specificity of FE1 for diagnosing pancreatic diarrhea were 77.8% and 89.5% as well as 50.0% and 42.9% of urine BT-PABA. (4) The sensitivity and specificity of FE1 for diagnosing chronic pancreatitis were 63.3% and 97.3% respectively, the sensitivity of urine BT-PABA was 83.3%. CONCLUSIONS: FE1 concentration is (966.93 +/- 256.17) microg/g in healthy controls. Our study clearly showed that there are no changes of FE1 concentration in different age groups. FE1 showed the higher specificity for chronic pancreatitis than urine BT-PABA. The test is noninvasive and can assist in diagnosing exocrine pancreatic insufficiency, and is better than the BT-PABA in differentiating pancreatic and non-pancreatic diarrhea.

[The diagnostic value of serum carcinoma markers, fecal K-ras and p53 gene mutation in pancreatic cancers].

OBJECTIVE: To evaluate the diagnostic value of serum carcinoma markers CA19-9, CA242, CA50 and carcinoembryonic antigens (CEA), fecal K-ras and p53 gene mutation in pancreatic cancer. METHODS: We collected 136 new cases of pancreatic cancer and 240 patients with benign digestive diseases including 49 patients with benign pancreatic diseases diagnosed in Peking Union Medical College Hospital, Chinese Academy of Medical Sciences Tumor Hospital and Shenyang PLA General Hospital from February 2002 to March 2004. Blood samples were collected and serum carcinoma markers CA19-9, CA242, CA50 and CEA were measured. Fecal K-ras and p53 gene mutation were also measured. We decided the optimal cut-off points with receiver operating characteristic curves and calculated the areas under the curve (AUC). RESULTS: The AUC of serum CA19-9 and CA242 were 0.855 +/- 0.031 (95% CI 0.794 - 0.916) and 0.859 +/- 0.031 (95% CI 0.799 - 0.920) respectively. The optimal cut-off point for serum CA19-9 was 68 U/ml, with the sensitivity of 84.4% (98/116) and the specificity of 84.3% (145/172) for the diagnosis of pancreatic cancer. The optimal cut-off point for serum CA242 was 25 U/ml, with the sensitivity of 88.4% (84/95) and the specificity of 79.1% (144/182). The sensitivity of fecal K-ras mutation was 77.8%, and the specificity was 82.2%. The sensitivity and specificity of fecal p53 gene mutation were 27.8% and 95.2% respectively. The diagnostic scale of pancreatic cancer was calculated by four variables: serum CA19-9, CA242, fecal K-ras and p53, of which each variable deserved one point if measured positive. The optimal cut-off point for the scale was 2, and the AUC of the diagnostic scale was 0.946 +/- 0.017 (95% CI 0.912 - 0.980). CONCLUSIONS: Serum CA19-9 and CA242 are valuable diagnostic tools for pancreatic cancer. The diagnostic value will be further improved when they are combined with the measurement of fecal K-ras and p53 gene mutation.

[Developing a hospital-based high risk scoring model and screening strategy for pancreatic cancer].

OBJECTIVE: To develop a high risk scoring model and screening strategy to improve the diagnosis of symptomatic pancreatic cancer. METHODS: A hospital-based case-control study was undertaken among a cohort comprising 136 pancreatic cancer patients and 191 patients with benign gastrointestinal diseases who were hospitalized between Feb, 2002 and Mar, 2004. All patients were consulted with an epidemiological questionnaire. Risk factors and symptoms described in the questionnaire were compared between these two groups. Significant and borderline risk factors and symptoms were selected to undergo multivariate logistic regression. A high risk scoring model was constructed according to the weighted numerical scores of every variable. The diagnostic values of 4 tumor markers of pancreatic cancers (serum CA19-9, CA242, stool K-ras and p53 mutation) and 2 imaging tests (abdominal spiral CT and ultrasonography) were evaluated to provide evidence for establishing the diagnostic strategy. RESULTS: The average score was significantly higher for the pancreatic cancer patients than for the control patients [mean 49.6 (95% CI: 45.6-53.7) vs 21.6 (95% CI: 19.3-23.9); P < 0.01]. With a cutoff value of 27 points, the sensitivity and specificity of the scoring model was 87.0% and 68.1% respectively. CT had the highest sensitivity (94.7%) among the 4 tumor markers and 2 imaging tests. Combination of the two tumor markers (CA19-9 and stool K-ras) with CT or ultrasonography could improve the sensitivity to 100% with a specificity of 67.5%-73.0%. It was suggested that for high risk patients with a risk score more than 27, the combination test be recommended as the primary test, endoscopic ultrasonography (EUS) and/or endoscopic retrograde cholangipancreatography (ERCP) be considered for patients with inconclusive CT studies when risk score and tumor markers nevertheless suggest pancreatic cancer. CONCLUSION: The high risk scoring model provides a simple and feasible way to screen pancreatic patients in hospitals at all levels. Once high risk patients are identified, they can be transferred to higher level hospitals to receive further examinations. This screening strategy may help detect more resectable pancreatic cancers.