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Zhou Y, Chen Y, Yang H, Xu Z, Zhuang J, Bian Q, Wang G. Metabolic syndrome and increased susceptibility to renal cell carcinoma - a meta-analysis. BMC Nephrol 2025; 26:102. [PMID: 40012054 DOI: 10.1186/s12882-025-04013-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 02/06/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) has been demonstrated to be associated with various types of cancer, but its specific relationship with kidney cancer remains inconclusive. Therefore, this study conducts a Meta-analysis to systematically evaluate the potential link between metabolic syndrome and the risk of kidney cancer development. METHODS Observational studies were retrieved from PubMed, Embase, Cochrane Library, and Web of Science. Two independent reviewers extracted study characteristics and assessed the quality of the studies. A random-effects model was employed to account for heterogeneity, and subgroup analyses were conducted to explore the impact of study characteristics on the results. Publication bias was evaluated using funnel plot symmetry and Egger's regression test. RESULTS Six studies were included, with 10 results extracted for the Meta-analysis. The findings indicated that MetS is an independent risk factor for kidney cancer (HR: 1.44, 95% CI: 1.31-1.59, P < 0.001). Heterogeneity between studies was significant (Cochran's Q test, P < 0.001; I2 = 83.7%), indicating substantial variability. Subgroup analyses revealed consistent associations across gender, follow-up duration, and MetS diagnostic criteria (P > 0.05), but significant variations by race and study design (P < 0.05). The funnel plot appeared symmetrical, and Egger's regression test (P = 0.425) confirmed a low risk of publication bias. CONCLUSION MetS is independently associated with an increased susceptibility to RCC in the adult population, although the strength of this association varies across different study designs and regions due to the observed heterogeneity.
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Affiliation(s)
- Yanyu Zhou
- Department of Urology, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 YongWai Street Surgery Building, 17th Floor, Nanchang, Jiangxi, 330006, China
| | - Yujun Chen
- Department of Urology, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 YongWai Street Surgery Building, 17th Floor, Nanchang, Jiangxi, 330006, China
- Jiangxi Provincial Key Laboratory of Urinary System Diseases, Nanchang, Jiangxi, 330000, China
| | - Heng Yang
- Department of Urology, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 YongWai Street Surgery Building, 17th Floor, Nanchang, Jiangxi, 330006, China
| | - Zhiqi Xu
- Department of Urology, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 YongWai Street Surgery Building, 17th Floor, Nanchang, Jiangxi, 330006, China
| | - Jinbiao Zhuang
- Department of Urology, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 YongWai Street Surgery Building, 17th Floor, Nanchang, Jiangxi, 330006, China
| | - Qitao Bian
- Department of Urology, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 YongWai Street Surgery Building, 17th Floor, Nanchang, Jiangxi, 330006, China
| | - Gongxian Wang
- Department of Urology, the 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 YongWai Street Surgery Building, 17th Floor, Nanchang, Jiangxi, 330006, China.
- Jiangxi Provincial Key Laboratory of Urinary System Diseases, Nanchang, Jiangxi, 330000, China.
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Avtanski D, Reddy V, Stojchevski R, Hadzi-Petrushev N, Mladenov M. The Microbiome in the Obesity-Breast Cancer Axis: Diagnostic and Therapeutic Potential. Pathogens 2023; 12:1402. [PMID: 38133287 PMCID: PMC10747404 DOI: 10.3390/pathogens12121402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 11/25/2023] [Accepted: 11/27/2023] [Indexed: 12/23/2023] Open
Abstract
A growing body of evidence has demonstrated a relationship between the microbiome, adiposity, and cancer development. The microbiome is emerging as an important factor in metabolic disease and cancer pathogenesis. This review aimed to highlight the role of the microbiome in obesity and its association with cancer, with a particular focus on breast cancer. This review discusses how microbiota dysbiosis may contribute to obesity and obesity-related diseases, which are linked to breast cancer. It also explores the potential of the gut microbiome to influence systemic immunity, leading to carcinogenesis via the modulation of immune function. This review underscores the potential use of the microbiome profile as a diagnostic tool and treatment target, with strategies including probiotics, fecal microbiota transplantation, and dietary interventions. However, this emphasizes the need for more research to fully understand the complex relationship between the microbiome, metabolic disorders, and breast cancer. Future studies should focus on elucidating the mechanisms underlying the impact of the microbiome on breast cancer and exploring the potential of the microbiota profile as a biomarker and treatment target.
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Affiliation(s)
- Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Varun Reddy
- New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11545, USA;
| | - Radoslav Stojchevski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Nikola Hadzi-Petrushev
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.); (M.M.)
| | - Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.); (M.M.)
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Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen-Responsive Cancer Cells via Activating Mutations. JOURNAL OF ONCOLOGY 2020; 2020:5418365. [PMID: 32774370 PMCID: PMC7407016 DOI: 10.1155/2020/5418365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/30/2020] [Accepted: 06/25/2020] [Indexed: 02/08/2023]
Abstract
Cancer cells are embarrassed human cells exhibiting the remnants of same mechanisms for DNA stabilization like patients have in their healthy cells. Antiestrogens target the liganded activation of ERs, which is the principal means of genomic regulation in both patients and their tumors. The artificial blockade of liganded ER activation is an emergency situation promoting strong compensatory actions even in cancer cells. When tumor cells are capable of an appropriate upregulation of ER signaling resulting in DNA repair, a tumor response may be detected. In contrast, when ER signaling is completely inhibited, tumor cells show unrestrained proliferation, and tumor growth may be observed. The laboratory investigations of genomic mechanisms in antiestrogen-responsive and antiestrogen-unresponsive tumor cells have considerably enhanced our knowledge regarding the principal regulatory capacity of estrogen signaling. In antiestrogen-responsive tumor cells, a compensatory increased expression and liganded activation of estrogen receptors (ERs) result in an apoptotic death. Conversely, in antiestrogen resistant tumors exhibiting a complete blockade of liganded ER activation, a compensatory effort for unliganded ER activation is characteristic, conferred by the increased expression and activity of growth factor receptors. However, even extreme unliganded ER activation is incapable of DNA restoration when the liganded ER activation is completely blocked. Researchers mistakenly suspect even today that in tumors growing under antiestrogen treatment, the increased unliganded activation of estrogen receptor via activating mutations is an aggressive survival technique, whilst it is a compensatory effort against the blockade of liganded ER activation. The capacity of liganded ERs for genome modification in emergency states provides possibilities for estrogen/ER use in medical practice including cancer cure.
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Li P, Wang T, Zeng C, Yang M, Li G, Han J, Wu W. Association between metabolic syndrome and prognosis of breast cancer: a meta-analysis of follow-up studies. Diabetol Metab Syndr 2020; 12:10. [PMID: 32015762 PMCID: PMC6990514 DOI: 10.1186/s13098-019-0514-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 12/27/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) has been suggested to be a risk factor for many cancers, including breast cancer. However, it remains unclear whether MetS predicts poor prognosis in women with breast cancer. A meta-analysis was performed to summarize the association between MetS and clinical outcome in women with breast cancer. METHODS Cohort studies were identified by search of PubMed and Embase databases. A random-effect model incorporating the potential heterogeneity was applied to pool the results. Subgroup analyses according to the ethnicity and study design were performed. RESULTS Nine cohort studies with 17,892 women with breast cancer were included. Pooled results showed that MetS was significantly associated with an increased risk of breast cancer recurrence (adjusted risk ratio [RR] = 1.52, 95%, p = 0.02). Subgroup analyses showed that MetS was independently associated with increased recurrence of breast cancer in Caucasians (adjusted RR = 1.75, p = 0.02), but not in Asians (adjusted RR = 1.07, p = 0.81), and MetS was associated with a trend of increased risk of breast cancer recurrence in both the prospective and retrospective studies. Although we failed to show a significant association between MetS and breast cancer related deaths (adjusted RR = 1.24, p = 0.41), MetS was associated with increased risk of all-cause deaths in these patients (adjusted RR = 1.80, p < 0.001). CONCLUSIONS MetS may predict the risk of cancer recurrence and mortality in women with breast cancer, particularly in Caucasians.
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Affiliation(s)
- Peiting Li
- Department of Breast Thyroid Surgery, The Third Xiangya Hospital of Central South University, No. 172 Tong Zi Po Road, Changsha, 410013 China
| | - Tianying Wang
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital of Central South University, No. 172 Tong Zi Po Road, Changsha, 410013 China
| | - Chen Zeng
- Department of Breast Thyroid Surgery, The Third Xiangya Hospital of Central South University, No. 172 Tong Zi Po Road, Changsha, 410013 China
| | - Meng Yang
- Department of Breast Thyroid Surgery, The Third Xiangya Hospital of Central South University, No. 172 Tong Zi Po Road, Changsha, 410013 China
| | - Gang Li
- Department of Breast Thyroid Surgery, The Third Xiangya Hospital of Central South University, No. 172 Tong Zi Po Road, Changsha, 410013 China
| | - Jiang Han
- Department of Breast Thyroid Surgery, The Third Xiangya Hospital of Central South University, No. 172 Tong Zi Po Road, Changsha, 410013 China
| | - Wei Wu
- Department of Breast Thyroid Surgery, The Third Xiangya Hospital of Central South University, No. 172 Tong Zi Po Road, Changsha, 410013 China
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Liu Z, Wang H, Zhang L, Li S, Fan Y, Meng Y, Hu S, Zhang Q, He Z, Zhou L, Han W, Yu W, Jin J. Metabolic syndrome is associated with improved cancer-specific survival in patients with localized clear cell renal cell carcinoma. Transl Androl Urol 2019; 8:507-518. [PMID: 31807427 DOI: 10.21037/tau.2019.10.04] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Metabolic syndrome (MetS) has been found to be prevalent in cancer and have implications in cancer outcomes. In this study, we attempted to evaluate the prognostic value of MetS in localized clear cell renal cell carcinoma (ccRCC) patients. Methods We retrospectively collected clinicopathological data and pre-treatment laboratory test results of 480 patients with localized (T1-2N0M0) ccRCC undergoing radical or partial nephrectomy in Peking University First Hospital. MetS was diagnosed by criteria of the 2004 Chinese Medical Association Diabetes Society. Univariate and multivariate analyses were conducted to analyze the association between clinicopathological characteristics, MetS, and disease outcomes. Results In our cohort, 136 patients (28.3%) were diagnosed with MetS. Among them, 113 (83.1%) were men, suggesting that men were more likely to have MetS. This syndrome was also associated with increased pre-treatment creatinine levels. Median follow-up time was 70 months (range, 1-118 months) and 5-year overall survival (OS) rate was 92%. MetS was an independent favorable factor of cancer-specific survival (CSS) (P=0.017), and similar results were observed in Fuhrman nuclear grade 1-2 ccRCC patients by further analysis. Neither of the four components of the MetS (hypertension, diabetes mellitus, overweight/obesity and dyslipidemia) was an independent predictor of CSS. Patients who met more than 3 of the 4 criteria for MetS had higher CSS than those who met fewer than 2 criteria. Conclusions MetS is an independent prognostic factor for better CSS in localized ccRCC patients.
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Affiliation(s)
- Zhenhua Liu
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Haifeng Wang
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Lian Zhang
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Shaobo Li
- School of Basic Medicine, Fudan University, Shanghai 200032, China
| | - Yu Fan
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Yisen Meng
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Shuai Hu
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Qian Zhang
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Zhisong He
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Wenke Han
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Wei Yu
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
| | - Jie Jin
- Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China
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Takeuchi M, Takino JI, Sakasai-Sakai A, Takata T, Tsutsumi M. Toxic AGE (TAGE) Theory for the Pathophysiology of the Onset/Progression of NAFLD and ALD. Nutrients 2017; 9:E634. [PMID: 28632197 PMCID: PMC5490613 DOI: 10.3390/nu9060634] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 06/06/2017] [Accepted: 06/16/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are among the most common causes of chronic liver diseases in the westernized world. NAFLD and ALD are frequently accompanied by extrahepatic complications, including hepatocellular carcinoma and cardiovascular diseases, which have a negative impact on patient survival. The chronic ingestion of an excessive daily diet containing sugar/high-fructose corn syrup increases the level of the fructose/glucose metabolite, glyceraldehyde (GA), while the chronic consumption of an excessive number of alcoholic beverages increases the level of the alcohol metabolite, acetaldehyde (AA) in the liver. GA and AA are known to react non-enzymatically with the ε- or α-amino groups of proteins, thereby generating advanced glycation end-products (AGEs, GA-AGEs, and AA-AGEs, respectively) in vivo. The interaction between GA-AGEs and the receptor for AGEs (RAGE) alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the production of reactive oxygen species by human hepatocytes and hepatic stellate cells, all of which may contribute to the pathological changes associated with chronic liver diseases. We herein discuss the pathophysiological roles of GA-AGEs and AA-AGEs (toxic AGEs, TAGE) and a related novel theory for preventing the onset/progression of NAFLD and ALD.
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Affiliation(s)
- Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
| | - Jun-Ichi Takino
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
| | - Akiko Sakasai-Sakai
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
| | - Takanobu Takata
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
| | - Mikihiro Tsutsumi
- Department of Hepatology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
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Examining the prevalence of metabolic syndrome among overweight/obese African-American breast cancer survivors vs. matched non-cancer controls. J Cancer Surviv 2016; 11:102-110. [PMID: 27562474 DOI: 10.1007/s11764-016-0566-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 08/07/2016] [Indexed: 12/19/2022]
Abstract
PURPOSE Metabolic Syndrome (MetS) is more predominant in overweight, obese and minority populations. This study examined the prevalence of MetS in an exclusively African-American (AA) cohort of breast cancer (BC) survivors; an underrepresented group in previous studies demonstrating negative BC outcomes disparities for females with MetS. METHODS Using a case-control design, overweight/obese AA women with treated Stage I-IIIa BC were matched 1:1 on age, race, sex, and body mass index (BMI) category with non-cancer population controls (n = 444). Three of the following conditions were used to define MetS: HDL cholesterol <50 mg/dL (1.3 mmol/L), serum triglycerides ≥150 mg/dL (1.7 mmol/L), blood glucose ≥100 mg/dL (or on treatment), waist circumference ≥88 cm, or ≥130 mmHg systolic or ≥85 mmHg diastolic blood pressure (or on treatment). Matched-pairs analyses were conducted. RESULTS For BC cases, most women had self-reported Stage I (n = 76) or Stage II (n = 91) disease and were 6.9 (±5.2) years post-diagnosis. MetS was significantly lower in BC survivors vs. their non-cancer population controls (43.2 vs. 51.4 %, respectively; p < 0.05). The diagnosis of MetS did not differ by BMI stratification. A lower prevalence of ≥2 risk factors (80.2 vs. 85.6 %, p < 0.05) was observed for all cases vs. CONTROLS CONCLUSIONS While MetS occurred less frequently in our BC cases vs. non-cancer controls, our estimates are nearly two times those reported in other BC survivors, suggesting important racial/ethnic differences. IMPLICATIONS FOR CANCER SURVIVORS The prognostic implications of MetS among AA BC survivors remain unknown and warrant further investigation.
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Wen YS, Huang C, Zhang X, Qin R, Lin P, Rong T, Zhang LJ. Impact of metabolic syndrome on the survival of Chinese patients with resectable esophageal squamous cell carcinoma. Dis Esophagus 2016; 29:607-13. [PMID: 26123618 DOI: 10.1111/dote.12376] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Metabolic syndrome (MetS) is associated with the risk of esophageal squamous cell carcinoma (ESCC). However, the impact of MetS on survival has not been evaluated. A retrospective review was performed on 596 consecutive Chinese patients with esophageal squamous cell carcinoma who received surgery between January 2005 and October 2007. The clinical data and pretreatment information related to MetS were reviewed. The impact of MetS on overall survival (OS) was estimated by Kaplan-Meier and Cox proportional hazards analyses. MetS was a significant and independent predictor for better survival in patients with resectable ESCC. The 3-year OS and 5-year OS for patients with and without MetS were 75.0% versus 57.8% and 65.1% versus 44.6%, respectively (P = 0.005 in the univariate analysis, P = 0.010 in multivariate analysis). However, there was no apparent influence of any single component of MetS on OS. The other independent prognostic factors identified in the univariate analysis included the following: gender, smoking status, alcohol use, the extent of radical surgical resection, T and N stage, and tumor differentiation. The results of the multivariate analysis included the extent of radical surgery resection, T and N stage, and tumor differentiation. MetS was also associated with greater tumor cell differentiation (P = 0.036). There was no association found between MetS status and postoperative complications. MetS is an independent prognostic factor for OS in patients with ESCC and is associated with better tumor cell differentiation.
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Affiliation(s)
- Y-S Wen
- Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
| | - C Huang
- Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
| | - X Zhang
- School of Medicine, University of Glasgow, Glasgow, UK
| | - R Qin
- Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
| | - P Lin
- Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
| | - T Rong
- Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
| | - L-J Zhang
- Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
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Agresti R, Meneghini E, Baili P, Minicozzi P, Turco A, Cavallo I, Funaro F, Amash H, Berrino F, Tagliabue E, Sant M. Association of adiposity, dysmetabolisms, and inflammation with aggressive breast cancer subtypes: a cross-sectional study. Breast Cancer Res Treat 2016; 157:179-89. [PMID: 27117160 DOI: 10.1007/s10549-016-3802-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 04/19/2016] [Indexed: 12/22/2022]
Abstract
Obesity and metabolic syndrome are risk and prognostic factors for breast cancer (BC) and are associated with chronic inflammation. We investigated the association between distinct BC subtypes and markers of adiposity, dysmetabolisms, and inflammation. We analyzed 1779 patients with primary invasive BC treated at a single institution, for whom anthropometric and clinical-pathological data were archived. BC subtypes were classified by immunohistochemical staining of ER, PR, HER2, and Ki67, and their relations with the study markers were assessed by multinomial logistic regression. Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated taking luminal A as reference. All subtypes more aggressive than luminal A were significantly more frequent in younger (<45 years) than older women. Before menopause, luminal B HER2-negative tumors were positively associated with large waist (OR 2.55, 95 % CI 1.53-4.24) and insulin resistance (OR 1.90, 95 % CI 1.05-3.41); luminal B HER2-positive tumors with large waist (OR 2.11, 95 % CI 1.03-4.35) and triple-negative tumors with overweight (OR 3.04, 95 % CI 1.43-6.43) and high C-reactive protein (p trend = 0.026). In postmenopausal women aged <65, luminal B HER2-negative (OR 1.94, 95 % CI 1.16-3.24) and luminal B HER2-positive tumors (OR 2.48, 95 % CI 1.16-5.27) were positively related with metabolic syndrome. Dysmetabolisms and inflammation may be related to different BC subtypes. Before menopause, triple-negative cancers were related to obesity and chronic inflammation, and aggressive luminal subtypes to abdominal adiposity. After menopause, in women aged <65 these latter subtypes were related to metabolic syndrome. Control of adiposity and dysmetabolism can reduce the risk of aggressive BC subtypes, improving the prognosis.
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Affiliation(s)
- Roberto Agresti
- Breast Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Elisabetta Meneghini
- Analytic Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy.
| | - Paolo Baili
- Analytic Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Pamela Minicozzi
- Analytic Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Alberto Turco
- Analytic Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Ilaria Cavallo
- Analytic Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Francesco Funaro
- Analytic Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Hade Amash
- Analytic Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Franco Berrino
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Elda Tagliabue
- Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Milena Sant
- Analytic Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
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Sandhir R, Gupta S. Molecular and biochemical trajectories from diabetes to Alzheimer’s disease: A critical appraisal. World J Diabetes 2015; 6:1223-1242. [PMID: 26464760 PMCID: PMC4598605 DOI: 10.4239/wjd.v6.i12.1223] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/25/2015] [Accepted: 09/08/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus (DM), a metabolic disorder is a major orchestra influencing brain and behavioral responses via direct or indirect mechanisms. Many lines of evidence suggest that diabetic patients apparently face severe brain complications, but the story is far from being fully understood. Type 2 diabetes, an ever increasing epidemic and its chronic brain complications are implicated in the development of Alzheimer’s disease (AD). Evidences from clinical and experimental studies suggest that insulin draws a clear trajectory from the peripheral system to the central nervous system. This review is a spot light on striking pathological, biochemical, molecular and behavioral commonalities of AD and DM. Incidence of cognitive decline in diabetic patients and diabetic symptoms in AD patients has brought the concept of brain diabetes to attention. Brain diabetes reflects insulin resistant brain state with oxidative stress, cognitive impairment, activation of various inflammatory cascade and mitochondrial vulnerability as a shared footprint of AD and DM. It has become extremely important for the investigators to understand the patho-physiology of brain complications in diabetes and put intensive pursuits for therapeutic interventions. Although, decades of research have yielded a range of molecules with potential beneficial effects, but they are yet to meet the expectations.
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11
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Zou L, Liu TR, Yang AK. Metabolic syndrome is associated with better prognosis in patients with tongue squamous cell carcinoma. CHINESE JOURNAL OF CANCER 2015; 34:184-8. [PMID: 25963193 PMCID: PMC4593369 DOI: 10.1186/s40880-015-0009-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 12/02/2014] [Indexed: 01/30/2023]
Abstract
Introduction Metabolic syndrome (MS) is associated with several cancers, but it is not clear whether MS affects the prognosis of tongue squamous cell carcinoma (TSCC). This study aimed to evaluate the prognostic value of MS in TSCC. Methods Clinical data from 252 patients with TSCC who were initially treated at the Sun Yat-sen University Cancer Center between April 1998 and June 2011 were collected, and the associations between MS and clinicopathologic factors were retrospectively analyzed. Prognostic outcomes were examined by Kaplan-Meier analysis and Cox regression analysis. Results Of the 252 patients, 48 were diagnosed with MS. MS was associated with early N category in TSCC (P < 0.001). The patients with MS showed longer survival than those without MS (P = 0.028). MS was an independent prognostic factor for patients with TSCC. Conclusions MS is associated with early N category in TSCC. It is an independent prognostic factor for better survival in patients with TSCC.
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Affiliation(s)
- Lan Zou
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.
| | - Tian-Run Liu
- Department of Otorhinolaryngology Head and Neck Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510655, P. R. China.
| | - An-Kui Yang
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.
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12
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Effect of metabolic syndrome and its components on recurrence and survival in early-stage non-small cell lung cancer. Med Oncol 2014; 32:423. [DOI: 10.1007/s12032-014-0423-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 11/28/2014] [Indexed: 01/10/2023]
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Association between oestrogens receptor expressions in breast cancer and comorbidities: a cross-sectional, population-based study. PLoS One 2014; 9:e98127. [PMID: 24848085 PMCID: PMC4029934 DOI: 10.1371/journal.pone.0098127] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 04/28/2014] [Indexed: 12/25/2022] Open
Abstract
Background Breast cancer with oestrogen receptor expression is common in older women. Several factors, such as age and reproductive hormone exposure, have been associated with oestrogen receptor expression in breast cancer. However, the association between comorbidities and the oestrogen receptor expression has been poorly studied. We hypothesized that there was an association between burden comorbidity and breast cancer with oestrogen receptor expression in older women. Objective To determine whether oestrogen receptor expression in breast cancer was associated with burden comorbidity in community-dwelling women. Methods A total of 1,707 women with breast cancer registered on the list of a breast cancer registry were included. The recorded data included: age, Charlson Comorbidity Index score≥1, breast cancer characteristics (coded according to the International Classification of Diseases for Oncology), and breast cancer pathological stage (the pathological-tumour-node-metastasis, Scarff Bloom Richardson, and hormonal status of oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor). Results Breast cancer with oestrogen receptor expression was identified in 1,378 patients (80·7%). The fully-adjusted logistic regression showed that oestrogen receptor expression was associated with Charlson Comorbidity Index score≥1 (odds ratio [OR] = 1·91,95%confidence interval [CI] = [1.01–3.61], P = 0·048), progesterone receptor expression (OR = 16·64, 95%CI = [11.62–23.81], P<0·001), human epidermal growth factor receptor (OR = 0·54, 95%CI = [0.34–0.84], P = 0·007), age (OR = 1.02, 95%CI = [1.00–1.03], P = 0.008), Scarff Bloom Richardson grade II and grade III (OR = 0·21with 95%CI = [0.10–0.44] and OR = 0·06 with 95%CI = [0.03–0.12], P<0·001). Conclusion Our findings provide new data showing an independent positive association between burden comorbidity and breast cancer with oestrogen receptor expression. This result confirms that evaluation of oestrogen receptor expression in breast cancer should not be limited to hormonal factors stratified by age.
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Abstract
OBJECTIVE The aim of this study was to assess the risk of metabolic syndrome (MetS) in postmenopausal breast cancer survivors as compared with postmenopausal women without breast cancer. METHODS In this cross-sectional study, 104 postmenopausal breast cancer survivors were compared with 208 postmenopausal women (controls) attending a university hospital. Eligibility criteria included the following: amenorrhea longer than 12 months and aged 45 years or older, treated for breast cancer, and metastasis-free for at least 5 years. The control group consisted of women with amenorrhea longer than 12 months and aged 45 years or older and without breast cancer, matched by age and menopause status (in a proportion of 1:2 as sample calculation). Clinical and anthropometric data were collected. Biochemical parameters, including total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and C-reactive protein, were measured. Women showing three or more diagnostic criteria were diagnosed as having MetS: waist circumference of 88 cm or larger, blood pressure of 130/85 mm Hg or higher, triglycerides level of 150 mg/dL or higher, high-density lipoprotein cholesterol level lower than 50 mg/dL, and glucose level of 100 mg/dL or higher. For statistical analysis, Student's t test, χ2 test, and logistic regression (odds ratio [OR]) were used. RESULTS The mean (SD) age of breast cancer survivors was 60.6 (8.6) years, with a mean (SD) follow-up of 9.4 (4.4) years. A higher percentage of breast cancer survivors (46.2%) were obese as compared with controls (32.7%; P < 0.05), and a smaller percentage showed optimal values for low-density lipoprotein cholesterol, glucose, and C-reactive protein versus controls (P < 0.05). MetS was diagnosed in 50% of breast cancer survivors and in 37.5% of control group women (P < 0.05). Among the MetS diagnostic criteria, the most prevalent was abdominal obesity (waist circumference >88 cm), affecting 62.5% and 67.8% of the participants, respectively. In the control group, breast cancer survivors had a higher risk for MetS (OR, 1.66; 95% CI, 1.04-2.68), dysglycemia (OR, 1.05; 95% CI, 1.09-3.03), and hypertension (OR, 1.71; 95% CI, 1.02-2.89). CONCLUSIONS Postmenopausal breast cancer survivors present a higher risk of developing MetS as compared with women without breast cancer.
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Wei XL, Qiu MZ, Lin HX, Zhang Y, Liu JX, Yu HM, Liang WP, Jin Y, Ren C, He MM, Chen WW, Luo HY, Wang ZQ, Zhang DS, Wang FH, Li YH, Xu RH. Patients with old age or proximal tumors benefit from metabolic syndrome in early stage gastric cancer. PLoS One 2014; 9:e89965. [PMID: 24599168 PMCID: PMC3943843 DOI: 10.1371/journal.pone.0089965] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 01/25/2014] [Indexed: 12/12/2022] Open
Abstract
Background Metabolic syndrome and/or its components have been demonstrated to be risk factors for several cancers. They are also found to influence survival in breast, colon and prostate cancer, but the prognostic value of metabolic syndrome in gastric cancer has not been investigated. Methods Clinical data and pre-treatment information of metabolic syndrome of 587 patients diagnosed with early stage gastric cancer were retrospectively collected. The associations of metabolic syndrome and/or its components with clinical characteristics and overall survival in early stage gastric cancer were analyzed. Results Metabolic syndrome was identified to be associated with a higher tumor cell differentiation (P = 0.036). Metabolic syndrome was also demonstrated to be a significant and independent predictor for better survival in patients aged >50 years old (P = 0.009 in multivariate analysis) or patients with proximal gastric cancer (P = 0.047 in multivariate analysis). No association was found between single metabolic syndrome component and overall survival in early stage gastric cancer. In addition, patients with hypertension might have a trend of better survival through a good control of blood pressure (P = 0.052 in univariate analysis). Conclusions Metabolic syndrome was associated with a better tumor cell differentiation in patients with early stage gastric cancer. Moreover, metabolic syndrome was a significant and independent predictor for better survival in patients with old age or proximal tumors.
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Affiliation(s)
- Xiao-li Wei
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Miao-zhen Qiu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Huan-xin Lin
- Department of Preventive Care, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ying Zhang
- Department of Preventive Care, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jian-xin Liu
- Department of Preventive Care, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hong-mei Yu
- Department of Preventive Care, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wei-ping Liang
- Department of Preventive Care, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ying Jin
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chao Ren
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ming-ming He
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wei-wei Chen
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hui-yan Luo
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhi-qiang Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dong-sheng Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Feng-hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yu-hong Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Rui-hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- * E-mail:
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Abstract
Epidemics of obesity, diabetes, nonalcoholic fatty liver disease, and cognitive impairment/Alzheimer disease have emerged over the past 3 to 4 decades. These diseases share in common target-organ insulin resistance with a constellation of molecular and biochemical abnormalities that lead to organ/tissue degeneration over time. This article discusses the fundamental links among these diseases and how peripheral organ insulin resistance diseases contribute to cognitive impairment and neurodegeneration. A future role of endocrinologists and diabetologists could be to provide integrative diagnostic and treatment approaches for this collection of diseases that seem to share pathophysiological and pathogenetic bases.
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Affiliation(s)
- Suzanne M de la Monte
- Department of Pathology (Neuropathology), Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Neurology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Neurosurgery, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.
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Suba Z. Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications. Onco Targets Ther 2014; 7:147-64. [PMID: 24482576 PMCID: PMC3905095 DOI: 10.2147/ott.s52600] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Epidemiologic studies strongly support that triple-negative breast cancers (TNBCs) may be distinct entities as compared with estrogen receptor (ER)+ tumors, suggesting that the etiologic factors, clinical characteristics, and therapeutic possibilities may vary by molecular subtypes. Many investigations propose that reproductive factors and exogenous hormone use differently or even quite inversely affect the risk of TNBCs and ER+ cancers. Controversies concerning the exact role of even the same risk factor in TNBC development justify that the biological mechanisms behind the initiation of both TNBCs and non-TNBCs are completely obscure. To arrive at a comprehensive understanding of the etiology of different breast cancer subtypes, we should also reconsider our traditional concepts and beliefs regarding cancer risk factors. Malignancies are multicausal, but the disturbance of proper estrogen signaling seems to be a crucial risk factor for the development of mammary cancers. The grade of defect in metabolic and hormonal equilibrium is directly associated with TNBC risk for women during their whole life. Inverse impact of menopausal status or parity on the development of ER+ and ER− breast cancers may not be possible; these controversial results derive from the misinterpretation of percentage-based statistical evaluations. Exogenous or parity-associated excessive estrogen supply is suppressive against breast cancer, though the lower the ER expression of tumors, the weaker the anticancer capacity. In women, the most important preventive strategy against breast cancers – included TNBCs – is the strict control and maintenance of hormonal equilibrium from early adolescence through the whole lifetime, particularly during the periods of great hormonal changes.
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Affiliation(s)
- Zsuzsanna Suba
- National Institute of Oncology, Surgical and Molecular Tumor Pathology Centre, Budapest, Hungary
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de la Monte SM, Tong M. Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem Pharmacol 2013; 88:548-59. [PMID: 24380887 DOI: 10.1016/j.bcp.2013.12.012] [Citation(s) in RCA: 332] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Revised: 12/16/2013] [Accepted: 12/16/2013] [Indexed: 02/06/2023]
Abstract
Growing evidence supports the concept that Alzheimer's disease (AD) is fundamentally a metabolic disease with molecular and biochemical features that correspond with diabetes mellitus and other peripheral insulin resistance disorders. Brain insulin/IGF resistance and its consequences can readily account for most of the structural and functional abnormalities in AD. However, disease pathogenesis is complicated by the fact that AD can occur as a separate disease process, or arise in association with systemic insulin resistance diseases, including diabetes, obesity, and non-alcoholic fatty liver disease. Whether primary or secondary in origin, brain insulin/IGF resistance initiates a cascade of neurodegeneration that is propagated by metabolic dysfunction, increased oxidative and ER stress, neuro-inflammation, impaired cell survival, and dysregulated lipid metabolism. These injurious processes compromise neuronal and glial functions, reduce neurotransmitter homeostasis, and cause toxic oligomeric pTau and (amyloid beta peptide of amyloid beta precursor protein) AβPP-Aβ fibrils and insoluble aggregates (neurofibrillary tangles and plaques) to accumulate in brain. AD progresses due to: (1) activation of a harmful positive feedback loop that progressively worsens the effects of insulin resistance; and (2) the formation of ROS- and RNS-related lipid, protein, and DNA adducts that permanently damage basic cellular and molecular functions. Epidemiologic data suggest that insulin resistance diseases, including AD, are exposure-related in etiology. Furthermore, experimental and lifestyle trend data suggest chronic low-level nitrosamine exposures are responsible. These concepts offer opportunities to discover and implement new treatments and devise preventive measures to conquer the AD and other insulin resistance disease epidemics.
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Affiliation(s)
- Suzanne M de la Monte
- Departments of Pathology (Neuropathology), Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA; Departments of Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA; Departments of Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA; Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
| | - Ming Tong
- Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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