{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T11:09:02Z","timestamp":1776769742884,"version":"3.51.2"},"reference-count":278,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The obesity epidemic is not just a health issue, it is increasingly driving a shift in the prevalence of chronic diseases, affecting 890 million adults and straining healthcare systems worldwide. Conditions such as type 2 diabetes mellitus, cardiovascular diseases, non-alcoholic fatty liver disease, and various cancer types are closely tied to this growing crisis. Betulinic acid has anti-inflammatory, antioxidant and anti-cancer properties and modulates key metabolic pathways such as NF-\u03baB and AMPK signaling. This compound improves insulin sensitivity, reduces hepatic steatosis, mitigates the progression of atherosclerosis and fibrosis, and suppresses inflammatory responses, which are important in treating those obesity-related disorders. Additionally, betulinic acid use in cancer treatment has been explored due to its potential in angiogenesis and metastasis inhibition and promotion of apoptosis. This review spotlights the therapeutic potential of the natural compound betulinic acid in processes such as insulin sensitivity, glucose and lipid metabolism, adiposity, inflammation, oxidative stress, intestinal microbiota, and other mechanisms underlying different obesity-related disorders. Overall, besides strong therapeutic potential of betulinic acid, described limitations such as poor aqueous solubility, limited bioavailability, production and extraction have resulted in scarce clinical data making it premature to draw definitive conclusions regarding its application in clinical practice.<\/jats:p>","DOI":"10.3389\/fphar.2025.1674713","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T05:33:48Z","timestamp":1758605628000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Betulinic acid and obesity-related disorders"],"prefix":"10.3389","volume":"16","author":[{"given":"Lara","family":"Azevedo","sequence":"first","affiliation":[]},{"given":"Ricardo","family":"Ferraz","sequence":"additional","affiliation":[]},{"given":"M\u00f3nica","family":"Vieira","sequence":"additional","affiliation":[]},{"given":"Cristina","family":"Prud\u00eancio","sequence":"additional","affiliation":[]},{"given":"S\u00edlvia","family":"Fernandes","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1002\/hep.23535","article-title":"Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease","volume":"51","author":"Abdelmalek","year":"2010","journal-title":"Hepatology"},{"key":"B2","first-page":"14","article-title":"Effect of betulinic acid on lipid homeostasis and atherosclerotic index","volume":"20","author":"Afghan","year":"2022","journal-title":"Int. J. Pathol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"209","DOI":"10.5534\/wjmh.2016.34.3.209","article-title":"Effects of betulinic acid on the Male reproductive system of a streptozotocin-nicotinamide-induced diabetic mouse model","volume":"34","author":"Ahangarpour","year":"2016","journal-title":"World J. men's health"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2939","DOI":"10.3390\/molecules17032939","article-title":"alpha-Mangostin enhances betulinic acid cytotoxicity and inhibits cisplatin cytotoxicity on HCT 116 colorectal carcinoma cells","volume":"17","author":"Aisha","year":"2012","journal-title":"Molecules"},{"key":"B5","doi-asserted-by":"publisher","first-page":"587","DOI":"10.2147\/DMSO.S67400","article-title":"Mechanism linking diabetes mellitus and obesity","volume":"7","author":"Al-Goblan","year":"2014","journal-title":"Diabetes, metabolic syndrome Obes. targets Ther."},{"key":"B6","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1111\/cbdd.12682","article-title":"Betulinic acid: recent advances in chemical modifications, effective delivery, and molecular mechanisms of a promising anticancer therapy","volume":"87","author":"Ali-Seyed","year":"2016","journal-title":"Chem. Biol. Drug Des."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e051121189015","DOI":"10.2174\/1573403X16999201210200342","article-title":"Relationship between hyperlipidemia, cardiovascular disease and stroke: a systematic review","volume":"17","author":"Alloubani","year":"2021","journal-title":"Curr. Cardiol. Rev."},{"key":"B8","doi-asserted-by":"publisher","first-page":"103043","DOI":"10.1016\/j.arcmed.2024.103043","article-title":"Global prevalence of nonalcoholic fatty liver disease: an updated review meta-analysis comprising a population of 78 million from 38 countries","volume":"55","author":"Amini-Salehi","year":"2024","journal-title":"Arch. Med. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"107409","DOI":"10.1016\/j.biotechadv.2019.06.008","article-title":"Betulin and its derivatives as novel compounds with different pharmacological effects","volume":"38","author":"Amiri","year":"2020","journal-title":"Biotechnol. Adv."},{"key":"B10","first-page":"s176","article-title":"Obesity: definition, comorbidities, causes, and burden","volume":"22","author":"Apovian","year":"2016","journal-title":"Am. J. Manag. Care"},{"key":"B11","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.metabol.2018.11.001","article-title":"Obesity and cancer risk: emerging biological mechanisms and perspectives","volume":"92","author":"Avgerinos","year":"2019","journal-title":"Metabolism"},{"key":"B12","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/1748-717X-6-111","article-title":"Increased betulinic acid induced cytotoxicity and radiosensitivity in glioma cells under hypoxic conditions","volume":"6","author":"Bache","year":"2011","journal-title":"Radiat. Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"15718","DOI":"10.1073\/pnas.0407076101","article-title":"The gut microbiota as an environmental factor that regulates fat storage","volume":"101","author":"B\u00e4ckhed","year":"2004","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/ijc.30115","article-title":"Obesity, weight gain, and ovarian cancer risk in African American women","volume":"139","author":"Bandera","year":"2016","journal-title":"Int. J. cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1097\/MOU.0000000000000424","article-title":"Obesity and prostate cancer","volume":"27","author":"Bandini","year":"2017","journal-title":"Curr. Opin. Urol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3","DOI":"10.2174\/1570163812666150602144310","article-title":"Targeted cancer therapy: the next generation of cancer treatment","volume":"12","author":"Baudino T","year":"2015","journal-title":"Curr. drug Discov. Technol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.3390\/biom12101540","article-title":"New betulin derivatives with Nitrogen heterocyclic moiety\u2014synthesis and anticancer activity in vitro","volume":"12","author":"B\u0119benek","year":"2022","journal-title":"Biomolecules"},{"key":"B18","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/s0031-9422(01)00312-0","article-title":"Ethnopharmacology and bioinformatic combination for leads discovery: application to phospholipase A2 inhibitors","volume":"58","author":"Bernard","year":"2001","journal-title":"Phytochemistry"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1056\/NEJMoa1000367","article-title":"Body-mass index and mortality among 1.46 million white adults","volume":"363","author":"Berrington de Gonzalez","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1515\/hmbci-2014-0037","article-title":"Adipose tissue, obesity and adipokines: role in cancer promotion","volume":"21","author":"Booth","year":"2015","journal-title":"Hormone Mol. Biol. Clin. investigation"},{"key":"B21","doi-asserted-by":"publisher","first-page":"53","DOI":"10.15406\/oajtmr.2017.01.00012","article-title":"Betulin a pentacyclic tri\u2013terpenoid: an hour to rethink the compound","volume":"1","author":"Boparai","year":"2017","journal-title":"Open Access J. Trans. Med. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1210\/jcem.79.3.7521354","article-title":"Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes","volume":"79","author":"Brismar","year":"1994","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B23","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/s41574-021-00487-0","article-title":"Metabolic pathways in obesity-related breast cancer","volume":"17","author":"Brown","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"G518","DOI":"10.1152\/ajpgi.00024.2006","article-title":"Increased intestinal permeability in Obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis","volume":"292","author":"Brun","year":"2007","journal-title":"Am. J. Physiology-Gastrointestinal Liver Physiology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1007\/s13679-019-00345-1","article-title":"Nonalcoholic fatty liver disease and obesity treatment","volume":"8","author":"Brunner","year":"2019","journal-title":"Curr. Obes. Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1136\/gut.2008.165886","article-title":"Changes in gut microbiota control inflammation in Obese mice through a mechanism involving GLP-2-driven improvement of gut permeability","volume":"58","author":"Cani","year":"2009","journal-title":"Gut"},{"key":"B27","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.biocel.2013.11.020","article-title":"Betulinic acid and 1,25(OH)\u2082 vitamin D\u2083 share intracellular signal transduction in glucose homeostasis in soleus muscle","volume":"48","author":"Castro","year":"2014","journal-title":"Int. J. Biochem. and Cell Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.abb.2018.04.015","article-title":"The potent insulin secretagogue effect of betulinic acid is mediated by potassium and chloride channels","volume":"648","author":"Castro","year":"2018","journal-title":"Archives Biochem. Biophysics"},{"key":"B29","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s13098-019-0468-0","article-title":"Cardiovascular risk and obesity","volume":"11","author":"Cercato","year":"2019","journal-title":"Diabetology and metabolic syndrome"},{"key":"B30","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1002\/hep.25762","article-title":"The diagnosis and management of non\u2010alcoholic fatty liver disease: practice guideline by the American association for the study of liver diseases, American college of gastroenterology, and the American gastroenterological association","volume":"55","author":"Chalasani","year":"2012","journal-title":"Hepatology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/s11060-011-0676-4","article-title":"Type 2 diabetes mellitus and obesity are independent risk factors for poor outcome in patients with high-grade glioma","volume":"106","author":"Chambless","year":"2012","journal-title":"J. neuro-oncology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"S136","DOI":"10.2337\/diabetes.53.2007.s136","article-title":"Uncoupling protein 2 and islet function","volume":"53","author":"Chan","year":"2004","journal-title":"Diabetes"},{"key":"B33","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.canlet.2005.05.047","article-title":"Serum adiponectin and leptin levels in Taiwanese breast cancer patients","volume":"237","author":"Chen","year":"2006","journal-title":"Cancer Lett."},{"key":"B34","first-page":"658","article-title":"The proliferative role of insulin and the mechanism underlying this action in human breast cancer cell line MCF-7","volume":"17","author":"Chen","year":"2012","journal-title":"J. BUON"},{"key":"B35","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1002\/cbf.3537","article-title":"Betulinic acid triggers apoptosis and inhibits migration and invasion of gastric cancer cells by impairing EMT progress","volume":"38","author":"Chen","year":"2020","journal-title":"Cell Biochem. Funct."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1331159","DOI":"10.3389\/fpubh.2023.1331159","article-title":"Association between systemic immune-inflammatory index and diabetes mellitus: mediation analysis involving obesity indicators in the NHANES","volume":"11","author":"Chen","year":"2023","journal-title":"Front. Public Health"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2816","DOI":"10.1158\/0008-5472.CAN-06-3735","article-title":"Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors","volume":"67","author":"Chintharlapalli","year":"2007","journal-title":"Cancer Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1186\/1471-2407-11-371","article-title":"Betulinic acid inhibits Colon cancer cell and tumor growth and induces proteasome-dependent and-independent downregulation of specificity proteins (sp) transcription factors","volume":"11","author":"Chintharlapalli","year":"2011","journal-title":"BMC cancer"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2482","DOI":"10.3390\/molecules26092482","article-title":"Betulinic acid affects the energy-related proteomic profiling in pancreatic ductal adenocarcinoma cells","volume":"26","author":"Chiu","year":"2021","journal-title":"Molecules"},{"key":"B40","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1097\/00005344-200308000-00019","article-title":"Hematein inhibits atherosclerosis by inhibition of reactive oxygen generation and NF-kappaB-dependent inflammatory mediators in hyperlipidemic mice","volume":"42","author":"Choi","year":"2003","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1016\/S0140-6736(11)60105-0","article-title":"Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies","volume":"377","author":"Collaboration","year":"2011","journal-title":"Lancet"},{"key":"B42","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.clinre.2019.10.001","article-title":"Does adipose tissue inflammation drive the development of non-alcoholic fatty liver disease in obesity?","volume":"44","author":"Cordeiro","year":"2020","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"4870","DOI":"10.3390\/ijms22094870","article-title":"Assessment of betulinic acid cytotoxicity and mitochondrial metabolism impairment in a human melanoma cell line","volume":"22","author":"Coricovac","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"3119","DOI":"10.1158\/1055-9965.EPI-10-0832","article-title":"Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis","volume":"19","author":"Crosbie","year":"2010","journal-title":"Cancer Epidemiol. Biomarkers and Prev."},{"key":"B45","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1517\/13543776.2014.927441","article-title":"Betulinic acid and its derivatives: a patent review (2008-2013)","volume":"24","author":"Csuk","year":"2014","journal-title":"Expert Opin. Ther. Pat."},{"key":"B46","doi-asserted-by":"publisher","first-page":"2549","DOI":"10.1016\/j.bmc.2010.02.042","article-title":"Synthesis and biological evaluation of antitumor-active \u03b3-butyrolactone substituted betulin derivatives","volume":"18","author":"Csuk","year":"2010","journal-title":"Bioorg. and Med. Chem."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1007\/s11695-019-04345-x","article-title":"Transdiaphragmatic pressure gradient (TPG) has a central role in the pathophysiology of gastroesophageal reflux disease (GERD) in the Obese and it correlates with abdominal circumference but not with body mass index (BMI)","volume":"30","author":"De Mello Del Grande","year":"2020","journal-title":"Obes. Surg."},{"key":"B48","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1053\/bega.2002.0333","article-title":"Pathogenesis of steatohepatitis","volume":"16","author":"Day","year":"2002","journal-title":"Best Pract. and Res. Clin. gastroenterology"},{"key":"B49","doi-asserted-by":"publisher","first-page":"8776","DOI":"10.1021\/jf900768w","article-title":"Betulinic acid, a natural pentacyclic triterpenoid, prevents abdominal fat accumulation in mice fed a high-fat diet","volume":"57","author":"de Melo","year":"2009","journal-title":"J. Agric. food Chem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"595371","DOI":"10.3389\/fmed.2021.595371","article-title":"Oxidative stress in non-alcoholic fatty liver disease. An updated mini review","volume":"8","author":"Delli Bovi","year":"2021","journal-title":"Front. Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"6991","DOI":"10.7150\/thno.35791","article-title":"Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles","volume":"9","author":"Deng","year":"2019","journal-title":"Theranostics"},{"key":"B52","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nature10189","article-title":"Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis","volume":"475","author":"DeNicola","year":"2011","journal-title":"Nature"},{"key":"B53","doi-asserted-by":"publisher","first-page":"680536","DOI":"10.5402\/2013\/680536","article-title":"The association between obesity and cancer risk: a meta\u2010analysis of observational studies from 1985 to 2011","volume":"2013","author":"Dobbins","year":"2013","journal-title":"Int. Sch. Res. Notices"},{"key":"B54","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1053\/j.gastro.2015.05.044","article-title":"Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease","volume":"149","author":"Du Plessis","year":"2015","journal-title":"Gastroenterology"},{"key":"B55","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1080\/00365520500535402","article-title":"Anthropometric correlates of intragastric pressure","volume":"41","author":"El-Serag","year":"2006","journal-title":"Scand. J. gastroenterology"},{"key":"B56","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1159\/000356856","article-title":"Cholesterol: the good, the bad, and the ugly-therapeutic targets for the treatment of dyslipidemia","volume":"23","author":"Elshourbagy","year":"2014","journal-title":"Med. Princ. Pract."},{"key":"B57","doi-asserted-by":"publisher","first-page":"11","DOI":"10.22270\/jddt.v13i10.5965","article-title":"Acute and delayed oral toxicity studies and observations on pregnancy, gestation and reproductive performance of wistar rats administered limit dose of purified extract from stem bark of antidiabetic Anogeissus leiocarpus (african birch Tree)","volume":"13","author":"Esievo","year":"2023","journal-title":"J. Drug Deliv. Ther."},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.70315\/uloap.ulmhs.2024.0204001","article-title":"The medicinal properties of Anogeissus leiocarpus (African birch tree) and the development of a drug for diabetes mellitus and its complications: a review","volume":"2","author":"Esievo","year":"2024","journal-title":"Univers. Libr. Med. Health Sci."},{"key":"B59","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.diabres.2014.04.006","article-title":"Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes","volume":"105","author":"Esser","year":"2014","journal-title":"Diabetes Res. Clin. Pract."},{"key":"B60","volume-title":"IDF diabetes atlas","author":"Federation","year":"2025"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.2337\/diab.36.11.1341","article-title":"Role of lipid oxidation in pathogenesis of insulin resistance of obesity and type II diabetes","volume":"36","author":"Felber","year":"1987","journal-title":"Diabetes"},{"key":"B62","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.3390\/ijms25042108","article-title":"Betulinic acid for glioblastoma treatment: reality, challenges and perspectives","volume":"25","author":"Fernandes","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B63","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/978-3-319-42542-9_3","article-title":"Obesity and breast cancer","volume":"208","author":"Fortner","year":"2016","journal-title":"Obes. Cancer"},{"key":"B64","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1007\/s004010051093","article-title":"Neutrophil infiltration into human gliomas","volume":"98","author":"Fossati","year":"1999","journal-title":"Acta neuropathol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1002\/1878-0261.12772","article-title":"Physical activity, obesity and sedentary behavior in cancer etiology: epidemiologic evidence and biologic mechanisms","volume":"15","author":"Friedenreich","year":"2021","journal-title":"Mol. Oncol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.3390\/ijms9061096","article-title":"Betulinic acid for cancer treatment and prevention","volume":"9","author":"Fulda","year":"2008","journal-title":"Int. J. Mol. Sci."},{"key":"B67","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/1096-911X(20001201)35:6<616::AID-MPO27>3.0.CO;2-N","article-title":"Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors","volume":"35","author":"Fulda","year":"2000","journal-title":"Med. Pediatr. Oncol."},{"key":"B68","first-page":"4956","article-title":"Betulinic acid triggers CD95 (APO-1\/Fas)-and p53-independent apoptosis via activation of caspases in neuroectodermal tumors","volume":"57","author":"Fulda","year":"1997","journal-title":"Cancer Res."},{"key":"B69","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1002\/(sici)1097-0215(19990730)82:3<435::aid-ijc18>3.0.co;2-1","article-title":"Betulinic acid: a new cytotoxic agent against malignant brain-tumor cells","volume":"82","author":"Fulda","year":"1999","journal-title":"Int. J. Cancer"},{"key":"B70","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1016\/j.cellsig.2010.05.003","article-title":"Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFkappaB\/HIF-1alpha activation","volume":"22","author":"Gonzalez-Perez","year":"2010","journal-title":"Cell. Signal."},{"key":"B71","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1080\/01635581.2019.1595037","article-title":"The comparison of different obesity indexes and the risk of lung cancer: a meta-analysis of prospective cohort studies","volume":"71","author":"Gao","year":"2019","journal-title":"Nutr. Cancer"},{"key":"B72","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.tem.2010.06.007","article-title":"The proliferating role of insulin and insulin-like growth factors in cancer","volume":"21","author":"Gallagher","year":"2010","journal-title":"Trends Endocrinol. and Metabolism"},{"key":"B73","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1158\/1078-0432.CCR-05-1913","article-title":"Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli","volume":"12","author":"Garofalo","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"B74","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s00125-003-1263-9","article-title":"Beta-cell dysfunction and glucose intolerance: results from the san antonio metabolism (SAM) study","volume":"47","author":"Gastaldelli","year":"2004","journal-title":"Diabetologia"},{"key":"B75","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1007\/s10549-011-1616-x","article-title":"Risk factors by molecular subtypes of breast cancer across a population-based study of women 56 years or younger","volume":"130","author":"Gaudet","year":"2011","journal-title":"Breast cancer Res. Treat."},{"key":"B76","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1002\/ijc.25794","article-title":"A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk","volume":"129","author":"Genkinger","year":"2011","journal-title":"Int. J. cancer"},{"key":"B77","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1515\/hsz-2013-0106","article-title":"Betulinic acid suppresses NGAL-Induced epithelial-to-mesenchymal transition in melanoma","volume":"394","author":"Gheorgheosu","year":"2013","journal-title":"Biol. Chem."},{"key":"B78","doi-asserted-by":"publisher","first-page":"986","DOI":"10.3390\/cells12070986","article-title":"Substances of natural origin in medicine: plants vs. cancer","volume":"12","author":"Gieleci\u0144ska","year":"2023","journal-title":"Cells"},{"key":"B79","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.dld.2014.02.010","article-title":"Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity","volume":"46","author":"Giorgio","year":"2014","journal-title":"Dig. Liver Dis."},{"key":"B80","doi-asserted-by":"publisher","first-page":"e89919","DOI":"10.1371\/journal.pone.0089919","article-title":"Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid","volume":"9","author":"Godugu","year":"2014","journal-title":"PloS one"},{"key":"B81","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/0026-0495(84)90121-5","article-title":"Study on lipid metabolism in obesity diabetes","volume":"33","author":"Golay","year":"1984","journal-title":"Metabolism"},{"key":"B82","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/s0009-9120(02)00320-x","article-title":"Involvement of leptin in the association between percentage of body fat and cardiovascular risk factors","volume":"35","author":"G\u00f3mez-Ambrosi","year":"2002","journal-title":"Clin. Biochem."},{"key":"B83","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.mito.2014.03.012","article-title":"Physical exercise prevents and mitigates non-alcoholic steatohepatitis-induced liver mitochondrial structural and bioenergetics impairments","volume":"15","author":"Gon\u00e7alves","year":"2014","journal-title":"Mitochondrion"},{"key":"B84","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1111\/bph.14570","article-title":"Betulinic acid alleviates endoplasmic reticulum stress\u2010mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice","volume":"176","author":"Gu","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/nrm2391","article-title":"Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes","volume":"9","author":"Guilherme","year":"2008","journal-title":"Nat. Rev. Mol. cell Biol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1186\/s12906-020-02976-7","article-title":"Chemopreventive effect of betulinic acid via mTOR-Caspases\/Bcl2\/Bax apoptotic signaling in pancreatic cancer","volume":"20","author":"Guo","year":"2020","journal-title":"BMC Complementary Med. Ther."},{"key":"B87","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1093\/neuonc\/noq029","article-title":"PI3K\/PTEN\/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541","volume":"12","author":"H\u00e4gerstrand","year":"2010","journal-title":"Neuro-oncology"},{"key":"B88","doi-asserted-by":"publisher","first-page":"e374","DOI":"10.1016\/j.orcp.2013.06.002","article-title":"Association of body mass index and prostate cancer mortality","volume":"8","author":"Haque","year":"2014","journal-title":"Obes. Res. and Clin. Pract."},{"key":"B89","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1146\/annurev-pathol-012615-044224","article-title":"Nonalcoholic fatty liver disease: pathogenesis and disease spectrum","volume":"11","author":"Hardy","year":"2016","journal-title":"Annu. Rev. pathology Mech. Dis."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1093\/ije\/dyad046","article-title":"Associations of life course obesity with endometrial cancer in the epidemiology of endometrial cancer consortium (E2C2)","volume":"52","author":"Harvey","year":"2023","journal-title":"Int. J. Epidemiol."},{"key":"B91","first-page":"215","article-title":"Obesity and diabetes","volume-title":"Textbook of Diabetes2016","author":"Hauner","year":"2016"},{"key":"B92","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/nature01137","article-title":"A central role for JNK in obesity and insulin resistance","volume":"420","author":"Hirosumi","year":"2002","journal-title":"Nature"},{"key":"B93","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1093\/ije\/dys176","article-title":"Body mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas: a pooled analysis from the international BEACON consortium","volume":"41","author":"Hoyo","year":"2012","journal-title":"Int. J. Epidemiol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1124\/mol.112.078485","article-title":"Betulinic acid decreases specificity protein 1 (Sp1) level via increasing the sumoylation of sp1 to inhibit lung cancer growth","volume":"82","author":"Hsu","year":"2012","journal-title":"Mol. Pharmacol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"140","DOI":"10.2337\/dc14-2441","article-title":"Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American diabetes association and the european association for the Study of Diabetes","volume":"38","author":"Inzucchi","year":"2015","journal-title":"Diabetes care"},{"key":"B96","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.3390\/medicina59091646","article-title":"Colorectal cancer: from risk factors to oncogenesis","volume":"59","author":"Ionescu","year":"2023","journal-title":"Med. Kaunas."},{"key":"B97","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/nature01478","article-title":"Free fatty acids regulate insulin secretion from pancreatic \u03b2 cells through GPR40","volume":"422","author":"Itoh","year":"2003","journal-title":"Nature"},{"key":"B98","doi-asserted-by":"publisher","first-page":"46","DOI":"10.14694\/EdBook_AM.2013.33.46","article-title":"Obesity and inflammation: new insights into breast cancer development and progression","volume":"33","author":"Iyengar","year":"2013","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"B99","doi-asserted-by":"publisher","first-page":"2016","DOI":"10.3390\/molecules14062016","article-title":"Pentacyclic triterpene distribution in various plants\u2013rich sources for a new group of multi-potent plant extracts","volume":"14","author":"J\u00e4ger","year":"2009","journal-title":"Molecules"},{"key":"B100","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1111\/j.1365-2036.2007.03586.x","article-title":"Adipokines and cytokines in non\u2010alcoholic fatty liver disease","volume":"27","author":"Jarrar","year":"2008","journal-title":"Alimentary Pharmacol. and Ther."},{"key":"B101","doi-asserted-by":"publisher","first-page":"111990","DOI":"10.1016\/j.biopha.2021.111990","article-title":"Betulinic acid in the treatment of tumour diseases: application and research progress","volume":"142","author":"Jiang","year":"2021","journal-title":"Biomed. and Pharmacother."},{"key":"B102","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1021\/acs.jafc.5b05416","article-title":"Betulinic acid increases eNOS phosphorylation and NO synthesis via the calcium-signaling pathway","volume":"64","author":"Jin","year":"2016","journal-title":"J. Agric. food Chem."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1038\/ajg.2011.130","article-title":"Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett's esophagus: a population-based study","volume":"106","author":"Jung","year":"2011","journal-title":"Official J. Am. Coll. Gastroenterology| ACG."},{"key":"B104","doi-asserted-by":"publisher","first-page":"4047","DOI":"10.1210\/jcem.86.9.7713","article-title":"Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes","volume":"86","author":"Kahn","year":"2001","journal-title":"J. Clin. Endocrinol. and Metabolism"},{"key":"B105","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1038\/nature05482","article-title":"Mechanisms linking obesity to insulin resistance and type 2 diabetes","volume":"444","author":"Kahn","year":"2006","journal-title":"Nature"},{"key":"B106","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1684\/ecn.2018.0415","article-title":"Obesity and inflammation","volume":"29","author":"Karczewski","year":"2018","journal-title":"Eur. cytokine Netw."},{"key":"B107","doi-asserted-by":"publisher","first-page":"2257","DOI":"10.1038\/oby.2012.110","article-title":"The microbiota of the gut in preschool children with normal and excessive body weight","volume":"20","author":"Karlsson","year":"2012","journal-title":"Obesity"},{"key":"B108","doi-asserted-by":"publisher","first-page":"361","DOI":"10.4149\/neo_2009_04_361","article-title":"Mechanism of betulinic acid inhibition of collagen biosynthesis in human endometrial adenocarcinoma cells","volume":"56","author":"Karna","year":"2009","journal-title":"Neoplasma"},{"key":"B109","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/s11010-010-0395-8","article-title":"Betulinic acid inhibits the expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in human endometrial adenocarcinoma cells","volume":"340","author":"Karna","year":"2010","journal-title":"Mol. Cell. Biochem."},{"key":"B110","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1002\/oby.23444","article-title":"Metabolic dysfunction and obesity\u2010related cancer: beyond obesity and metabolic syndrome","volume":"30","author":"Karra","year":"2022","journal-title":"Obesity"},{"key":"B111","doi-asserted-by":"publisher","first-page":"9663","DOI":"10.1007\/s11033-023-08809-3","article-title":"Cancer treatment therapies: traditional to modern approaches to combat cancers","volume":"50","author":"Kaur","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"B112","doi-asserted-by":"publisher","first-page":"181643","DOI":"10.1155\/2015\/181643","article-title":"Molecular events linking oxidative stress and inflammation to insulin resistance and \u03b2\u2010cell dysfunction","volume":"2015","author":"Keane","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"B113","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1056\/NEJMoa020245","article-title":"Obesity and the risk of heart failure","volume":"347","author":"Kenchaiah","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"B114","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.canlet.2006.11.003","article-title":"Broad in vitro efficacy of plant-derived betulinic acid against cell lines derived from the most prevalent human cancer types","volume":"251","author":"Kessler","year":"2007","journal-title":"Cancer Lett."},{"key":"B115","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/bjc.1988.44","article-title":"The dose-effect relationship between'unopposed'oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk","volume":"57","author":"Key","year":"1988","journal-title":"Br. J. cancer"},{"key":"B116","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1038\/sj.bjc.6604942","article-title":"Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system","volume":"100","author":"Killeen","year":"2009","journal-title":"Br. J. cancer"},{"key":"B117","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1111\/jnc.12496","article-title":"Co-administration of betulinic acid and methamphetamine causes toxicity to dopaminergic and serotonergic nerve terminals in the striatum of late adolescent rats","volume":"128","author":"Killinger","year":"2014","journal-title":"J. Neurochem."},{"key":"B118","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1021\/jf4030739","article-title":"Beneficial effect of betulinic acid on hyperglycemia via suppression of hepatic glucose production","volume":"62","author":"Kim","year":"","journal-title":"J. Agric. food Chem."},{"key":"B119","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.bbrc.2014.07.115","article-title":"Inhibition of estrogen signaling through depletion of estrogen receptor alpha by ursolic acid and betulinic acid from Prunella vulgaris var. lilacina","volume":"451","author":"Kim","year":"","journal-title":"Biochem. biophysical Res. Commun."},{"key":"B120","doi-asserted-by":"publisher","first-page":"3560","DOI":"10.1093\/eurheartj\/ehv509","article-title":"Obesity and cardiovascular disease: friend or foe?","volume":"37","author":"Kim","year":"2016","journal-title":"Eur. heart J."},{"key":"B121","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.numecd.2018.12.001","article-title":"Betulinic acid inhibits high-fat diet-induced obesity and improves energy balance by activating AMPK","volume":"29","author":"Kim","year":"2019","journal-title":"Metabolism Cardiovasc. Dis."},{"key":"B122","doi-asserted-by":"publisher","first-page":"8471","DOI":"10.1007\/s13277-016-5035-9","article-title":"Major apoptotic mechanisms and genes involved in apoptosis","volume":"37","author":"Kiraz","year":"2016","journal-title":"Tumor Biol."},{"key":"B123","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/s11060-011-0738-7","article-title":"Improved survival time trends for glioblastoma using the SEER 17 population-based registries","volume":"107","author":"Koshy","year":"2012","journal-title":"J. neuro-oncology"},{"key":"B124","doi-asserted-by":"publisher","first-page":"1472","DOI":"10.1161\/01.cir.98.14.1472","article-title":"Obesity: impact of cardiovascular disease","volume":"98","author":"Krauss","year":"1998","journal-title":"Circulation"},{"key":"B125","doi-asserted-by":"publisher","first-page":"382063","DOI":"10.1155\/2013\/382063","article-title":"Enzymes inhibition and antidiabetic effect of isolated constituents from Dillenia indica","volume":"2013","author":"Kumar","year":"2013","journal-title":"BioMed Res. Int."},{"key":"B126","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.lfs.2018.07.056","article-title":"Betulinic acid as apoptosis activator: molecular mechanisms, mathematical modeling and chemical modifications","volume":"209","author":"Kumar","year":"2018","journal-title":"Life Sci."},{"key":"B127","doi-asserted-by":"publisher","first-page":"216","DOI":"10.5603\/ah.2016.0025","article-title":"Arterial hypertension, obesity and non-alcoholic fatty liver disease: is there any connection? Arterial","volume":"20","author":"Kuzminova","year":"2016","journal-title":"Hypertension"},{"key":"B128","doi-asserted-by":"publisher","first-page":"2664","DOI":"10.3390\/nu11112664","article-title":"Relevance of leptin and other adipokines in obesity-associated cardiovascular risk","volume":"11","author":"Landecho","year":"2019","journal-title":"Nutrients"},{"key":"B129","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1016\/j.jacc.2014.01.022","article-title":"Obesity and cardiovascular diseases: implications regarding fitness, fatness, and severity in the obesity paradox","volume":"63","author":"Lavie","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"B130","doi-asserted-by":"publisher","first-page":"15366","DOI":"10.1074\/jbc.273.25.15366","article-title":"Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor","volume":"273","author":"Lee","year":"1998","journal-title":"J. Biol. Chem."},{"key":"B131","doi-asserted-by":"publisher","first-page":"257","DOI":"10.3390\/biom9070257","article-title":"Betulinic acid suppresses ovarian cancer cell proliferation through induction of apoptosis","volume":"9","author":"Lee","year":"2019","journal-title":"Biomolecules"},{"key":"B132","doi-asserted-by":"publisher","first-page":"103247","DOI":"10.1016\/j.eclinm.2025.103247","article-title":"Excess adiposity and cancer: evaluating a preclinical-clinical obesity framework for risk stratification","volume":"83","author":"Leitzmann","year":"2025","journal-title":"eClinicalMedicine"},{"key":"B133","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.2147\/PPA.S103649","article-title":"Weight loss intervention adherence and factors promoting adherence: a meta-analysis","volume":"10","author":"Lemstra","year":"2016","journal-title":"Patient Prefer Adherence"},{"key":"B134","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s12951-022-01238-7","article-title":"Betulinic acid self-assembled nanoparticles for effective treatment of glioblastoma","volume":"20","author":"Li","year":"2022","journal-title":"J. nanobiotechnology"},{"key":"B135","doi-asserted-by":"publisher","first-page":"e13278","DOI":"10.1111\/jfbc.13278","article-title":"Betulinic acid induces apoptosis and impairs migration and invasion in a mouse model of ovarian cancer","volume":"44","author":"Liao","year":"2020","journal-title":"J. Food Biochem."},{"key":"B136","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.ejphar.2004.07.103","article-title":"Apoptotic activity of betulinic acid derivatives on murine melanoma B16 cell line","volume":"498","author":"Liu","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"B137","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1158\/1535-7163.MCT-12-0026","article-title":"Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a: ZBTB10 in breast cancer","volume":"11","author":"Liu","year":"2012","journal-title":"Mol. cancer Ther."},{"key":"B138","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1080\/19336918.2015.1134404","article-title":"LPS-induced CXCR4-dependent migratory properties and a mesenchymal-like phenotype of colorectal cancer cells","volume":"11","author":"Liu","year":"2017","journal-title":"Cell Adhesion and Migr."},{"key":"B139","doi-asserted-by":"publisher","first-page":"981","DOI":"10.3390\/cancers12040981","article-title":"Betulinic acid-mediated tuning of PERK\/CHOP signaling by Sp1 inhibition as a novel therapeutic strategy for glioblastoma","volume":"12","author":"Lo","year":"2020","journal-title":"Cancers"},{"key":"B140","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/s1575-0922(09)73516-8","article-title":"Obesity and diabetes","volume":"56","author":"Lois","year":"2009","journal-title":"Endocrinol. Nutr."},{"key":"B141","doi-asserted-by":"publisher","first-page":"5583","DOI":"10.3390\/molecules26185583","article-title":"A review on preparation of betulinic acid and its biological activities","volume":"26","author":"Lou","year":"2021","journal-title":"Molecules"},{"key":"B142","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1016\/j.biopha.2016.10.018","article-title":"Multiple molecular targets in breast cancer therapy by betulinic acid","volume":"84","author":"Luo","year":"2016","journal-title":"Biomed. and Pharmacother."},{"key":"B143","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.jhep.2006.06.013","article-title":"Hepatic histology in obese patients undergoing bariatric surgery","volume":"45","author":"Machado","year":"2006","journal-title":"J. hepatology"},{"key":"B144","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s12917-021-02905-x","article-title":"High cytotoxicity of betulin towards fish and murine fibroblasts: is betulin safe for nonneoplastic cells?","volume":"17","author":"Ma\u0142aczewska","year":"2021","journal-title":"BMC Veterinary Res."},{"key":"B145","doi-asserted-by":"publisher","first-page":"354","DOI":"10.4239\/wjd.v7.i17.354","article-title":"Update on the treatment of type 2 diabetes mellitus","volume":"7","author":"Mar\u00edn-Pe\u00f1alver","year":"2016","journal-title":"World J. Diabetes"},{"key":"B146","doi-asserted-by":"publisher","first-page":"800","DOI":"10.3390\/nu16060800","article-title":"Healthy lifestyle and cancer risk: modifiable risk factors to prevent cancer","volume":"16","author":"Marino","year":"2024","journal-title":"Nutrients"},{"key":"B147","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1172\/JCI108764","article-title":"A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis","volume":"60","author":"Mcgarry","year":"1977","journal-title":"J. Clin. investigation"},{"key":"B148","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1055\/s-2006-957542","article-title":"Betulinic acid inhibits aminopeptidase N activity","volume":"64","author":"Melzig","year":"1998","journal-title":"Planta medica"},{"key":"B149","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1016\/j.clinbiochem.2009.05.018","article-title":"Hepatic insulin resistance, metabolic syndrome and cardiovascular disease","volume":"42","author":"Meshkani","year":"2009","journal-title":"Clin. Biochem."},{"key":"B150","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1002\/hep.22848","article-title":"Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease","volume":"49","author":"Miele","year":"2009","journal-title":"Hepatology"},{"key":"B151","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1093\/carcin\/bgg175","article-title":"Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancer","volume":"25","author":"Mobley","year":"2004","journal-title":"Carcinogenesis"},{"key":"B152","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.ygyno.2006.10.045","article-title":"Impact of body mass index on treatment outcomes in endometrial cancer patients receiving doxorubicin and cisplatin: a Gynecologic Oncology Group study","volume":"105","author":"Modesitt","year":"2007","journal-title":"Gynecol. Oncol."},{"key":"B153","doi-asserted-by":"publisher","first-page":"13033","DOI":"10.1096\/fj.202000546R","article-title":"Betulinic acid improves nonalcoholic fatty liver disease through YY1\/FAS signaling pathway","volume":"34","author":"Mu","year":"2020","journal-title":"Faseb J."},{"key":"B154","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1002\/pca.1232","article-title":"Rapid validated HPTLC method for estimation of betulinic acid in Nelumbo nucifera (Nymphaeaceae) rhizome extract","volume":"21","author":"Mukherjee","year":"2010","journal-title":"Phytochem. Anal."},{"key":"B155","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1097\/CAD.0b013e3283357c62","article-title":"Betulinic acid, a natural compound with potent anticancer effects","volume":"21","author":"Mullauer","year":"2010","journal-title":"Anticancer Drugs"},{"key":"B156","doi-asserted-by":"publisher","first-page":"e5947","DOI":"10.1371\/journal.pone.0005947","article-title":"Modulation of angiogenic and inflammatory response in glioblastoma by hypoxia","volume":"4","author":"Murat","year":"2009","journal-title":"PloS one"},{"key":"B157","doi-asserted-by":"publisher","first-page":"17117","DOI":"10.1073\/pnas.1114420108","article-title":"Tumor suppressor protein (p)53, is a regulator of NF-kappaB repression by the glucocorticoid receptor","volume":"108","author":"Murphy","year":"2011","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B158","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/s0016-6480(02)00072-2","article-title":"Immunocytochemical detection of leptin in non-mammalian vertebrate stomach","volume":"128","author":"Muruz\u00e1bal","year":"2002","journal-title":"General Comp. Endocrinol."},{"key":"B159","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.jhep.2021.02.037","article-title":"Muscle fat content is strongly associated with NASH: a longitudinal study in patients with morbid obesity","volume":"75","author":"Nachit","year":"2021","journal-title":"J. hepatology"},{"key":"B160","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.jjcc.2013.11.006","article-title":"Adipokines: a link between obesity and cardiovascular disease","volume":"63","author":"Nakamura","year":"2014","journal-title":"J. Cardiol."},{"key":"B161","doi-asserted-by":"publisher","first-page":"577","DOI":"10.12998\/wjcc.v6.i13.577","article-title":"Role of bile acids in colon carcinogenesis","volume":"6","author":"Nguyen","year":"2018","journal-title":"World J. Clin. Cases"},{"key":"B162","doi-asserted-by":"publisher","first-page":"113610","DOI":"10.1016\/j.biopha.2022.113610","article-title":"Natural products as chemo-radiation therapy sensitizers in cancers","volume":"154","author":"Nisar","year":"2022","journal-title":"Biomed. and Pharmacother."},{"key":"B163","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.3892\/ijo.2015.2845","article-title":"Long-term exposure to leptin enhances the growth of prostate cancer cells","volume":"46","author":"Noda","year":"2015","journal-title":"Int. J. Oncol."},{"key":"B164","first-page":"1664","article-title":"Colonic mucosal proliferation is related to serum deoxycholic acid levels","volume":"85","author":"Ochsenk\u00fchn","year":"1999","journal-title":"Cancer Interdiscip. Int. J. Am. Cancer Soc."},{"key":"B165","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.1080\/01635581.2020.1856889","article-title":"Obesity, inflammation, and advanced prostate cancer","volume":"73","author":"Olivas","year":"2021","journal-title":"Nutr. Cancer"},{"key":"B166","doi-asserted-by":"publisher","first-page":"883857","DOI":"10.3389\/fphar.2022.883857","article-title":"Anti-inflammatory activities of betulinic acid: a review","volume":"13","author":"Oliveira-Costa","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B167","doi-asserted-by":"publisher","first-page":"4225","DOI":"10.1200\/JCO.2016.69.4638","article-title":"Addressing the role of obesity in endometrial cancer risk, prevention, and treatment","volume":"34","author":"Onstad","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"B168","unstructured":"Global cancer burden growing, amidst mounting need for services Lyon, France; Geneva, Switzerland\n          \n          \n            \n              Organization\n              W. H.\n            \n          \n          \n          2024"},{"key":"B169","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s12933-018-0762-4","article-title":"Association between insulin resistance and the development of cardiovascular disease","volume":"17","author":"Ormazabal","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"B170","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1161\/CIRCRESAHA.115.306883","article-title":"Obesity and cardiovascular disease","volume":"118","author":"Ortega","year":"2016","journal-title":"Circ. Res."},{"key":"B171","doi-asserted-by":"publisher","first-page":"110708","DOI":"10.1016\/j.biopha.2020.110708","article-title":"Type II diabetes mellitus: a review on recent drug based therapeutics","volume":"131","author":"Padhi","year":"2020","journal-title":"Biomed. and Pharmacother."},{"key":"B172","doi-asserted-by":"publisher","first-page":"886","DOI":"10.3390\/biom10060886","article-title":"Leptin and notch signaling cooperate in sustaining glioblastoma multiforme progression","volume":"10","author":"Panza","year":"2020","journal-title":"Biomolecules"},{"key":"B173","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/s0367-326x(03)00123-0","article-title":"Antiviral activity of betulin, betulinic and betulonic acids against some enveloped and non-enveloped viruses","volume":"74","author":"Pavlova","year":"2003","journal-title":"Fitoterapia"},{"key":"B174","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S2213-8587(17)30366-2","article-title":"Worldwide burden of cancer attributable to diabetes and high body-mass index: a comparative risk assessment","volume":"6","author":"Pearson-Stuttard","year":"2018","journal-title":"Lancet Diabetes and Endocrinol."},{"key":"B175","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1016\/j.jhep.2022.06.012","article-title":"Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits","volume":"77","author":"Peiseler","year":"2022","journal-title":"J. Hepatol."},{"key":"B176","doi-asserted-by":"publisher","first-page":"3010","DOI":"10.1158\/0008-5472.CAN-11-3768","article-title":"Stromal estrogen receptor-\u03b1 promotes tumor growth by normalizing an increased angiogenesis","volume":"72","author":"P\u00e9queux","year":"2012","journal-title":"Cancer Res."},{"key":"B177","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1007\/s13679-014-0124-9","article-title":"Low-grade inflammation, obesity, and diabetes","volume":"3","author":"Pereira","year":"2014","journal-title":"Curr. Obes. Rep."},{"key":"B178","doi-asserted-by":"publisher","first-page":"46","DOI":"10.3390\/children4060046","article-title":"The role of lipid and lipoprotein metabolism in non-alcoholic fatty liver disease","volume":"4","author":"Perla","year":"2017","journal-title":"Children"},{"key":"B179","doi-asserted-by":"publisher","first-page":"12587","DOI":"10.1073\/pnas.0705408104","article-title":"The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome","volume":"104","author":"Petersen","year":"2007","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B180","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.3390\/biology11111622","article-title":"Gut\u2013liver axis and non-alcoholic fatty liver disease: a vicious circle of dysfunctions orchestrated by the gut microbiome","volume":"11","author":"Pezzino","year":"2022","journal-title":"Biology"},{"key":"B181","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1210\/er.2007-0023","article-title":"Glucolipotoxicity: fuel excess and \u03b2-cell dysfunction","volume":"29","author":"Poitout","year":"2008","journal-title":"Endocr. Rev."},{"key":"B182","doi-asserted-by":"publisher","first-page":"e2037","DOI":"10.1038\/cddis.2015.381","article-title":"Obesity and cancer, a case for insulin signaling","volume":"6","author":"Poloz","year":"2015","journal-title":"Cell Death and Dis."},{"key":"B183","doi-asserted-by":"publisher","first-page":"92","DOI":"10.23736\/S0391-1977.16.02563-3","article-title":"Adipose tissue, obesity and non-alcoholic fatty liver disease","volume":"42","author":"Polyzos","year":"2016","journal-title":"Minerva Endocrinol."},{"key":"B184","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.metabol.2018.11.014","article-title":"Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics","volume":"92","author":"Polyzos","year":"2019","journal-title":"Metabolism"},{"key":"B185","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.3389\/fphys.2018.01813","article-title":"Intestinal microbiota modulation in obesity-related non-alcoholic fatty liver disease","volume":"9","author":"Porras","year":"2018","journal-title":"Front. Physiol."},{"key":"B186","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1016\/j.bcp.2013.02.007","article-title":"Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK\u2013mTOR\u2013SREBP signaling pathway","volume":"85","author":"Quan","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"B187","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1080\/21548331.1999.11443925","article-title":"Improving management of type 2 diabetes mellitus: 2. Biguanides","volume":"34","author":"Quillen","year":"1999","journal-title":"Hosp. Pract."},{"key":"B188","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1002\/mc.20447","article-title":"Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells","volume":"47","author":"Rabi","year":"2008","journal-title":"Mol. Carcinog. Publ. Coop. Univ. Tex. MD Anderson Cancer Cent."},{"key":"B189","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/0016-5085(93)90017-7","article-title":"Barrett's esophagus: cell cycle abnormalities in advancing stages of neoplastic progression","volume":"105","author":"Reid","year":"1993","journal-title":"Gastroenterology"},{"key":"B190","doi-asserted-by":"publisher","first-page":"e56234","DOI":"10.1371\/journal.pone.0056234","article-title":"Betulinic acid selectively increases protein degradation and enhances prostate cancer-specific apoptosis: possible role for inhibition of deubiquitinase activity","volume":"8","author":"Reiner","year":"2013","journal-title":"PloS one"},{"key":"B191","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1055\/s-0043-123472","article-title":"New pharmacological opportunities for betulinic acid","volume":"84","author":"R\u00edos","year":"2018","journal-title":"Planta Medica"},{"key":"B192","doi-asserted-by":"publisher","first-page":"2086","DOI":"10.1039\/c4fo00013g","article-title":"Nutraceutical potential of Aerva lanata (L.) juss. Ex schult ameliorates secondary complications in streptozotocin-induced diabetic rats","volume":"5","author":"Riya","year":"2014","journal-title":"Food and Funct."},{"key":"B193","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1161\/ATVBAHA.110.219055","article-title":"Insulin resistance and the relationship of a dyslipidemia to coronary heart disease: the Framingham Heart Study","volume":"31","author":"Robins","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B194","doi-asserted-by":"publisher","first-page":"105489","DOI":"10.1155\/2010\/105489","article-title":"Leptin inhibits the proliferation of vascular smooth muscle cells induced by angiotensin II through nitric oxide\u2010dependent mechanisms","volume":"2010","author":"Rodr\u00edguez","year":"2010","journal-title":"Mediat. Inflamm."},{"key":"B195","doi-asserted-by":"publisher","first-page":"E691","DOI":"10.1152\/ajpendo.00297.2015","article-title":"Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism","volume":"309","author":"Rodr\u00edguez","year":"2015","journal-title":"Am. J. Physiology-Endocrinology Metabolism"},{"key":"B196","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.3390\/jpm13091328","article-title":"Nanoparticle-Based treatment in glioblastoma","volume":"13","author":"Roque","year":"2023","journal-title":"J. Personalized Med."},{"key":"B197","doi-asserted-by":"publisher","first-page":"4960","DOI":"10.3390\/cancers14194960","article-title":"Advances in preclinical\/clinical glioblastoma treatment: can nanoparticles be of help?","volume":"14","author":"Ruiz-Molina","year":"2022","journal-title":"Cancers"},{"key":"B198","doi-asserted-by":"publisher","first-page":"2383","DOI":"10.2337\/diacare.26.8.2383","article-title":"Plasma adiponectin and leptin levels, body composition, and glucose utilization in adult women with wide ranges of age and obesity","volume":"26","author":"Ryan","year":"2003","journal-title":"Diabetes Care"},{"key":"B199","doi-asserted-by":"publisher","first-page":"538","DOI":"10.5604\/01.3001.0010.0284","article-title":"Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis","volume":"16","author":"Said","year":"2017","journal-title":"Ann. Hepatology"},{"key":"B200","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1080\/1062936X.2024.2352729","article-title":"Exploring the inhibitory action of betulinic acid on key digestive enzymes linked to diabetes via in vitro and computational models: approaches to anti-diabetic mechanisms","volume":"35","author":"Salau","year":"2024","journal-title":"SAR QSAR Environ. Res."},{"key":"B201","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1053\/gast.2001.23256","article-title":"Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities","volume":"120","author":"Sanyal","year":"2001","journal-title":"Gastroenterology"},{"key":"B202","doi-asserted-by":"publisher","first-page":"533","DOI":"10.2147\/DMSO.S146339","article-title":"Obesity and nonalcoholic fatty liver disease: current perspectives","volume":"11","author":"Sarwar","year":"2018","journal-title":"Diabetes, Metabolic Syndrome Obes. Targets Ther."},{"key":"B203","first-page":"1055","article-title":"Cell proliferation and migration in glioblastoma multiforme cell lines are influenced by insulin-like growth factor I in vitro","volume":"28","author":"Schlenska-Lange","year":"2008","journal-title":"Anticancer Res."},{"key":"B204","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1080\/17474124.2020.1764348","article-title":"Obesity and esophageal cancer: GERD, Barrett s esophagus, and molecular carcinogenic pathways","volume":"14","author":"Schlottmann","year":"2020","journal-title":"Expert Rev. Gastroenterology and Hepatology"},{"key":"B205","doi-asserted-by":"publisher","first-page":"2795","DOI":"10.1038\/onc.2010.46","article-title":"Cross talk between stimulated NF-kappaB and the tumor suppressor p53","volume":"29","author":"Schneider","year":"2010","journal-title":"Oncogene"},{"key":"B206","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1055\/s-1999-14054","article-title":"New triterpenoids with antibacterial activity from Zizyphus joazeiro","volume":"65","author":"Sch\u00fchly","year":"1999","journal-title":"Planta Medica"},{"key":"B207","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1046\/j.1523-1747.2000.00972.x","article-title":"Effects of betulinic acid alone and in combination with irradiation in human melanoma cells","volume":"114","author":"Selzer","year":"2000","journal-title":"J. Investigative Dermatology"},{"key":"B208","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1093\/carcin\/bgt480","article-title":"Cancer as a metabolic disease: implications for novel therapeutics","volume":"35","author":"Seyfried","year":"2014","journal-title":"Carcinogenesis"},{"key":"B209","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1007\/s10620-010-1447-3","article-title":"Small intestinal bacterial overgrowth in nonalcoholic steatohepatitis: association with toll-like receptor 4 expression and plasma levels of interleukin 8","volume":"56","author":"Shanab","year":"2011","journal-title":"Dig. Dis. Sci."},{"key":"B210","doi-asserted-by":"publisher","first-page":"264","DOI":"10.3390\/molecules22020264","article-title":"Betulinic acid-mediated apoptosis in human prostate cancer cells involves p53 and nuclear factor-kappa B (NF-\u03baB) pathways","volume":"22","author":"Shankar","year":"2017","journal-title":"Molecules"},{"key":"B211","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/978-3-319-42542-9_7","article-title":"Obesity and endometrial cancer","volume":"208","author":"Shaw","year":"2016","journal-title":"Obes. Cancer"},{"key":"B212","doi-asserted-by":"publisher","first-page":"e21492","DOI":"10.1371\/journal.pone.0021492","article-title":"Suppression of STAT3 and HIF-1 alpha mediates anti-angiogenic activity of betulinic acid in hypoxic PC-3 prostate cancer cells","volume":"6","author":"Shin","year":"2011","journal-title":"PloS one"},{"key":"B213","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1056\/NEJM199001253220403","article-title":"Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy","volume":"322","author":"Shulman","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"B214","doi-asserted-by":"publisher","first-page":"2991","DOI":"10.1021\/acs.jafc.5b06021","article-title":"Oleanolic, ursolic, and betulinic acids as food supplements or pharmaceutical agents for type 2 diabetes: promise or illusion?","volume":"64","author":"Silva","year":"2016","journal-title":"J. Agric. Food Chem."},{"key":"B215","doi-asserted-by":"publisher","first-page":"5682","DOI":"10.1021\/acsomega.8b03691","article-title":"Antiproliferative organic salts derived from betulinic acid: disclosure of an ionic liquid selective against lung and liver cancer cells","volume":"4","author":"Silva","year":"2019","journal-title":"Acs Omega"},{"key":"B216","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1016\/j.cgh.2013.05.009","article-title":"Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysis","volume":"11","author":"Singh","year":"2013","journal-title":"Clin. Gastroenterology Hepatology"},{"key":"B217","doi-asserted-by":"publisher","first-page":"100002","DOI":"10.1016\/j.fufo.2020.100002","article-title":"Managing obesity through natural polyphenols: a review","volume":"1","author":"Singh","year":"2020","journal-title":"Future Foods"},{"key":"B218","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/978-3-0348-0837-8_4","article-title":"The role of inflammation in brain cancer","volume":"816","author":"Sowers","year":"2014","journal-title":"Inflamm. Cancer"},{"key":"B219","doi-asserted-by":"publisher","first-page":"5180707","DOI":"10.1155\/2017\/5180707","article-title":"Helicteric acid, oleanic acid, and betulinic acid, three triterpenes from Helicteres angustifolia L., inhibit proliferation and induce apoptosis in HT\u201029 colorectal cancer cells via suppressing NF\u2010\u03baB and STAT3 signaling","volume":"2017","author":"Su","year":"2017","journal-title":"Evidence\u2010Based Complementary Altern. Med."},{"key":"B220","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/978-3-642-13517-0_6","article-title":"Adipose tissue dysfunction: a multistep process","volume-title":"Novel Insights Into Adipose Cell Functions","author":"Sun","year":"2010"},{"key":"B221","doi-asserted-by":"publisher","first-page":"1998","DOI":"10.1016\/j.foodchem.2012.10.079","article-title":"Apoptosis of human breast cancer cells induced by microencapsulated betulinic acid from sour jujube fruits through the mitochondria transduction pathway","volume":"138","author":"Sun","year":"2013","journal-title":"Food Chem."},{"key":"B222","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3892\/ijo.2018.4604","article-title":"Betulinic acid inhibits stemness and EMT of pancreatic cancer cells via activation of AMPK signaling","volume":"54","author":"Sun","year":"2018","journal-title":"Int. J. Oncol."},{"key":"B223","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA a Cancer J. Clin."},{"key":"B224","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1016\/j.bmcl.2011.12.102","article-title":"New ionic derivatives of betulinic acid as highly potent anti-cancer agents","volume":"22","author":"Suresh","year":"2012","journal-title":"Bioorg. and Med. Chem. Lett."},{"key":"B225","doi-asserted-by":"publisher","first-page":"208","DOI":"10.5534\/wjmh.200010","article-title":"Anti-obesity drugs: long-term efficacy and safety: an updated review","volume":"39","author":"Tak","year":"2020","journal-title":"World J. Men's Health"},{"key":"B226","first-page":"2866","article-title":"Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation","volume":"9","author":"Tan","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"B227","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1002\/ijc.24710","article-title":"Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha\/VEGF signaling pathways in human breast cancer cells","volume":"126","author":"Tang","year":"2010","journal-title":"Int. J. Cancer"},{"key":"B228","doi-asserted-by":"publisher","first-page":"e0149822","DOI":"10.1371\/journal.pone.0149822","article-title":"The activation of ERK1\/2 and JNK MAPK signaling by insulin\/IGF-1 is responsible for the development of colon cancer with type 2 diabetes mellitus","volume":"11","author":"Teng","year":"2016","journal-title":"PLoS One"},{"key":"B229","doi-asserted-by":"publisher","first-page":"612385","DOI":"10.3389\/fonc.2020.612385","article-title":"Prognostic and therapeutic roles of the insulin growth factor System in glioblastoma","volume":"10","author":"Tirr\u00f2","year":"2020","journal-title":"Front. Oncol."},{"key":"B230","doi-asserted-by":"publisher","first-page":"402","DOI":"10.3109\/07357907.2014.933234","article-title":"Betulinic acid-induced cytotoxicity in human breast tumor cell lines MCF-7 and T47D and its modification by tocopherol","volume":"32","author":"Tiwari","year":"2014","journal-title":"Cancer investig."},{"key":"B231","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/j.drudis.2021.11.001","article-title":"Obesity and insulin resistance: pathophysiology and treatment","volume":"27","author":"Tong","year":"2022","journal-title":"Drug Discov. Today"},{"key":"B232","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.breast.2012.08.005","article-title":"Association between common risk factors and molecular subtypes in breast cancer patients","volume":"22","author":"Turkoz","year":"2013","journal-title":"breast"},{"key":"B233","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1002\/hep.23622","article-title":"Homozygosity for the patatin\u2010like phospholipase\u20103\/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease","volume":"51","author":"Valenti","year":"2010","journal-title":"Hepatology"},{"key":"B234","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg effect: the metabolic requirements of cell proliferation","volume":"324","author":"Vander Heiden","year":"2009","journal-title":"Science"},{"key":"B235","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.dsx.2016.06.017","article-title":"Obesity and diabetes: an update","volume":"11","author":"Verma","year":"2017","journal-title":"Diabetes and Metabolic Syndrome Clin. Res. and Rev."},{"key":"B236","doi-asserted-by":"publisher","first-page":"2936","DOI":"10.1158\/1055-9965.EPI-14-0795","article-title":"Obesity increases the risk for high-grade prostate cancer: results from the REDUCE study","volume":"23","author":"Vidal","year":"2014","journal-title":"Cancer Epidemiol. Biomarkers and Prev."},{"key":"B237","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1111\/j.1476-5381.2010.01112.x","article-title":"Betulinic acid inhibits endotoxin\u2010stimulated phosphorylation cascade and pro\u2010inflammatory prostaglandin E2 production in human peripheral blood mononuclear cells","volume":"162","author":"Viji","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"B238","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1001\/jama.282.22.2131","article-title":"Elevated C-reactive protein levels in overweight and obese adults","volume":"282","author":"Visser","year":"1999","journal-title":"Jama"},{"key":"B239","doi-asserted-by":"publisher","first-page":"3052","DOI":"10.1161\/hc5001.101061","article-title":"Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS)","volume":"104","author":"Wallace","year":"2001","journal-title":"Circulation"},{"key":"B240","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1007\/s11064-016-2147-y","article-title":"Betulinic acid induces apoptosis in differentiated PC12 cells via ROS-mediated mitochondrial pathway","volume":"42","author":"Wang","year":"2017","journal-title":"Neurochem. Res."},{"key":"B241","doi-asserted-by":"publisher","first-page":"106925","DOI":"10.1016\/j.phrs.2023.106925","article-title":"Natural products in non-alcoholic fatty liver disease (NAFLD): novel lead discovery for drug development","volume":"196","author":"Wang","year":"2023","journal-title":"Pharmacol. Res."},{"key":"B242","doi-asserted-by":"publisher","first-page":"14075","DOI":"10.2147\/IJN.S493489","article-title":"Advancements in betulinic acid-loaded nanoformulations for enhanced anti-tumor therapy","volume":"19","author":"Wang","year":"2024","journal-title":"Int. J. Nanomedicine"},{"key":"B243","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the origin of cancer cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"B244","doi-asserted-by":"publisher","DOI":"10.1177\/2050312114551974","article-title":"The efficacy of betulinic acid in triple-negative breast cancer","volume":"2","author":"Weber","year":"2014","journal-title":"SAGE Open Med."},{"key":"B245","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/s13046-016-0446-4","article-title":"Leptin promotes epithelial-mesenchymal transition of breast cancer via the upregulation of pyruvate kinase M2","volume":"35","author":"Wei","year":"2016","journal-title":"J. Exp. and Clin. Cancer Res."},{"key":"B246","doi-asserted-by":"publisher","first-page":"745","DOI":"10.3892\/ijo.2012.1480","article-title":"A novel role for insulin resistance in the connection between obesity and postmenopausal breast cancer","volume":"41","author":"Weichhaus","year":"2012","journal-title":"Int. J. Oncol."},{"key":"B247","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.1172\/JCI19246","article-title":"Obesity is associated with macrophage accumulation in adipose tissue","volume":"112","author":"Weisberg","year":"2003","journal-title":"J. Clin. Investigation"},{"key":"B248","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1172\/JCI7231","article-title":"The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus","volume":"104","author":"Weyer","year":"1999","journal-title":"J. Clin. Investigation"},{"key":"B249","unstructured":"Obesity and overweight\n          \n          \n          2025"},{"key":"B250","unstructured":"2025"},{"key":"B251","doi-asserted-by":"publisher","first-page":"169","DOI":"10.3390\/nu14010169","article-title":"Nutrition concepts for the treatment of obesity in adults","volume":"14","author":"Wiechert","year":"2021","journal-title":"Nutrients"},{"key":"B252","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/S0025-7125(03)00128-7","article-title":"Insulin and insulin resistance","volume":"26","author":"Wilcox","year":"2005","journal-title":"Clin. Biochem. Rev."},{"key":"B253","doi-asserted-by":"publisher","first-page":"2819","DOI":"10.1111\/liv.15059","article-title":"The role of hepatic lipid composition in obesity\u2010related metabolic disease","volume":"41","author":"Willis","year":"2021","journal-title":"Liver Int."},{"key":"B254","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1634\/theoncologist.2009-0285","article-title":"Obesity and cancer","volume":"15","author":"Wolin","year":"2010","journal-title":"Oncol."},{"key":"B255","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1161\/CIRCRESAHA.119.315896","article-title":"Metabolic inflammation and insulin resistance in obesity","volume":"126","author":"Wu","year":"2020","journal-title":"Circulation Res."},{"key":"B256","doi-asserted-by":"publisher","first-page":"3490","DOI":"10.1038\/s41467-018-05467-z","article-title":"Evaluating intrinsic and non-intrinsic cancer risk factors","volume":"9","author":"Wu","year":"2018","journal-title":"Nat. Commun."},{"key":"B257","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1039\/c6fo01601d","article-title":"The protective effect of betulinic acid (BA) diabetic nephropathy on streptozotocin (STZ)-induced diabetic rats","volume":"8","author":"Xie","year":"2017","journal-title":"Food and Funct."},{"key":"B258","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.canlet.2017.02.014","article-title":"IGF1\/IGF1R\/STAT3 signaling-inducible IFITM2 promotes gastric cancer growth and metastasis","volume":"393","author":"Xu","year":"2017","journal-title":"Cancer Lett."},{"key":"B259","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1016\/j.neo.2014.09.011","article-title":"The transcriptional repressor ZBTB4 regulates EZH2 through a MicroRNA-ZBTB4-specificity protein signaling axis","volume":"16","author":"Yang","year":"2014","journal-title":"Neoplasia"},{"key":"B260","doi-asserted-by":"publisher","first-page":"272","DOI":"10.3390\/molecules28010272","article-title":"Terpenoids: natural compounds for non-alcoholic fatty liver disease (NAFLD) therapy","volume":"28","author":"Yao","year":"2022","journal-title":"Molecules"},{"key":"B261","doi-asserted-by":"publisher","first-page":"2545","DOI":"10.4314\/tjpr.v19i12.9","article-title":"Betulinic acid inhibits glioma cell viability by downregulation of NF-\u03baB and enhancement of apoptosis","volume":"19","author":"Yaozu","year":"2020","journal-title":"Trop. J. Pharm. Res."},{"key":"B262","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.3390\/cancers12061408","article-title":"Linking obesity with colorectal cancer: epidemiology and mechanistic insights","volume":"12","author":"Ye","year":"2020","journal-title":"Cancers"},{"key":"B263","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1002\/glia.20773","article-title":"Leptin induces migration and invasion of glioma cells through MMP\u201013 production","volume":"57","author":"Yeh","year":"2009","journal-title":"Glia"},{"key":"B264","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.bbrc.2009.11.009","article-title":"Protective role of betulinic acid on TNF-\u03b1-induced cell adhesion molecules in vascular endothelial cells","volume":"391","author":"Yoon","year":"2010","journal-title":"Biochem. biophysical Res. Commun."},{"key":"B265","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.ejphar.2016.11.044","article-title":"Protective effect of betulinic acid on early atherosclerosis in diabetic apolipoprotein-E gene knockout mice","volume":"796","author":"Yoon","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"B266","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"B267","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1007\/BF02994763","article-title":"Immunomodulatory activity of betulinic acid by producing pro-inflammatory cytokines and activation of macrophages","volume":"26","author":"Yun","year":"2003","journal-title":"Archives pharmacal Res."},{"key":"B268","doi-asserted-by":"publisher","first-page":"3794","DOI":"10.18632\/oncotarget.23376","article-title":"Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models","volume":"9","author":"Zeng","year":"2017","journal-title":"Oncotarget"},{"key":"B269","doi-asserted-by":"publisher","first-page":"2546","DOI":"10.1016\/j.bmc.2019.03.033","article-title":"Betulinic acid induces apoptosis and inhibits metastasis of human colorectal cancer cells in vitro and in vivo","volume":"27","author":"Zeng","year":"2019","journal-title":"Bioorg. and Med. Chem."},{"key":"B270","doi-asserted-by":"publisher","first-page":"3628","DOI":"10.3892\/ol.2018.9097","article-title":"Betulinic acid exerts potent antitumor effects on paclitaxel-resistant human lung carcinoma cells (H460) via G2\/M phase cell cycle arrest and induction of mitochondrial apoptosis","volume":"16","author":"Zhan","year":"2018","journal-title":"Oncol. Lett."},{"key":"B271","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.3892\/ol.2014.2841","article-title":"Impact of obesity upon prostate cancer-associated mortality: a meta-analysis of 17 cohort studies","volume":"9","author":"Zhang","year":"2015","journal-title":"Oncol. Lett."},{"key":"B272","doi-asserted-by":"publisher","first-page":"104544","DOI":"10.1016\/j.yrtph.2019.104544","article-title":"Berberine decreases insulin resistance in a PCOS rats by improving GLUT4: dual regulation of the PI3K\/AKT and MAPK pathways","volume":"110","author":"Zhang","year":"2020","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"B273","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1021\/tx0502645","article-title":"Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol","volume":"19","author":"Zhao","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"B274","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1007\/s00011-010-0163-y","article-title":"Association between serum amyloid A and obesity: a meta-analysis and systematic review","volume":"59","author":"Zhao","year":"2010","journal-title":"Inflamm. Res."},{"key":"B275","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1161\/CIRCRESAHA.120.314458","article-title":"Adiponectin, leptin and cardiovascular disorders","volume":"128","author":"Zhao","year":"2021","journal-title":"Circulation Res."},{"key":"B276","doi-asserted-by":"publisher","first-page":"115459","DOI":"10.1016\/j.jep.2022.115459","article-title":"Betulinic acid prevents liver fibrosis by binding Lck and suppressing Lck in HSC activation and proliferation","volume":"296","author":"Zhao","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"B277","first-page":"100259","article-title":"A review: Anti-obesity drug discovery from natural plant metabolites and endogenous peptides","volume-title":"Current Research In Biotechnology","author":"Zhu","year":"2024"},{"key":"B278","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/s0304-3835(01)00718-2","article-title":"Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells","volume":"175","author":"Zuco","year":"2002","journal-title":"Cancer Lett."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1674713\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T05:34:01Z","timestamp":1758605641000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1674713\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,23]]},"references-count":278,"alternative-id":["10.3389\/fphar.2025.1674713"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1674713","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,23]]},"article-number":"1674713"}}