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2000
Volume 28, Issue 8
  • ISSN: 1386-2073
  • E-ISSN: 1875-5402

Abstract

Background and Aim

Diabetes and Urinary Tract Infections (UTIs) are both common and serious health problems. Shuangdong capsule, a Chinese patent medicine, has been used to treat these conditions. This study assesses its efficacy and mechanism in treating diabetes combined with UTIs.

Methods

We induced diabetes in rats using streptozotocin and UTIs with Escherichia coli, dividing the rats into five groups: control, model, levofloxacin, Shuangdong capsule, and levofloxacin + Shuangdong capsule. After two weeks, we measured blood glucose, insulin, infection indicators, and bladder histology. We also detected the expression of insulin receptor substrate 1 (IRS1)-phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)-C-X-C motif chemokine ligand 2 (CXCL2) signaling pathway by Western Blot and the myeloperoxidase (MPO) levels by Enzyme-Linked Immunosorbent Assay (ELISA). Additionally, we conducted a Mendelian randomization study using genetic variants of the insulin receptor to assess its causal effect on UTI risk.

Results

Shuangdong capsule improved bladder pathology and infection indicators, similar to levofloxacin. It did not affect blood glucose or insulin levels. Moreover, it reversed the suppression of the IRS1-PI3K-Akt-CXCL2 pathway and MPO levels caused by UTI in diabetic rats. The Mendelian randomization study showed that increased insulin receptor expression reduced UTI risk, which was consistent with the results of the animal experiments.

Conclusion

The Shuangdong capsule was effective in treating diabetes with UTIs. It may function by activating the IRS1-PI3K-Akt signaling pathway, thereby increasing CXCL2 and MPO levels, enhancing innate immunity, and promoting bacterial clearance. The Mendelian randomization study provided further evidence supporting the causal role of the insulin receptor in UTI prevention.

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2025-05-01
2025-09-15
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References

  1. MirelesF.A.L. WalkerJ.N. CaparonM. HultgrenS.J. Urinary tract infections: Epidemiology, mechanisms of infection and treatment options.Nat. Rev. Microbiol.201513526928410.1038/nrmicro3432 25853778
    [Google Scholar]
  2. ZhuC. WangD.Q. ZiH. HuangQ. GuJ.M. LiL.Y. GuoX.P. LiF. FangC. LiX.D. ZengX.T. Epidemiological trends of urinary tract infections, urolithiasis and benign prostatic hyperplasia in 203 countries and territories from 1990 to 2019.Mil. Med. Res.2021816410.1186/s40779‑021‑00359‑8 34879880
    [Google Scholar]
  3. SunH. SaeediP. KarurangaS. PinkepankM. OgurtsovaK. DuncanB.B. SteinC. BasitA. ChanJ.C.N. MbanyaJ.C. PavkovM.E. RamachandaranA. WildS.H. JamesS. HermanW.H. ZhangP. BommerC. KuoS. BoykoE.J. MaglianoD.J. IDF diabetes atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045.Diabetes Res. Clin. Pract.202218310911910.1016/j.diabres.2021.109119 34879977
    [Google Scholar]
  4. McDonaldH.I. NitschD. MillettE.R.C. SinclairA. ThomasS.L. New estimates of the burden of acute community‐acquired infections among older people with diabetes mellitus: A retrospective cohort study using linked electronic health records.Diabet. Med.201431560661410.1111/dme.12384 24341529
    [Google Scholar]
  5. BenfieldT. JensenJ.S. NordestgaardB.G. Influence of diabetes and hyperglycaemia on infectious disease hospitalisation and outcome.Diabetologia200750354955410.1007/s00125‑006‑0570‑3 17187246
    [Google Scholar]
  6. BarkaiL.J. SipterE. CsukaD. ProhászkaZ. PilelyK. GarredP. HosszúfalusiN. Decreased ficolin-3-mediated complement lectin pathway activation and alternative pathway amplification during bacterial infections in patients with type 2 diabetes mellitus.Front. Immunol.20191050910.3389/fimmu.2019.00509 30949171
    [Google Scholar]
  7. OzerA. AltuntasC.Z. BicerF. IzgiK. HultgrenS.J. LiuG. DaneshgariF. Impaired cytokine expression, neutrophil infiltration and bacterial clearance in response to urinary tract infection in diabetic mice.Pathog. Dis.2015733ftv00210.1093/femspd/ftv002 25663347
    [Google Scholar]
  8. GeerlingsS.E. Urinary tract infections in patients with diabetes mellitus: Epidemiology, pathogenesis and treatment.Int. J. Antimicrob. Agents200831S1545710.1016/j.ijantimicag.2007.07.042 18054467
    [Google Scholar]
  9. BillipsB.K. SchaefferA.J. KlumppD.J. Molecular basis of uropathogenic Escherichia coli evasion of the innate immune response in the bladder.Infect. Immun.20087693891390010.1128/IAI.00069‑08 18559433
    [Google Scholar]
  10. MehrabiM. SalehiB. RassiH. DehghanA. Evaluating the antibiotic resistance and frequency of adhesion markers among Escherichia coli isolated from type 2 diabetes patients with urinary tract infection and its association with common polymorphism of mannose-binding lectin gene.New Microbes New Infect.20203810082710.1016/j.nmni.2020.100827 33364032
    [Google Scholar]
  11. WoldemariamH.K. GeletaD.A. TuluK.D. AberN.A. LegeseM.H. FentaG.M. AliI. Common uropathogens and their antibiotic susceptibility pattern among diabetic patients.BMC Infect. Dis.20191914310.1186/s12879‑018‑3669‑5 30630427
    [Google Scholar]
  12. TangY. ZhouQ. Changes in serum CRP and PCT levels in patients with acute simple lower urinary tract infection and evaluation of the efficacy of treatment with shuangdong capsules.Emerg. Med. Int.202220221710.1155/2022/9750237 36052218
    [Google Scholar]
  13. XuJ. WangY. XuD.S. RuanK.F. FengY. WangS. Hypoglycemic effects of MDG-1, a polysaccharide derived from Ophiopogon japonicas, in the ob/ob mouse model of type 2 diabetes mellitus.Int. J. Biol. Macromol.201149465766210.1016/j.ijbiomac.2011.06.026 21756932
    [Google Scholar]
  14. YanY. LiX. ZhangC. LvL. GaoB. LiM. Research progress on antibacterial activities and mechanisms of natural alkaloids: A review.Antibiotics202110331810.3390/antibiotics10030318 33808601
    [Google Scholar]
  15. ZhangN. BianY. YaoL. Essential oils of Gardenia jasminoides J. ellis and Gardenia jasminoides f. longicarpa Z.W. Xie & M. okada flowers: Chemical characterization and assessment of anti-inflammatory effects in alveolar macrophage.Pharmaceutics202214596610.3390/pharmaceutics14050966 35631552
    [Google Scholar]
  16. AnE.K. ZhangW. KwakM. LeeP.C.W. JinJ.O. Polysaccharides from Astragalus membranaceus elicit T cell immunity by activation of human peripheral blood dendritic cells.Int. J. Biol. Macromol.2022223Pt A37037710.1016/j.ijbiomac.2022.11.048 36368354
    [Google Scholar]
  17. Davey SmithG. EbrahimS. ‘Mendelian randomization’: Can genetic epidemiology contribute to understanding environmental determinants of disease?Int. J. Epidemiol.200332112210.1093/ije/dyg070 12689998
    [Google Scholar]
  18. GheibiS. KashfiK. GhasemiA. A practical guide for induction of type-2 diabetes in rat: Incorporating a high-fat diet and streptozotocin.Biomed. Pharmacother.20179560561310.1016/j.biopha.2017.08.098 28881291
    [Google Scholar]
  19. MulveyM.A. SchillingJ.D. HultgrenS.J. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection.Infect. Immun.20016974572457910.1128/IAI.69.7.4572‑4579.2001 11402001
    [Google Scholar]
  20. FerkingstadE. SulemP. AtlasonB.A. SveinbjornssonG. MagnussonM.I. StyrmisdottirE.L. GunnarsdottirK. HelgasonA. OddssonA. HalldorssonB.V. JenssonB.O. ZinkF. HalldorssonG.H. MassonG. ArnadottirG.A. KatrinardottirH. JuliussonK. MagnussonM.K. MagnussonO.T. FridriksdottirR. SaevarsdottirS. GudjonssonS.A. StaceyS.N. RognvaldssonS. EiriksdottirT. OlafsdottirT.A. SteinthorsdottirV. TraganteV. UlfarssonM.O. StefanssonH. JonsdottirI. HolmH. RafnarT. MelstedP. SaemundsdottirJ. NorddahlG.L. LundS.H. GudbjartssonD.F. ThorsteinsdottirU. StefanssonK. Large-scale integration of the plasma proteome with genetics and disease.Nat. Genet.202153121712172110.1038/s41588‑021‑00978‑w 34857953
    [Google Scholar]
  21. BurgessS. DaviesN.M. ThompsonS.G. Bias due to participant overlap in two‐sample Mendelian randomization.Genet. Epidemiol.201640759760810.1002/gepi.21998 27625185
    [Google Scholar]
  22. ZhangY. XuG. HuangB. ChenD. YeR. AstragalosideI.V. Astragaloside IV regulates insulin resistance and inflammatory response of adipocytes via modulating CTRP3 and PI3K/AKT signaling.Diabetes Ther.20221311-121823183410.1007/s13300‑022‑01312‑1 36103112
    [Google Scholar]
  23. LiC. LiuY. ZhangY. LiJ. LaiJ. Astragalus polysaccharide: A review of its immunomodulatory effect.Arch. Pharm. Res.202245636738910.1007/s12272‑022‑01393‑3 35713852
    [Google Scholar]
  24. AraiC. MiyakeM. MatsumotoY. MizoteA. YoshizaneC. HanayaY. KoideK. YamadaM. HanayaT. AraiS. FukudaS. Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance in mice with established obesity.J. Nutr. Sci. Vitaminol.201359539340110.3177/jnsv.59.393 24418873
    [Google Scholar]
  25. WuG. ZhangL. LiT. ZunigaA. LopaschukG.D. LiL. JacobsR.L. VanceD.E. Choline supplementation promotes hepatic insulin resistance in phosphatidylethanolamine N-methyltransferase-deficient mice via increased glucagon action.J. Biol. Chem.2013288283784710.1074/jbc.M112.415117 23179947
    [Google Scholar]
  26. KathirvelE. MorganK. NandgiriG. SandovalB.C. CaudillM.A. BottiglieriT. FrenchS.W. MorganT.R. Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: A potential mechanism for hepatoprotection by betaine.Am. J. Physiol. Gastrointest. Liver Physiol.20102995G1068G107710.1152/ajpgi.00249.2010 20724529
    [Google Scholar]
  27. GómezL.C. FernándezS.C. SerranoG.S. EscobarG.E. RepisoG.C. DíazR.C. PlágaroH.A. ReyesM.F. SánchezG.L. ValdésS. CañeteR.A. PachecoR.F. FuentesG.E. Oleic acid protects against insulin resistance by regulating the genes related to the PI3K signaling pathway.J. Clin. Med.202098261510.3390/jcm9082615 32806641
    [Google Scholar]
  28. HeH. WeirR.L. ToutounchianJ.J. PagadalaJ. SteinleJ.J. BaudryJ. MillerD.D. YatesC.R. The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism.PLoS One2017128e018080810.1371/journal.pone.0180808 28796787
    [Google Scholar]
  29. WilliamsD.L. LiC. HaT. SkeltonO.T. KalbfleischJ.H. PreisznerJ. BrooksL. BreuelK. SchweitzerJ.B. Modulation of the phosphoinositide 3-kinase pathway alters innate resistance to polymicrobial sepsis.J. Immunol.2004172144945610.4049/jimmunol.172.1.449 14688354
    [Google Scholar]
  30. KenzelS. MergenM. von SchwendiS.J. WennekampJ. DeshmukhS.D. HaeffnerM. TriantafyllopoulouA. FuchsS. FarmandS. SierraS.S. SeufertJ. van den BergT.K. KuijpersT.W. HennekeP. Insulin modulates the inflammatory granulocyte response to streptococci via phosphatidylinositol 3-kinase.J. Immunol.201218994582459110.4049/jimmunol.1200205 23018458
    [Google Scholar]
  31. RafiiS. RodaD. GeunaE. JimenezB. RihawiK. CapelanM. YapT.A. MolifeL.R. KayeS.B. de BonoJ.S. BanerjiU. Higher risk of infections with PI3K–AKT–mTOR pathway inhibitors in patients with advanced solid tumors on phase I clinical trials.Clin. Cancer Res.20152181869187610.1158/1078‑0432.CCR‑14‑2424 25649020
    [Google Scholar]
  32. KuwabaraW.M.T. YokotaC.N.F. CuriR. LoureiroA.T.C. Obesity and type 2 diabetes mellitus induce lipopolysaccharide tolerance in rat neutrophils.Sci. Rep.2018811753410.1038/s41598‑018‑35809‑2 30510205
    [Google Scholar]
  33. FengM. LiuF. XingJ. ZhongY. ZhouX. Anemarrhena saponins attenuate insulin resistance in rats with high-fat diet-induced obesity via the IRS-1/PI3K/AKT pathway.J. Ethnopharmacol.202127711425110.1016/j.jep.2021.114251 34052350
    [Google Scholar]
  34. LiD. ZhangS. YangC. LiQ. WangS. XuX. HaoJ. LiC. A novel PTP1B inhibitor-phosphate of polymannuronic acid ameliorates insulin resistance by regulating IRS-1/Akt signaling.Int. J. Mol. Sci.202122231269310.3390/ijms222312693 34884501
    [Google Scholar]
  35. YueL. XieZ. LiH. PangZ. JunkinsR.D. TremblayM.L. ChenX. LinT.J. Protein tyrosine phosphatase-1B negatively impacts host defense against pseudomonas aeruginosa infection.Am. J. Pathol.201618651234124410.1016/j.ajpath.2016.01.005 27105736
    [Google Scholar]
  36. EichlerT.E. BecknellB. EasterlingR.S. IngrahamS.E. CohenD.M. SchwadererA.L. HainsD.S. LiB. CohenA. MethenyJ. TridandapaniS. SpencerJ.D. Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract.Kidney Int.201690356857910.1016/j.kint.2016.04.025 27401534
    [Google Scholar]
  37. ZasloffM. Why are diabetics prone to kidney infections?J. Clin. Invest.2018128125213521510.1172/JCI124922 30418173
    [Google Scholar]
  38. MurthaM.J. EichlerT. BenderK. MethenyJ. LiB. SchwadererA.L. MosqueraC. JamesC. SchwartzL. BecknellB. SpencerJ.D. Insulin receptor signaling regulates renal collecting duct and intercalated cell antibacterial defenses.J. Clin. Invest.2018128125634564610.1172/JCI98595 30418175
    [Google Scholar]
  39. HunstadD.A. JusticeS.S. HungC.S. LauerS.R. HultgrenS.J. Suppression of bladder epithelial cytokine responses by uropathogenic Escherichia coli.Infect. Immun.20057373999400610.1128/IAI.73.7.3999‑4006.2005 15972487
    [Google Scholar]
  40. BillipsB.K. ForrestalS.G. RycykM.T. JohnsonJ.R. KlumppD.J. SchaefferA.J. Modulation of host innate immune response in the bladder by uropathogenic Escherichia coli.Infect. Immun.200775115353536010.1128/IAI.00922‑07 17724068
    [Google Scholar]
  41. HaraokaM. HangL. FrendéusB. GodalyG. BurdickM. StrieterR. SvanborgC. Neutrophil recruitment and resistance to urinary tract infection.J. Infect. Dis.199918041220122910.1086/315006 10479151
    [Google Scholar]
  42. AmanzadaA. MoriconiF. MansurogluT. CameronS. RamadoriG. MalikA.I. Induction of chemokines and cytokines before neutrophils and macrophage recruitment in different regions of rat liver after TAA administration.Lab. Invest.201494223524710.1038/labinvest.2013.134 24276236
    [Google Scholar]
  43. DaviesM.J. Myeloperoxidase: Mechanisms, reactions and inhibition as a therapeutic strategy in inflammatory diseases.Pharmacol. Ther.202121810768510.1016/j.pharmthera.2020.107685 32961264
    [Google Scholar]
  44. HawkinsC.L. DaviesM.J. Role of myeloperoxidase and oxidant formation in the extracellular environment in inflammation-induced tissue damage.Free Radic. Biol. Med.202117263365110.1016/j.freeradbiomed.2021.07.007 34246778
    [Google Scholar]
  45. WangY. RenT. ZhengL. ChenH. KoJ.K. AuyeungK.K. Astragalus saponins inhibits lipopolysaccharide-induced inflammation in mouse macrophages.Am. J. Chin. Med.201644357959310.1142/S0192415X16500324 27109155
    [Google Scholar]
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