Repurposing of dipeptidyl peptidase FDA-approved drugs in alzheimer’s disease using network pharmacology and in-silico approaches

Computational Biology and Chemistry, Journal Year: 2025, Volume and Issue: 116, P. 108378 - 108378

Published: Feb. 8, 2025

Language: Английский

---

Zirconium Nanoparticles Decorated Chitosan@Hematoxylin/Pencil Graphite as a Novel Voltammetric Sensor for Monitoring of Linagliptin/Dapagliflozin Co-therapy

Talanta, Journal Year: 2025, Volume and Issue: unknown, P. 127790 - 127790

Published: Feb. 1, 2025

Language: Английский

---

Empagliflozin Repurposing for Lafora Disease: A Pilot Clinical Trial and Preclinical Investigation of Novel Therapeutic Targets

Methods and Protocols, Journal Year: 2025, Volume and Issue: 8(3), P. 48 - 48

Published: May 6, 2025

Background: Lafora disease (LD) is an ultra-rare and fatal neurodegenerative disorder with limited therapeutic options. Current treatments primarily address symptoms, modest efficacy in halting progression, thus highlighting the urgent need for novel approaches. Gene therapy, antisense oligonucleotides, recombinant enzymes have recently been, still are, under investigation. Drug repurposing may offer a promising approach to identify new, possibly effective, therapies. Methods: This study aims investigate conditions empagliflozin, SGLT2 (sodium/glucose cotransporter-2) inhibitor, as potential treatment LD establish clinical protocol. Clinical phase: 12-month prospective observational will assess safety of empagliflozin two patients early intermediate stage. The primary endpoints include changes severity epilepsy cognitive function, while secondary motor global autonomy. Multiple instrumental evaluations (including MRI PET 18F-fluorodeoxyglucose) be performed before during treatment. Safety monitoring regular assessments reports adverse events. Preclinical In silico studies (using both molecular docking calculations reverse ligand-based screening) vitro cell-based assays allow us effects (and other gliflozins) on some key targets likely implicated pathogenesis, such GLUT1, GLUT3, glycogen synthase (hGYS), phosphorylase (GP), suggested literature digital platforms target fishing. Results: expected outcome this twofold, i.e., (i) assessing tolerability (ii) gathering preliminary data its improving neurologic features. Additionally, provide new insights into mechanisms through which exert LD. Conclusion: findings are evidence support

Language: Английский

---

Insights from in silico exploration of major curcumin analogs targeting human dipeptidyl peptidase IV

Journal of Biomolecular Structure and Dynamics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 14

Published: Jan. 23, 2024

The goal of this work is to use a variety in-silico techniques identify anti-diabetic agents against DPP-IV enzyme from five main curcumin analogues. To produce the successful molecules, analogues were docked into active site enzyme. In comparison control molecule (Saxagliptin, −6.9 kcal/mol), all compounds have highest binding affinity (-7.6 −7.7 kcal/mol) for These underwent further testing studies on drug-likeness, pharmacokinetics, and acute toxicity see efficacy safety compounds. assess stability docking complex posture identified during experiment, our study got THC as lead compound, which was then exposed 200 ns molecular dynamic simulation PCA analysis. Additionally, DFT calculations conducted determine thermodynamic, orbital, electrostatic potential characteristics compound. Overall, chemical has shown strong drug-like properties, non-toxic, sizable

Language: Английский

---

Harnessing memantine in Alzheimer's disease therapy through inhibition of microtubule affinity-regulating kinase: Mechanistic insights

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 262, P. 130090 - 130090

Published: Feb. 9, 2024

Language: Английский

---

Preclinical Studies of Canagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, and Donepezil Combined Therapy in Alzheimer’s Disease

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(11), P. 1620 - 1620

Published: Nov. 16, 2023

The incidence of neurodegenerative diseases, such as Alzheimer’s disease (AD), is continuously growing worldwide, which leads to a heavy economic and societal burden. lack safe effective causal therapy in cognitive decline an aggravating factor requires investigations into the repurposing commonly used drugs. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are new efficient class hypoglycemic drugs and, due their pleiotropic effects, have indications that go beyond diabetes. There emerging data from murine studies SGLT2i can cross blood–brain barrier may neuroprotective increasing brain-derived neurotrophic (BDNF), reducing amyloid burden, inhibiting acetylcholinesterase (AChE) restoring circadian rhythm mammalian target rapamycin (mTOR) activation. current study investigates effect donepezil, under separate or combined 21-day treatment on AD-relevant behaviors brain pathology mice. canagliflozin was found significantly improve novelty preference index percentage time spent open arms maze novel object recognition elevated plus test, respectively. In addition, decreased AChE activity, mTOR glial fibrillary acidic protein expression. results also recorded acetylcholine M1 receptor canagliflozin-treated mice compared scopolamine group. hippocampus, reduced microgliosis astrogliosis males, but not female These findings emphasize value clinical practice. By represents compound resembles AD-registered therapies this respect, supporting need for further evaluation dementia trials.

Language: Английский

---

Interaction of Sp1 and Setd8 promotes vascular smooth muscle cells apoptosis by activating Mark4 in vascular calcification

Aging, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

Vascular calcification (VC) is directly related to high mortality in chronic kidney disease (CKD), and cellular apoptosis of vascular smooth muscle cells (VSMCs) a crucial process the initiation VC. Microtubule affinity-regulating kinase 4 (Mark4), known as serine/threonine protein kinase, can induce cell autophagy by modulating Akt phosphorylation. However, potential functions molecular mechanisms Mark4 VSMCs need be further explored. Initially, our data indicated that mRNA expression was prominently elevated phosphorus-stimulated human compared with other members Marks. Consistently, found significantly increased calcified arteries both CKD patients rats. In vitro, silencing suppressed apoptosis-specific marker promoting phosphorylation, finally attenuating induced phosphate. Mechanically, transcription factor Sp1 enriched promoter region modulated transcription. Moreover, SET domain-containing 8 (Setd8) proved interact jointly participated transcriptional regulation Mark4. Finally, rescue experiments revealed Setd8 contributed expression. conclusion, these findings reveal transcriptionally activated Sp1, which interacted Setd8, promote through Akt-mediated antiapoptotic effects, suggesting represents potent promising therapeutic target for VC CKD.

Language: Английский

---

Artificial Intelligence in The Management of Neurodegenerative Disorders

CNS & Neurological Disorders - Drug Targets, Journal Year: 2023, Volume and Issue: 23(8), P. 931 - 940

Published: Oct. 19, 2023

Neurodegenerative disorders are characterized by a gradual but irreversible loss of neurological function. The ability to detect and treat these conditions successfully is crucial for ensuring the best possible quality life people who suffer from them. development effective new methods managing treating neurodegenerative illnesses has been made recent developments in computer technology. In this overview, we take look at prospects applying computational approaches, such as drug design, AI, ML, DL, treatment diseases. To review current state field, article discusses potential early disease detection, quantifying progression, understanding underlying biological mechanisms diseases, well challenges associated with approaches future directions. Moreover, it delves into creation models individualization care concludes suggestions studies clinical applications, highlighting advantages disadvantages using techniques

Language: Английский

---

Association between dipeptidyl peptidase-4 inhibitor use and risk of Parkinson’s disease among patients with diabetes mellitus: a retrospective cohort study

Aging, Journal Year: 2024, Volume and Issue: 16(16), P. 11994 - 12007

Published: Aug. 22, 2024

Background: How a person's Parkinson disease (PD) risk is affected by dipeptidyl peptidase-4 (DPP-4) inhibitors remains unclear. We evaluated the association of PD with use these in individuals diagnosed as having diabetes mellitus (DM). Methods: Individuals new-onset DM were enrolled into case group and comparison group, comprising patients who received DPP-4 inhibitor sulfonylurea, respectively. These groups matched through propensity score matching on basis income level, gender, urbanization enrollment year, age, complications severity index score. The was divided subgroups whether they had cumulative defined daily dose (cDDD) <75, 75–150, or >150. inhibitor–PD Cox proportional hazards model. Bonferroni adjustment test employed to adjust P-values reduce false positive rate. Results: Compared those (treatment sulfonylurea), cDDD >150 hazard ratio (HR) 1.30 for development (95% confidence interval [CI]: 0.97-1.73; adjusted P = .263); HRs <75 75–150 0.95 CI: 0.71-1.27; .886) 1.06 0.75-1.50; .886), noted nonsignificant differences regarding associations between various (linagliptin, saxagliptin, sitagliptin, vildagliptin) after any individual (adjusted > .05). Conclusions: discovered this study not be associated increased risk. This result confirmed when analysis conducted individually 4 investigated (sitagliptin, linagliptin, vildagliptin).

Language: Английский

---

In Silico Approach for Identification of Potential Tetracyclic Triterpenoids from Mushroom as HMG-CoA Reductase Inhibitor

Aspects of Molecular Medicine, Journal Year: 2024, Volume and Issue: 4, P. 100053 - 100053

Published: Sept. 5, 2024

Language: Английский

---