Cannabis and Cannabidiol: Pioneering Treatment for the Nervous System with Alzheimer's Disease and Peripheral Organ Involvement with Nonalcoholic Fatty Liver Disease (NAFLD)

References

1. Battista N. Fezza F. Maccarrone M. Endocannabinoids and their involvement in the neurovascular system. Curr. Neurovasc. Res. 2004 1 2 129 140 10.2174/1567202043480107 16185189
   [Google Scholar]
2. De Caro C. Leo A. Citraro R. The potential role of cannabinoids in epilepsy treatment. Expert Rev. Neurother. 2017 17 11 1069 1079 10.1080/14737175.2017.1373019 28845714
   [Google Scholar]
3. Esposito G. De Filippis D. Carnuccio R. Izzo A.A. Iuvone T. The marijuana component cannabidiol inhibits β-amyloid-induced tau protein hyperphosphorylation through Wnt/β-catenin pathway rescue in PC12 cells. J. Mol. Med. (Berl.) 2006 84 3 253 258 10.1007/s00109‑005‑0025‑1 16389547
   [Google Scholar]
4. Esposito G. De Filippis D. Maiuri M.C. De Stefano D. Carnuccio R. Iuvone T. Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in β-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-κB involvement. Neurosci. Lett. 2006 399 1-2 91 95 10.1016/j.neulet.2006.01.047 16490313
   [Google Scholar]
5. Kalkman H.O. The role of the phosphatidylinositide 3-kinase–protein kinase B pathway in schizophrenia. Pharmacol. Ther. 2006 110 1 117 134 10.1016/j.pharmthera.2005.10.014 16434104
   [Google Scholar]
6. Lanphier C.M. McCauley L.G.F. Prevalence and consequences of nonmedical use of drugs among Canadian Forces personnel: 1982. Am. J. Drug Alcohol Abuse 1985 11 3-4 231 247 10.3109/00952998509016864 4091160
   [Google Scholar]
7. Chen S. Kim J.K. The role of cannabidiol in liver disease: A systemic review. Int. J. Mol. Sci. 2024 25 4 2370 10.3390/ijms25042370 38397045
   [Google Scholar]
8. Maiese K. Cardiovascular and nonalcoholic fatty liver disease: Sharing common ground through SIRT1 pathways. World J. Cardiol. 2024 16 11 632 643 10.4330/wjc.v16.i11.632 39600987
   [Google Scholar]
9. Abo El-Magd N.F. El-Kashef D.H. El-Sherbiny M. Eraky S.M. Hepatoprotective and cognitive-enhancing effects of hesperidin against thioacetamide-induced hepatic encephalopathy in rats. Life Sci. 2023 313 121280 10.1016/j.lfs.2022.121280 36526046
   [Google Scholar]
10. González D. Campos G. Pütter L. Role of WISP1 in stellate cell migration and liver fibrosis. Cells 2024 13 19 1629 10.3390/cells13191629 39404393
    [Google Scholar]
11. Schiavoni L.C. Baptista V.I.A. Quintana H.T. Lazzarin M.C. de Oliveira F. Protective effects of insulin treatment in the morphological alterations and oxidative damage to DNA in the liver of young rats subjected to skin scald burn injury. Int. J. Burns Trauma 2025 15 3 115 124 10.62347/ANQA2365 40688052
    [Google Scholar]
12. Shoff S. Thomas S. Ji P. Parenti M. Slupsky C.M. Dual impact of iron deficiency and antibiotics on host metabolism: A tissue-level analysis. Metabolites 2025 15 8 549 10.3390/metabo15080549 40863165
    [Google Scholar]
13. Sun W.D. Zhu X.J. Li J.J. Mei Y.Z. Li W.S. Li J.H. Nicotinamide N-methyltransferase (NNMT): A novel therapeutic target for metabolic syndrome. Front. Pharmacol. 2024 15 1410479 10.3389/fphar.2024.1410479 38919254
    [Google Scholar]
14. Zhang Z. Wu G. Yang J. Integrated network pharmacology, transcriptomics and metabolomics to explore the material basis and mechanism of Danggui-Baishao herb pair for treating hepatic fibrosis. J. Ethnopharmacol. 2025 337 Pt 1 118834 10.1016/j.jep.2024.118834 39299362
    [Google Scholar]
15. Vrechi T.A.M. Guarache G.C. Oliveira R.B. Cannabidiol-induced autophagy ameliorates tau protein clearance. Neurotox. Res. 2025 43 1 8 10.1007/s12640‑025‑00729‑3 39900844
    [Google Scholar]
16. Colín-Martínez E. Espino-de-la-Fuente C. Arias C. Age- and sex-associated wnt signaling dysregulation is exacerbated from the early stages of neuropathology in an alzheimer’s disease model. Neurochem. Res. 2024 49 11 3094 3104 10.1007/s11064‑024‑04224‑7 39167347
    [Google Scholar]
17. Ebrahimifar A. Ahmadi S. Rostamzadeh J. Rahimi K. Vanadyl sulfate restores memory impairment in streptozotocin-induced rat model of sporadic alzheimer’s disease by repressing FoxO1 gene expression. Sci. Rep. 2025 15 1 27293 10.1038/s41598‑025‑12426‑4 40715349
    [Google Scholar]
18. Haratizadeh S. Nemati M. Basiri M. Nozari M. Erythropoietin and glial cells in central and peripheral nervous systems. Mol. Biol. Rep. 2024 51 1 1065 10.1007/s11033‑024‑09997‑2 39422776
    [Google Scholar]
19. Ibrahim W.W. Sayed R.H. Abdelhameed M.F. Neuroprotective potential of Erigeron bonariensis ethanolic extract against ovariectomized/D-galactose-induced memory impairments in female rats in relation to its metabolite fingerprint as revealed using UPLC/MS. Inflammopharmacology 2024 32 2 1091 1112 10.1007/s10787‑023‑01418‑3 38294617
    [Google Scholar]
20. Jahan R. Yousaf M. Khan H. Zinc ortho methyl carbonodithioate improved pre and post-synapse memory impairment via SIRT1/p-JNK pathway against scopolamine in adult mice. J. Neuroimmune Pharmacol. 2023 18 1-2 183 194 10.1007/s11481‑023‑10067‑w 37261605
    [Google Scholar]
21. Maiese K. Novel applications of trophic factors, Wnt and WISP for neuronal repair and regeneration in metabolic disease. Neural Regen. Res. 2015 10 4 518 528 10.4103/1673‑5374.155427 26170801
    [Google Scholar]
22. Maiese K. FoxO proteins in the nervous system. Anal. Cell. Pathol. (Amst.) 2015 2015 1 15 10.1155/2015/569392 26171319
    [Google Scholar]
23. Maiese K. Cognitive impairment and dementia: Gaining insight through circadian clock gene pathways. Biomolecules 2021 11 7 1002 10.3390/biom11071002 34356626
    [Google Scholar]
24. Maiese K. Cellular metabolism: A fundamental component of degeneration in the nervous system. Biomolecules 2023 13 5 816 10.3390/biom13050816 37238686
    [Google Scholar]
25. Maiese K. The metabolic basis for nervous system dysfunction in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Curr. Neurovasc. Res. 2023 20 3 314 333 10.2174/1567202620666230721122957 37488757
    [Google Scholar]
26. Mishra P. Davies D.A. Albensi B.C. The interaction between NF-κB and estrogen in Alzheimer’s disease. Mol. Neurobiol. 2023 60 3 1515 1526 10.1007/s12035‑022‑03152‑3 36512265
    [Google Scholar]
27. Mosharaf M.P. Alam K. Gow J. Mahumud R.A. Mollah M.N.H. Common molecular and pathophysiological underpinnings of delirium and Alzheimer’s disease: Molecular signatures and therapeutic indications. BMC Geriatr. 2024 24 1 716 10.1186/s12877‑024‑05289‑3 39210294
    [Google Scholar]
28. Pattanaik S.K. Anil P.M. Jena S. Rath D. Interlinking diabetes and Alzheimer’s disease: A pathway through medicinal plant-based treatments. J. Ethnopharmacol. 2025 351 120092 10.1016/j.jep.2025.120092 40484255
    [Google Scholar]
29. Poddar N.K. Khan A. Fatima F. Saxena A. Ghaley G. Khan S. Association of mTOR pathway and conformational alterations in C-reactive protein in neurodegenerative diseases and infections. Cell. Mol. Neurobiol. 2023 43 8 3815 3832 10.1007/s10571‑023‑01402‑z 37665407
    [Google Scholar]
30. Sharma C. Mazumder A. A comprehensive review on potential molecular drug targets for the management of alzheimer’s disease. Cent. Nerv. Syst. Agents Med. Chem. 2024 24 1 45 56 10.2174/0118715249263300231116062740 38305393
    [Google Scholar]
31. Zhang W. Huang Y. Guo X. Zhang M. Yuan X. Zu H. DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice. Acta Neuropathol. Commun. 2023 11 1 102 10.1186/s40478‑023‑01593‑y 37344916
    [Google Scholar]
32. Zhao J. Wei M. Guo M. GSK3: A potential target and pending issues for treatment of Alzheimer’s disease. CNS Neurosci. Ther. 2024 30 7 e14818 10.1111/cns.14818 38946682
    [Google Scholar]
33. Abdalla M.M.I. Insulin resistance as the molecular link between diabetes and Alzheimer’s disease. World J. Diabetes 2024 15 7 1430 1447 10.4239/wjd.v15.i7.1430 39099819
    [Google Scholar]
34. Amini J. Sanchooli N. Milajerdi M.H. Baeeri M. Haddadi M. Sanadgol N. The interplay between tauopathy and aging through interruption of UPR/Nrf2/autophagy crosstalk in the Alzheimer’s disease transgenic experimental models. Int. J. Neurosci. 2024 134 10 1049 1067 10.1080/00207454.2023.2210409 37132251
    [Google Scholar]
35. Chongtham A. Ramakrishnan A. Farinas M. Neocortical tau propagation is a mediator of clinical heterogeneity in Alzheimer’s disease. Mol. Psychiatry 2025 30 9 4194 4213 10.1038/s41380‑025‑02998‑y 40234685
    [Google Scholar]
36. Dasgupta A. Kalidass K. Farisha S. Saha R. Ghosh S. Ampasala D.R. Identification of novel brain penetrant GSK-3β inhibitors toward Alzheimer’s disease therapy by virtual screening, molecular docking, dynamic simulation, and MMPBSA analysis. J. Biomol. Struct. Dyn. 2024 ••• 1 27 10.1080/07391102.2024.2411524 39427335
    [Google Scholar]
37. Shiravandi A. Yari F. Tofigh N. Earlier detection of alzheimer’s disease based on a novel biomarker cis P-tau by a label-free electrochemical immunosensor. Biosensors 2022 12 10 879 10.3390/bios12100879 36291017
    [Google Scholar]
38. Clemmensen F.K. Gramkow M.H. Simonsen A.H. Short-term variability of Alzheimer’s disease plasma biomarkers in a mixed memory clinic cohort. Alzheimers Res. Ther. 2025 17 1 26 10.1186/s13195‑024‑01658‑7 39838483
    [Google Scholar]
39. Hunjan G. Aran K.R. Role of mGluR7 in Alzheimer’s disease: Pathophysiological insights and therapeutic approaches. Inflammopharmacology 2025 33 6 2977 2995 10.1007/s10787‑025‑01765‑3 40316832
    [Google Scholar]
40. Ci L. Yang X. Gu X. Cystathionine γ-lyase deficiency exacerbates CCl4-induced acute hepatitis and fibrosis in the mouse liver. Antioxid. Redox Signal. 2017 27 3 133 149 10.1089/ars.2016.6773 27848249
    [Google Scholar]
41. Cui W. Matsuno K. Iwata K. NOX1/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase promotes proliferation of stellate cells and aggravates liver fibrosis induced by bile duct ligation. Hepatology 2011 54 3 949 958 10.1002/hep.24465 21618578
    [Google Scholar]
42. Dutta R.K. Jun J. Du K. Diehl A.M. Hedgehog signaling: Implications in liver pathophysiology. Semin. Liver Dis. 2023 43 4 418 428 10.1055/a‑2187‑3382 37802119
    [Google Scholar]
43. Jian Y Wang J Dong S Wnt-induced secreted protein 1/CCN4 in liver fibrosis both in vitro and in vivo. Clin Lab 2014 60 01/2014 29 35 10.7754/Clin.Lab.2013.121035 24600972
    [Google Scholar]
44. Jun J.I. Lau L.F. Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat. Rev. Drug Discov. 2011 10 12 945 963 10.1038/nrd3599 22129992
    [Google Scholar]
45. Klimontov V.V. Bulumbaeva D.M. Fazullina O.N. Circulating Wnt1-inducible signaling pathway protein-1 (WISP-1/CCN4) is a novel biomarker of adiposity in subjects with type 2 diabetes. J. Cell Commun. Signal. 2020 14 1 101 109 10.1007/s12079‑019‑00536‑4 31782053
    [Google Scholar]
46. Klionsky D.J. Abdel-Aziz A.K. Abdelfatah S. Abdellatif M. Abdoli A. Abel S. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy 2021 17 1 1 382 10.1080/15548627.2020.1797280 33634751
    [Google Scholar]
47. Königshoff M. Kramer M. Balsara N. WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J. Clin. Invest. 2009 119 4 772 787 10.1172/JCI33950 19287097
    [Google Scholar]
48. Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: Innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev. Clin. Pharmacol. 2020 13 1 23 34 10.1080/17512433.2020.1698288 31794280
    [Google Scholar]
49. Maiese K. Wnt Signaling and WISP1 (CCN4): Critical Components in Neurovascular Disease, Blood Brain Barrier Regulation, and Cerebral Hemorrhage. Curr. Neurovasc. Res. 2022 19 4 379 382 10.2174/1567202620666221019162248 36264015
    [Google Scholar]
50. Maiese K. The impact of aging and oxidative stress in metabolic and nervous system disorders: Programmed cell death and molecular signal transduction crosstalk. Front. Immunol. 2023 14 1273570 10.3389/fimmu.2023.1273570 38022638
    [Google Scholar]
51. Maiese K. Cornerstone cellular pathways for metabolic disorders and diabetes mellitus: Non-coding RNAs, Wnt signaling, and AMPK. Cells 2023 12 22 2595 10.3390/cells12222595 37998330
    [Google Scholar]
52. Eshraghi M. Ahmadi M. Afshar S. Enhancing autophagy in Alzheimer’s disease through drug repositioning. Pharmacol. Ther. 2022 237 108171 10.1016/j.pharmthera.2022.108171 35304223
    [Google Scholar]
53. Hou S.J. Zhang S.X. Li Y. Xu S.Y. Rapamycin responds to Alzheimer’s disease: A potential translational therapy. Clin. Interv. Aging 2023 18 1629 1639 10.2147/CIA.S429440 37810956
    [Google Scholar]
54. Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen. Res. 2016 11 3 372 385 10.4103/1673‑5374.179032 27127460
    [Google Scholar]
55. Maiese K. The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders. Biochem. Soc. Trans. 2018 46 2 351 360 10.1042/BST20170121 29523769
    [Google Scholar]
56. Maiese K. Targeting the core of neurodegeneration: FoxO, mTOR, and SIRT1. Neural Regen. Res. 2021 16 3 448 455 10.4103/1673‑5374.291382 32985464
    [Google Scholar]
57. Maiese K. Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm. Front. Biosci. 2021 26 9 614 627 10.52586/4971 34590471
    [Google Scholar]
58. Trisal A. Singh A.K. Clinical insights on caloric restriction mimetics for mitigating brain aging and related neurodegeneration. Cell. Mol. Neurobiol. 2024 44 1 67 10.1007/s10571‑024‑01493‑2 39412683
    [Google Scholar]
59. Ying C. He Y. Guo Y. Application of traditional chinese medicine in alzheimer’s disease treatment: A focus on the Wnt/β-catenin pathway. Am. J. Chin. Med. 2025 53 6 1641 1683 10.1142/S0192415X25500624 40744715
    [Google Scholar]
60. Afrisham R. Jadidi Y. Moradi N. Circulating CCN6/WISP3 in type 2 diabetes mellitus patients and its correlation with insulin resistance and inflammation: Statistical and machine learning analyses. BMC Med. Inform. Decis. Mak. 2025 25 1 114 10.1186/s12911‑025‑02957‑1 40050813
    [Google Scholar]
61. Barchetta I. Cimini F.A. Capoccia D. WISP1 is a marker of systemic and adipose tissue inflammation in dysmetabolic subjects with or without type 2 diabetes. J. Endocr. Soc. 2017 1 6 660 670 10.1210/js.2017‑00108 29264519
    [Google Scholar]
62. Fernandez-Ruiz R. García-Alamán A. Esteban Y. Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells. Nat. Commun. 2020 11 1 5982 10.1038/s41467‑020‑19657‑1 33239617
    [Google Scholar]
63. Kitaghenda F.K. Wang J. Li T. Hong J. Yao L. Zhu X. Normalization of WISP1 circulating level and tissue expression following metabolic and bariatric surgery using rat model. Updates Surg. 2024 76 8 2841 2849 10.1007/s13304‑024‑01977‑2 39407056
    [Google Scholar]
64. Liu L. Hu J. Yang L. Association of WISP1/CCN4 with risk of overweight and gestational diabetes mellitus in chinese pregnant women. Dis. Markers 2020 2020 1 10 10.1155/2020/4934206 32377270
    [Google Scholar]
65. Maiese K. Fox O. FoxO transcription factors and regenerative pathways in diabetes mellitus. Curr. Neurovasc. Res. 2015 12 4 404 413 10.2174/1567202612666150807112524 26256004
    [Google Scholar]
66. Maiese K. Sirtuins: Developing innovative treatments for aged-related memory loss and Alzheimer’s disease. Curr. Neurovasc. Res. 2019 15 4 367 371 10.2174/1567202616666181128120003 30484407
    [Google Scholar]
67. Zhu Y. Fang Q. Zhou Y. Lu W. Du X. Shi B. Serum Wnt1-Inducible signalling pathway Protein-1 levels are associated with cerebral infarction in patients with type 2 diabetes mellitus. J. Endocrinol. Invest. 2025 10.1007/s40618‑025‑02662‑w 40719953
    [Google Scholar]
68. Maiese K. Chong Z.Z. Shang Y.C. Wang S. mTOR: On target for novel therapeutic strategies in the nervous system. Trends Mol. Med. 2013 19 1 51 60 10.1016/j.molmed.2012.11.001 23265840
    [Google Scholar]
69. Christopoulou M.E. Aletras A.J. Papakonstantinou E. Stolz D. Skandalis S.S. WISP1 and macrophage migration inhibitory factor in respiratory inflammation: Novel insights and therapeutic potentials for asthma and COPD. Int. J. Mol. Sci. 2024 25 18 10049 10.3390/ijms251810049 39337534
    [Google Scholar]
70. Fu C. Lu Z. Shi J. Liu F. Su X. Knockdown of WISP1/DKK1 restrains phenotypic plasticity in esophageal squamous cell carcinoma by suppressing epithelial–mesenchymal transition and stemness. Clin. Transl. Oncol. 2024 27 2 580 592 10.1007/s12094‑024‑03639‑6 39093516
    [Google Scholar]
71. Singh K. Oladipupo S.S. An overview of CCN4 (WISP1) role in human diseases. J. Transl. Med. 2024 22 1 601 10.1186/s12967‑024‑05364‑8 38937782
    [Google Scholar]
72. Singh K. Witek M. Brahmbhatt J. McEntire J. Thirunavukkarasu K. Oladipupo S.S. Stage-dependent fibrotic gene profiling of WISP1-mediated fibrogenesis in human fibroblasts. Cells 2024 13 23 2005 10.3390/cells13232005 39682753
    [Google Scholar]
73. Maiese K. Stem cell guidance through the mechanistic target of rapamycin. World J. Stem Cells 2015 7 7 999 1009 26328016
    [Google Scholar]
74. Maiese K. Biological gases, oxidative stress, artificial intelligence, and machine learning for neurodegeneration and metabolic disorders. Med. Gas Res. 2025 15 1 145 147 10.4103/mgr.MEDGASRES‑D‑24‑00059 39436188
    [Google Scholar]
75. Maiese K. Diabetes mellitus and glymphatic dysfunction: Roles for oxidative stress, mitochondria, circadian rhythm, artificial intelligence, and imaging. World J. Diabetes 2025 16 1 98948 10.4239/wjd.v16.i1.98948 39817214
    [Google Scholar]
76. Maiese K. Anxiety and depression: Triggers for cognitive loss, alzheimer’s disease, and neurodegeneration. Curr. Neurovasc. Res. 2025 22 1 1 8 10.2174/0115672026423887250627095817 40551494
    [Google Scholar]
77. Griñán-Ferré C. Servin-Muñoz I.V. Palomera-Ávalos V. Changes in gene expression profile with age in SAMP8: Identifying transcripts involved in cognitive decline and sporadic Alzheimer’s disease. Genes (Basel) 2024 15 11 1411 10.3390/genes15111411 39596610
    [Google Scholar]
78. Guo T. Chen M. Liu J. Neuropilin-1 promotes mitochondrial structural repair and functional recovery in rats with cerebral ischemia. J. Transl. Med. 2023 21 1 297 10.1186/s12967‑023‑04125‑3 37138283
    [Google Scholar]
79. Maiese K. The bright side of reactive oxygen species: Lifespan extension without cellular demise. J. Transl. Sci. 2016 2 3 185 187 10.15761/JTS.1000138 27200181
    [Google Scholar]
80. Sanabria-de la Torre R. García-Fontana C. González-Salvatierra S. The contribution of Wnt signaling to vascular complications in type 2 diabetes mellitus. Int. J. Mol. Sci. 2022 23 13 6995 10.3390/ijms23136995 35805996
    [Google Scholar]
81. Vallée A. Vallée J.N. Lecarpentier Y. Parkinson’s disease: Potential actions of lithium by targeting the WNT/β-Catenin pathway, oxidative stress, inflammation and glutamatergic pathway. Cells 2021 10 2 230 10.3390/cells10020230 33503974
    [Google Scholar]
82. Xu J.X. Fang K. Gao X.R. Liu S. Ge J.F. Resveratrol protects SH-SY5Y cells against oleic acid-induced glucolipid metabolic dysfunction and cell injuries via the Wnt/β-catenin signalling pathway. Neurochem. Res. 2021 46 11 2936 2947 10.1007/s11064‑021‑03398‑8 34260003
    [Google Scholar]
83. Zhang M. Liu Q. Meng H. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct. Target. Ther. 2024 9 1 12 10.1038/s41392‑023‑01688‑x 38185705
    [Google Scholar]
84. Liu D. Zhang M. Tian J. WNT1-inducible signalling pathway protein 1 stabilizes atherosclerotic plaques in apolipoprotein-E-deficient mice via the focal adhesion kinase/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase pathway. J. Hypertens. 2022 40 9 1666 1681 10.1097/HJH.0000000000003195 35881419
    [Google Scholar]
85. Adeerjiang Y. Gan X.X. Li W.T. The dual role and therapeutic implications of the Wnt/β-Catenin pathway in diabetic kidney disease. Int. J. Gen. Med. 2025 18 2757 2768 10.2147/IJGM.S524138 40458228
    [Google Scholar]
86. Ehtewish H. Mesleh A. Ponirakis G. Blood-based proteomic profiling identifies potential biomarker candidates and pathogenic pathways in dementia. Int. J. Mol. Sci. 2023 24 9 8117 10.3390/ijms24098117 37175824
    [Google Scholar]
87. Maiese K. New insights for oxidative stress and diabetes mellitus. Oxid. Med. Cell. Longev. 2015 2015 875961 10.1155/2015/875961 26064426
    [Google Scholar]
88. Maiese K. Erythropoietin and diabetes mellitus. World J. Diabetes 2015 6 14 1259 1273 10.4239/wjd.v6.i14.1259 26516410
    [Google Scholar]
89. Maiese K. Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer. Curr. Neurovasc. Res. 2017 14 3 299 304 28721811
    [Google Scholar]
90. Nie X. Wei X. Ma H. Fan L. Chen W.D. The complex role of Wnt ligands in type 2 diabetes mellitus and related complications. J. Cell. Mol. Med. 2021 25 14 6479 6495 10.1111/jcmm.16663 34042263
    [Google Scholar]
91. Maiese K. The challenges for drug development: Cytokines, genes, and stem cells. Curr. Neurovasc. Res. 2012 9 4 231 232 10.2174/156720212803530690 23030554
    [Google Scholar]
92. Murahovschi V. Pivovarova O. Ilkavets I. WISP1 is a novel adipokine linked to inflammation in obesity. Diabetes 2015 64 3 856 866 10.2337/db14‑0444 25281430
    [Google Scholar]
93. Tanaka S. Sugimachi K. Kameyama T. Human WISP1v, a member of the CCN family, is associated with invasive cholangiocarcinoma. Hepatology 2003 37 5 1122 1129 10.1053/jhep.2003.50187 12717393
    [Google Scholar]
94. Wang Q.Y. Feng Y.J. Ji R. High expression of WISP1 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma. Eur. Rev. Med. Pharmacol. Sci. 2020 24 20 10445 10451 33155200
    [Google Scholar]
95. Damstra-Oddy J.L. Warren E.C. Perry C.J. Phytocannabinoid‐dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity. Br. J. Pharmacol. 2021 178 5 1149 1163 10.1111/bph.15351 33347604
    [Google Scholar]
96. Liu L. Li J. Wang C. Cannabidiol attenuates methamphetamine-induced conditioned place preference in male rats and viability in PC12 cells through the Sigma1R/AKT/GSK3β/CREB signaling pathway. Am. J. Drug Alcohol Abuse 2022 48 5 548 561 10.1080/00952990.2022.2073450 35881880
    [Google Scholar]
97. Bi S.Z. Sun W.D. Zhu X.J. Nicotinamide N-methyltransferase in cardiovascular Diseases: Mechanistic insights and therapeutic potential. Eur. J. Med. Chem. 2025 295 117790 10.1016/j.ejmech.2025.117790 40412299
    [Google Scholar]
98. Chen M. Zhang H. Ji P. Therapeutic potential of ACMSD inhibitors in NAD+ deficient diseases. Drugs and Drug Candidates 2025 4 1 7 10.3390/ddc4010007
    [Google Scholar]
99. Deng Q. Chen S. Pei D. Untargeted cell metabolomics and network analysis of CORT-Injured HT22 cells treated with albiflorin. J. Pharm. Biomed. Anal. 2025 265 117044 10.1016/j.jpba.2025.117044 40618436
    [Google Scholar]
100. Hu Z. Cai Y. Cao C. Metabolome and transcriptome analyses reveal the mechanism underlying the differences in skin development between the two duck breeds during embryonic stage. Poult. Sci. 2025 104 9 105403 10.1016/j.psj.2025.105403 40499236
     [Google Scholar]
101. Ma X. Jin W. Wang L. Metabolic response of Sinosolenaia oleivora to heat and drought stress using a quasi-targeted metabolomics approach. Comp. Biochem. Physiol. Part D Genomics Proteomics 2025 55 101499 10.1016/j.cbd.2025.101499 40215765
     [Google Scholar]
102. Maiese K. Warming up to new possibilities with the capsaicin receptor TRPV1: mTOR, AMPK, and erythropoietin. Curr. Neurovasc. Res. 2017 14 2 184 189 28294062
     [Google Scholar]
103. Maiese K. New Insights for nicotinamide metabolic disease autophagy and mTOR. Front. Biosci. 2020 25 11 1925 1973 10.2741/4886 32472766
     [Google Scholar]
104. Maiese K. Innovative therapeutic strategies for cardiovascular disease. EXCLI J. 2023 22 690 715 37593239
     [Google Scholar]
105. Maiese K. Cognitive impairment in multiple sclerosis. Bioengineering 2023 10 7 871 10.3390/bioengineering10070871 37508898
     [Google Scholar]
106. Traister A. Breitman I. Bar-Lev E. Nicotinamide induces apoptosis and reduces collagen I and pro-inflammatory cytokines expression in rat hepatic stellate cells. Scand. J. Gastroenterol. 2005 40 10 1226 1234 10.1080/00365520510023341 16165703
     [Google Scholar]
107. Castro-Portuguez R. Sutphin G.L. Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan. Exp. Gerontol. 2020 132 110841 10.1016/j.exger.2020.110841 31954874
     [Google Scholar]
108. Doroftei B. Ilie O.D. Cojocariu R.O. Minireview exploring the biological cycle of vitamin B3 and its influence on oxidative stress: Further molecular and clinical aspects. Molecules 2020 25 15 3323 10.3390/molecules25153323 32707945
     [Google Scholar]
109. Du X. Cui Z. Zhang R. The effects of rumen-protected choline and rumen-protected nicotinamide on liver transcriptomics in periparturient dairy cows. Metabolites 2023 13 5 594 10.3390/metabo13050594 37233635
     [Google Scholar]
110. Maiese K. Nicotinamide: Oversight of metabolic dysfunction through SIRT1, mTOR, and clock genes. Curr. Neurovasc. Res. 2021 17 5 765 783 10.2174/18755739MTEx2NDIjx 33183203
     [Google Scholar]
111. Maiese K. Nicotinamide as a foundation for treating neurodegenerative disease and metabolic disorders. Curr. Neurovasc. Res. 2021 18 1 134 149 10.2174/18755739MTEzaMDMw2 33397266
     [Google Scholar]
112. Osorio Alves J. Matta Pereira L. Cabral Coutinho do Rego Monteiro I. Strenuous acute exercise induces slow and fast twitch-dependent NADPH oxidase expression in rat skeletal muscle. Antioxidants 2020 9 1 57 7 10.3390/antiox9010057 31936265
     [Google Scholar]
113. Ramírez-Cruz A. Gómez-González B. Baiza-Gutman L.A. Nicotinamide, an acetylcholinesterase uncompetitive inhibitor, protects the blood‒brain barrier and improves cognitive function in rats fed a hypercaloric diet. Eur. J. Pharmacol. 2023 959 176068 10.1016/j.ejphar.2023.176068 37775016
     [Google Scholar]
114. Rehman I.U. Khan A. Ahmad R. Neuroprotective effects of nicotinamide against MPTP-induced parkinson’s disease in mice: Impact on oxidative stress, neuroinflammation, Nrf2/HO-1 and TLR4 signaling pathways. Biomedicines 2022 10 11 2929 10.3390/biomedicines10112929 36428497
     [Google Scholar]
115. Braidy N. Liu Y. NAD+ therapy in age-related degenerative disorders: A benefit/risk analysis. Exp. Gerontol. 2020 132 110831 10.1016/j.exger.2020.110831 31917996
     [Google Scholar]
116. Goulart Nacácio e Silva S. Occhiutto M.L. Costa V.P. The use of nicotinamide and nicotinamide riboside as an adjunct therapy in the treatment of glaucoma. Eur. J. Ophthalmol. 2023 33 5 1801 1815 10.1177/11206721231161101 36916064
     [Google Scholar]
117. Jobst M. Kiss E. Gerner C. Marko D. Del Favero G. Activation of autophagy triggers mitochondrial loss and changes acetylation profile relevant for mechanotransduction in bladder cancer cells. Arch. Toxicol. 2023 97 1 217 233 10.1007/s00204‑022‑03375‑2 36214828
     [Google Scholar]
118. Maiese K. Chong Z.Z. Nicotinamide: Necessary nutrient emerges as a novel cytoprotectant for the brain. Trends Pharmacol. Sci. 2003 24 5 228 232 10.1016/S0165‑6147(03)00078‑6 12767721
     [Google Scholar]
119. Wang X.Y. Liu K.J. Zhang F.Y. Xiang B. Nicotinamide mitigates radiation injury in submandibular gland by protecting mitochondrial structure and functions. J. Oral Pathol. Med. 2022 51 9 801 809 10.1111/jop.13347 35996988
     [Google Scholar]
120. Wasserfurth P. Nebl J. Rühling M.R. Impact of dietary modifications on plasma sirtuins 1, 3 and 5 in older overweight individuals undergoing 12-weeks of circuit training. Nutrients 2021 13 11 3824 10.3390/nu13113824 34836079
     [Google Scholar]
121. Yuan X. Liu Y. Bijonowski B.M. NAD+/NADH redox alterations reconfigure metabolism and rejuvenate senescent human mesenchymal stem cells in vitro. Commun. Biol. 2020 3 1 774 10.1038/s42003‑020‑01514‑y 33319867
     [Google Scholar]
122. Zhang G.Z. Deng Y.J. Xie Q.Q. Sirtuins and intervertebral disc degeneration: Roles in inflammation, oxidative stress, and mitochondrial function. Clin. Chim. Acta 2020 508 33 42 10.1016/j.cca.2020.04.016 32348785
     [Google Scholar]
123. Nejabati H.R. Samadi N. Shahnazi V. Nicotinamide and its metabolite N1-Methylnicotinamide alleviate endocrine and metabolic abnormalities in adipose and ovarian tissues in rat model of Polycystic Ovary Syndrome. Chem. Biol. Interact. 2020 324 109093 10.1016/j.cbi.2020.109093 32298659
     [Google Scholar]
124. Babighian S. Gattazzo I. Zanella M.S. Nicotinamide: Bright potential in glaucoma management. Biomedicines 2024 12 8 1655 10.3390/biomedicines12081655 39200120
     [Google Scholar]
125. Miller R. Wentzel A.R. Richards G.A. COVID-19: NAD+ deficiency may predispose the aged, obese and type2 diabetics to mortality through its effect on SIRT1 activity. Med. Hypotheses 2020 144 110044 10.1016/j.mehy.2020.110044 32758884
     [Google Scholar]
126. Sharma N. Shandilya A. Kumar N. Mehan S. Dysregulation of SIRT-1 signaling in multiple sclerosis and neuroimmune disorders: A systematic review of SIRTUIN activators as potential immunomodulators and their influences on other dysfunctions. Endocr. Metab. Immune Disord. Drug Targets 2021 21 10 1845 1868 10.2174/1871530321666210309112234 33687904
     [Google Scholar]
127. Ye M. Zhao Y. Wang Y. NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis. Nat. Nanotechnol. 2022 17 8 880 890 10.1038/s41565‑022‑01137‑w 35668170
     [Google Scholar]
128. Atalay S. Gęgotek A. Domingues P. Skrzydlewska E. Protective effects of cannabidiol on the membrane proteins of skin keratinocytes exposed to hydrogen peroxide via participation in the proteostasis network. Redox Biol. 2021 46 102074 10.1016/j.redox.2021.102074 34298466
     [Google Scholar]
129. Pereira G.J.S. Leão A.H.F.F. Erustes A.G. Pharmacological modulators of autophagy as a potential strategy for the treatment of COVID-19. Int. J. Mol. Sci. 2021 22 8 4067 10.3390/ijms22084067 33920748
     [Google Scholar]
130. Guo W. Qian L. Zhang J. Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling. J. Neurosci. Res. 2011 89 11 1723 1736 10.1002/jnr.22725 21826702
     [Google Scholar]
131. Li W. Zhu L. Ruan Z.B. Wang M.X. Ren Y. Lu W. Nicotinamide protects chronic hypoxic myocardial cells through regulating mTOR pathway and inducing autophagy. Eur. Rev. Med. Pharmacol. Sci. 2019 23 12 5503 5511 31298404
     [Google Scholar]
132. Tabibzadeh S. Signaling pathways and effectors of aging. Front. Biosci. 2021 26 1 50 96 10.2741/4889 33049665
     [Google Scholar]
133. Zhang S. Cai G. Fu B. SIRT1 is required for the effects of rapamycin on high glucose-inducing mesangial cells senescence. Mech. Ageing Dev. 2012 133 6 387 400 10.1016/j.mad.2012.04.005 22561310
     [Google Scholar]
134. Asir A.R.V. Unlocking the therapeutic potential of protein kinase inhibitors in neurodegenerative and psychiatric disorders. Explor Drug Sci 2025 3 100892 10.37349/eds.2025.100892
     [Google Scholar]
135. Elbaz E.M. Ibrahim S.M. Rashad E. Yasin N.A.E. Ghaiad H.R. Mehana N.A. Therapeutic role of 1-theanine in mitigating cognitive dysfunction and neuropathology in scopolamine-treated mice. ACS Chem. Neurosci. 2025 16 13 2528 2545 10.1021/acschemneuro.5c00351 40504752
     [Google Scholar]
136. Fedor A. Bryniarski K. Nazimek K. mTOR signaling in macrophages: All depends on the context. Int. J. Mol. Sci. 2025 26 15 7598 10.3390/ijms26157598 40806725
     [Google Scholar]
137. Jiang T. Du P. Liu D. Exploring the glucose-lowering and anti-inflammatory immune mechanism of artemether by AMPK/mTOR pathway and microbiome based on multi-omics. Front. Pharmacol. 2025 16 1520439 10.3389/fphar.2025.1520439 40046742
     [Google Scholar]
138. Mubarak H.M. Racette B.A. Killion J.A. Exploring the neuroprotective potential of immunosuppressants in Parkinson’s disease. Parkinsonism Relat. Disord. 2025 132 107294 10.1016/j.parkreldis.2025.107294 39874798
     [Google Scholar]
139. Santos G.X. dos Anjos-Garcia T. Vieira A.C.J. Galdino G. Spinal involvement of TRPV1 and PI3K/AKT/mTOR pathway during chronic postoperative pain in mice. Brain Sci. 2025 15 1 53 10.3390/brainsci15010053 39851421
     [Google Scholar]
140. Tang J. Lu L. Yuan J. Feng L. Exercise-induced activation of SIRT1/BDNF/mTORC1 signaling pathway: A novel mechanism to reduce neuroinflammation and improve post-stroke depression. Actas Esp. Psiquiatr. 2025 53 2 366 378 10.62641/aep.v53i2.1838 40071363
     [Google Scholar]
141. Xia W. Xie X. Wang C. Zhang L. Cai Y. Ge Z. Reduction in cardiac STAT3 phosphorylation at site ser-727 subsequent to mTOR overactivation exacerbated myocardial ischemia reperfusion injury in type 1 diabetic rats. Fortune J Health Sci 2025 8 607 617 10.26502/fjhs.313
     [Google Scholar]
142. Yong J. Kim H. Lee E. Jung Y. Regulation of transcriptome plasticity by mTOR signaling pathway. Exp. Mol. Med. 2025 57 8 1623 1630 10.1038/s12276‑025‑01508‑y 40804480
     [Google Scholar]
143. Zeidan M.A. Alkabbani M.A. Giovannuzzi S. Shooting an arrow against convulsion: Novel triazole-grafted benzenesulfonamide derivatives as carbonic anhydrase II and VII inhibitors. J. Med. Chem. 2025 68 8 8873 8893 10.1021/acs.jmedchem.5c00526 40237575
     [Google Scholar]
144. Maiese K. Taking aim at Alzheimer’s disease through the mammalian target of rapamycin. Ann. Med. 2014 46 8 587 596 10.3109/07853890.2014.941921 25105207
     [Google Scholar]
145. Maiese K. mTOR: Driving apoptosis and autophagy for neurocardiac complications of diabetes mellitus. World J. Diabetes 2015 6 2 217 224 10.4239/wjd.v6.i2.217 25789103
     [Google Scholar]
146. Maiese K. Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders. Br. J. Clin. Pharmacol. 2016 82 5 1245 1266 10.1111/bcp.12804 26469771
     [Google Scholar]
147. Maiese K. Dysregulation of metabolic flexibility: The impact of mTOR on autophagy in neurodegenerative disease. Int. Rev. Neurobiol. 2020 155 1 35 10.1016/bs.irn.2020.01.009 32854851
     [Google Scholar]
148. Maiese K. Prospects and perspectives for WISP1 (CCN4) in diabetes mellitus. Curr. Neurovasc. Res. 2020 17 3 327 331 10.2174/1567202617666200327125257 32216738
     [Google Scholar]
149. Gonzalez-Alcocer A. Gopar-Cuevas Y. Soto-Dominguez A. Peripheral tissular analysis of rapamycin’s effect as a neuroprotective agent in vivo. Naunyn Schmiedebergs Arch. Pharmacol. 2022 395 10 1239 1255 10.1007/s00210‑022‑02276‑6 35895156
     [Google Scholar]
150. Maiese K. Chong Z.Z. Shang Y.C. Wang S. Novel directions for diabetes mellitus drug discovery. Expert Opin. Drug Discov. 2013 8 1 35 48 10.1517/17460441.2013.736485 23092114
     [Google Scholar]
151. Wu Z. Li H. Zhang Y. Liver transcriptome analyses of acute poisoning and recovery of male ICR mice exposed to the mushroom toxin α-amanitin. Arch. Toxicol. 2022 96 6 1751 1766 10.1007/s00204‑022‑03278‑2 35384471
     [Google Scholar]
152. Zhou Q. Tang S. Zhang X. Chen L. Targeting PRAS40: A novel therapeutic strategy for human diseases. J Drug Target 2021 2021 29 7 703 15 10.1080/1061186X.2021.1882470 33504218
     [Google Scholar]