RESUMO
Sulfur is widely existent in natural products and synthetic organic compounds as organosulfur, which are often associated with a multitude of biological activities. OBenzothiazole, in which benzene ring is fused to the 4,5-positions of the thiazolerganosulfur compounds continue to garner increasing amounts of attention in the field of medicinal chemistry, especially in the development of therapeutic agents for Alzheimer's disease (AD). AD is a fatal neurodegenerative disease and the primary cause of age-related dementia posing severe societal and economic burdens. Unfortunately, there is no cure for AD. A lot of research has been conducted on sulfur-containing compounds in the context of AD due to their innate antioxidant potential and some are currently being evaluated in clinical trials. In this review, we have described emerging trends in the field, particularly the concept of multi-targeting and formulation of disease-modifying strategies. SAR, pharmacological targets, in vitro/vivo ADMET, efficacy in AD animal models, and applications in clinical trials of such sulfur compounds have also been discussed. This article provides a comprehensive review of organosulfur-based AD therapeutic agents and provides insights into their future development.
RESUMO
Cancer cell metabolism is characterized by aerobic glycolysis or the "Warburg effect". Enhanced Akt signaling is associated with activation of various downstream enzymes involved in the glycolytic process, whereas activation of 5'-AMP-activated kinase (AMPK) acts to terminate energy expending mechanisms and decrease glycolytic enzyme expression. Studies were conducted to determine if the anticancer effects of γ-tocotrienol, are mediated through a suppression in aerobic glycolysis. Results show that treatment with 0-7 µM γ-tocotrienol throughout a 4-day culture period resulted in a dose-responsive increase in AMPK activation, and corresponding decrease in Akt activity in human MCF-7 and MDA-MB-231 breast cancer cells. γ-Tocotrienol treatment was also found to induce a dose-responsive decrease in phosphorylated-Fox03 (inactivated), a transcription factor that acts to inhibit in the levels of glycolytic enzyme, and this decrease was associated with a reduction in glycolytic enzyme levels and activity, as well as glucose consumption in these cells. PCR microarray analysis shows that γ-tocotrienol treatment decreases the expression of genes associate with metabolic signaling and glycolysis in MCF-7 and MDA-MB-231 breast cancer cells. In summary, these findings demonstrate that the anticancer effects of γ-tocotrienol are mediated, at least in part, by a suppression in the Warburg effect.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias da Mama/tratamento farmacológico , Cromanos/farmacologia , Vitamina E/análogos & derivados , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Proteína Forkhead Box O3/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vitamina E/farmacologiaRESUMO
Supplementation of glutathione (GSH) levels through varying formulations or precursors has thus far appeared to be a tenable strategy to ameliorate disease-associated oxidative stress. Metabolic liability of GSH and its precursors, i.e., hydrolysis by the ubiquitous γ-glutamyl transpeptidase (γ-GT), has limited successful clinical translation due to poor bioavailability. We addressed this problem through the design of γ-GT-resistant GSH analogue, ψ-GSH, which successfully substituted in GSH-dependent enzymatic systems and also offered promise as a therapeutic for Alzheimer's disease (AD). With the aim to improve its bioavailability, we studied the utility of a ψ-GSH precursor, dipeptide 2, as a potential AD therapeutic. Compound 2 retains the γ-GT stable ureide linkage and the thiol group for antioxidant property. By engaging glutathione synthetase, compound 2 was able to generate ψ-GSH in vivo. It was found to be a modest cofactor of glutathione peroxidase and prevented cytotoxicity of Aß1-42-aggregates in vitro. Studies of compound 2 in an acute AD model generated by intracerebroventricular injection of Aß1-42 showed cognitive benefits, which were augmented by its combination with glycine along with mitigation of oxidative stress and inflammatory pathology. Collectively, these results support further optimization and evaluation of ψ-GSH dipeptide as a potential therapeutic in transgenic AD models.
RESUMO
Increased oxidative stress and inflammation are implicated in the pathogenesis of Alzheimer's disease. Treatment with hydrogen sulfide (H2S) and H2S donors such as sodium hydrosulfide (NaSH) can reduce oxidative stress in preclinical studies, however clinical benefits of such treatments are rather ambiguous. This is partly due to poor stability and bioavailability of the H2S donors, requiring impractically large doses that are associated with dose-limiting toxicity. Herein, we identified a bioavailable 3-mercaptopyruvate prodrug, sulfanegen, which is able to pose as a sacrificial redox substrate for 3-mercaptopyruvate sulfurtransferase (3MST), one of the H2S biosynthetic enzymes in the brain. Sulfanegen is able to mitigate toxicity emanating from oxidative insults and the Aß1-42 peptide by releasing H2S through the 3MST pathway. When administered to symptomatic transgenic mouse model of AD (APP/PS1; 7 and 12 months) and mice that were intracerebroventricularly administered with the Aß1-42 peptide, sulfanegen was able to reverse oxidative and neuroinflammatory consequences of AD pathology by restoring 3MST function. Quantitative neuropathological analyses confirmed significant disease modifying effect of the compound on amyloid plaque burden and brain inflammatory markers. More importantly, sulfanegen treatment attenuated progressive neurodegeneration in these mice, as evident from the restoration of TH+ neurons in the locus coeruleus. This study demonstrates a previously unknown concept that supplementation of 3MST function in the brain may be a viable approach for the management of AD. Finally, brought into the spotlight is the potential of sulfanegen as a promising AD therapeutic for future drug development efforts.
RESUMO
BACKGROUND: Rods and cones are photoreceptor neurons in the retina that are required for visual sensation in vertebrates, wherein the perception of vision is initiated when these neurons respond to photons in the light stimuli. The photoreceptor cell is structurally studied as outer segments (OS) and inner segments (IS) where proper protein sorting, localization, and compartmentalization are critical for phototransduction, visual function, and survival. In human retinal diseases, improper protein transport to the OS or mislocalization of proteins to the IS and other cellular compartments could lead to impaired visual responses and photoreceptor cell degeneration that ultimately cause loss of visual function. RESULTS: Therefore, studying and identifying mechanisms involved in facilitating and maintaining proper protein transport in photoreceptor cells would help our understanding of pathologies involving retinal cell degeneration in inherited retinal dystrophies, age-related macular degeneration, and Usher Syndrome. CONCLUSIONS: Our mini-review will discuss mechanisms of protein transport within photoreceptors and introduce a novel role for an unconventional motor protein, MYO1C, in actin-based motor transport of the visual chromophore Rhodopsin to the OS, in support of phototransduction and visual function.