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Molecular Medicine Reports May 2024Following the publication of the above article, the authors contacted the Editorial Office to explain that a couple of errors concerning data handling/labelling had been...
Following the publication of the above article, the authors contacted the Editorial Office to explain that a couple of errors concerning data handling/labelling had been made, firstly during the preparation of the representative images in Fig. 3B, resulting in the wrong image being selected for the data panel showing the ACHN cells treated with 'Inhibitor NC' at 0 h experiment, and secondly in Fig. 5A, resulting in the wrong image being selected for the data panel showing the ACHN cells treated with 'Inhibitor NC' experiment. The authors requested that a corrigendum be published to take account of the errors that were made during the preparation of this figure. Subsequently, an independent investigation of the published data was undertaken by the Editorial Office, which revealed that the 'Inhibitor' data panel in Fig. 6A and the 'Mimic NC' data panel in Fig. 6B were also overlapping, such that these data were likely to have been derived from the same original source, even though these data panels were intended to have shown the results from differently performed experiments. The Editor of has considered the authors' request to publish a corrigendum, but given the number of overlapping data panels that have been identified and the number of figures that would be in need of correction, the Editor has decided to decline the authors' request to publish a corrigendum on account of an overall lack of confidence in the presented data, and instead has determined that the paper should be retracted. Upon receiving this news from the Editor, the authors accepted the Editor's decision. The Editor apologizes to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 17: 2051‑2060, 2018; DOI: 10.3892/mmr.2017.8052].
PubMed: 38551158
DOI: 10.3892/mmr.2024.13210 -
Chemical Science Mar 2024Peptidyl-prolyl / isomerase NIMA-interacting 1 (Pin1) is overexpressed and/or overactivated in many human cancers and has been shown to play a critical role during...
Peptidyl-prolyl / isomerase NIMA-interacting 1 (Pin1) is overexpressed and/or overactivated in many human cancers and has been shown to play a critical role during oncogenesis. Despite the potential of Pin1 as a drug target, its successful targeting has proved to be challenging. We speculate that only blocking the enzymatic function of Pin1 with inhibitors may not be sufficient to lead to a total loss-of-function. Here, we report the discovery of P1D-34, a first-in-class and potent PROTAC degrader of Pin1, which induced Pin1 degradation with a DC value of 177 nM and exhibited potent degradation-dependent anti-proliferative activities in a panel of acute myeloid leukemia (AML) cell lines. In contrast, Pin1 inhibitor Sulfopin did not show activity. More significantly, P1D-34 could sensitize Bcl-2 inhibitor ABT-199 in Bcl-2 inhibitor-resistant AML cells, highlighting the potential therapeutic value of targeted Pin1 degradation for Bcl-2 inhibitor-resistant AML treatment. Further mechanism study revealed that P1D-34 led to the up-regulation of ROS pathway and down-regulation of UPR pathway to induce cell DNA damage and apoptosis. Notably, we further demonstrated that treatment with the combination formula of glucose metabolism inhibitor 2-DG and P1D-34 led to a notable synergistic anti-proliferative effect, further expanding its applicability. These data clearly reveal the practicality and importance of PROTAC as a preliminary tool compound suitable for assessment of Pin1-dependent pharmacology and a promising strategy for AML treatment.
PubMed: 38550694
DOI: 10.1039/d3sc06558h -
RSC Advances Mar 2024Monoamine oxidases (MAOs) inhibitors could decrease reactive oxygen species (ROS) generation, enhance mono-aminergic neural transmission, and have major therapeutic...
Exploitation of the multitarget role of new ferulic and gallic acid derivatives in oxidative stress-related Alzheimer's disease therapies: design, synthesis and bioevaluation.
Monoamine oxidases (MAOs) inhibitors could decrease reactive oxygen species (ROS) generation, enhance mono-aminergic neural transmission, and have major therapeutic benefits for the treatment of Alzheimer's disease (AD). Following the conjunction of ferulic acid (FA)/gallic acid (GA) with sulfonamide, alanine and 2-aminobenzothiazole, we planned to assess the radical scavenging and antioxidant properties of synthesized analogs by using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric ion reducing antioxidant power (FRAP) assays. GA analog 28 was identified as the most potent antioxidant compound with IC values of 1.77 μM and 2.06 μM in DPPH and ABTS assays respectively. In the enzyme inhibition assays, synthesized derivative 23 emerged as a potent multitarget inhibitor of hMAO-B, eeAChE. COX-2 and 5-LOX with IC values of 0.037 μM, 0.071 μM, 14.3 μM and 0.59 μM, respectively. Moreover, selected compounds 23, 25, 26 and 28 displayed good to moderate inhibition of self-mediated amyloid β peptide aggregation. More importantly, compounds 23, 25, 28 and 29 showed no neurotoxicity on SH-SY5Y cells and also showed excellent neuroprotective effects against HO-induced SH-SY5Y cells. In the experiment, antioxidant enzymes superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) were studied in the brain of male BALB/c mice at the dose of 5 mg kg. All the tested compounds, except 29, have shown good to antioxidant potential. Docking studies on 3D crystallographic structures of AChE and MAO-B showed significant interactions with catalytic amino acid residues. In conclusion, the current study showed that FA/GA derivatives could be further exploited for their multitarget role in oxidative stress-related AD therapies.
PubMed: 38549798
DOI: 10.1039/d4ra00766b -
Advanced Science (Weinheim,... Jun 2024Cutaneous sympathetic nerve is a crucial part of neuropsychiatric factors contributing to skin immune response, but its role in the psoriasis pathogenesis remains...
Cutaneous sympathetic nerve is a crucial part of neuropsychiatric factors contributing to skin immune response, but its role in the psoriasis pathogenesis remains unclear. It is found that cutaneous calcium/calmodulin-dependent protein kinase II-γ (CAMK2γ), expressed mainly in sympathetic nerves, is activated by stress and imiquimod in mouse skin. Camk2g-deficient mice exhibits attenuated imiquimod-induced psoriasis-like manifestations and skin inflammation. CaMK2γ regulates dermal γδT-cell interleukin-17 production in imiquimod-treated mice, dependent on norepinephrine production following cutaneous sympathetic nerve activation. Adrenoceptor β1, the primary skin norepinephrine receptor, colocalises with γδT cells. CaMK2γ aggravates psoriasiform inflammation via sympathetic nerve-norepinephrine-γδT cell-adrenoceptor β1-nuclear factor-κB and -p38 axis activation. Application of alcaftadine, a small-molecule CaMK2γ inhibitor, relieves imiquimod-induced psoriasis-like manifestations in mice. This study reveals the mechanisms of sympathetic-nervous-system regulation of γδT-cell interleukin-17 secretion, and provides insight into neuropsychiatric factors dictating psoriasis pathogenesis and new potential targets for clinical psoriasis treatment.
Topics: Animals; Psoriasis; Mice; Norepinephrine; Sympathetic Nervous System; Disease Models, Animal; Imiquimod; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Skin; Mice, Inbred C57BL; Interleukin-17
PubMed: 38544478
DOI: 10.1002/advs.202306772 -
Molecules (Basel, Switzerland) Mar 2024()-Homobenzylic amines are key structural motifs present in ()-selegiline, a drug indicated for the treatment of early-stage Parkinson's disease. Herein, we report a new...
()-Homobenzylic amines are key structural motifs present in ()-selegiline, a drug indicated for the treatment of early-stage Parkinson's disease. Herein, we report a new short chemoenzymatic approach (in 2 steps) towards the synthesis of ()-selegiline via stereoselective biocatalytic reductive amination as the key step. The imine reductase IR36-M5 mutant showed high conversion (97%) and stereoselectivity (97%) toward the phenylacetone and propargyl amine substrates, offering valuable biocatalysts for synthesizing alkylated homobenzylic amines.
Topics: Oxidoreductases; Selegiline; Imines; Stereoisomerism; Amines; Amination; Biocatalysis
PubMed: 38542964
DOI: 10.3390/molecules29061328 -
Physiological Reports Mar 2024Ovarian cancer is one of the most prevalent malignancies in women. Harmaline is reported to have powerful anticancer properties. We aimed to investigate the apoptotic...
Ovarian cancer is one of the most prevalent malignancies in women. Harmaline is reported to have powerful anticancer properties. We aimed to investigate the apoptotic and antimetastatic properties of harmaline in A2780 ovarian cancer cells. Cell viability, apoptosis, migration, and invasion were investigated in cells treated with harmaline. Reactive oxygen species (ROS) production, mRNA expression of apoptosis-associated genes, MMP-2, and MMP-9 were measured. Harmaline attenuated the viability of A2780 ovarian cancer cells in a dose- and time-dependent way. Furthermore, compared to NIH/3T3 mouse normal cell line (IC50 = 417 μM), the malignant A2080 cells were more sensitive to harmaline (IC50 = 300 μM after 24 h). Harmaline increased the production of ROS, raised the mRNA expression of p53 and the Bax/Bcl2 ratio. Harmaline also increased the proportion of cells in the late apoptotic and necrotic phases. MMP-2 and MMP-9's mRNA expression, gelatinase activity, and migration of A2780 cells also decreased by harmaline. These findings suggest that harmaline may have the potential to be a therapeutic drug for ovarian cancer by triggering apoptosis and suppressing invasion and migration.
Topics: Humans; Female; Animals; Mice; Ovarian Neoplasms; Harmaline; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Cell Line, Tumor; Reactive Oxygen Species; Cell Proliferation; Apoptosis; RNA, Messenger
PubMed: 38531560
DOI: 10.14814/phy2.15984 -
Medicine Mar 2024Sacubitril/Valsartan, the combination of angiotensin receptor inhibitor and neprilysin inhibitor, is now becoming the class 1 recommendation for HFrEF. Some studies have... (Observational Study)
Observational Study
Sacubitril/Valsartan, the combination of angiotensin receptor inhibitor and neprilysin inhibitor, is now becoming the class 1 recommendation for HFrEF. Some studies have shown the positive effect of Sacubitril/Valsartan on HFrEF cancer patients, while there is devoid of evidence about the effect of this drug in aged cancer patients with HFmrEF and HFpEF. By searching the patients with a diagnosis of both cancer and Heart failure (HF) over 65, the patients who had received treatment with Sacubitril/Valsartan were selected as the candidates for Sacubitril/Valsartan group, and the patients who had received conventional HF therapy without Sacubitril/Valsartan were chosen as the control group. Data were collected for up to 9 months. We filtered 38 patients and 50 patients valid for Sacubitril/Valsartan group and control group, respectively. After initiation of heart failure management, our study found a better cardiac condition in Sacubitril/Valsartan group, having better LVEF, LVFS, NT-proBNP in 3rd, 6th, 9th month (P < .05) and better NYHA function classification after the treatment. We also observed fewer cases of deterioration on LAD (P = .029) and LVEDD (P = .023) in Sacubitril/Valsartan group. In subgroup analysis, our study showed that all 3 kinds of HF patients had better LVEF, LVFS, and NT-proBNP in Sacubitril/Valsartan group (P < .05). Our study further indicated that Sacubitril/Valsartan can improve cardiac function and benefit cardiac remolding in aged cancer patients of all 3 kinds of HF. This is the first study to provide new evidence for the use of Sacubitril/Valsartan in aged cancer patients of 3 kinds of HF.
Topics: Aged; Humans; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Drug Combinations; Heart Failure; Neoplasms; Stroke Volume; Tetrazoles; Valsartan
PubMed: 38517992
DOI: 10.1097/MD.0000000000037613 -
Inflammopharmacology Apr 2024Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system that injures the myelin sheath, provoking progressive axonal...
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system that injures the myelin sheath, provoking progressive axonal degeneration and functional impairments. No efficient therapy is available at present to combat such insults, and hence, novel safe and effective alternatives for MS therapy are extremely required. Rutin (RUT) is a flavonoid that exhibits antioxidant, anti-inflammatory, and neuroprotective effects in several brain injuries. The present study evaluated the potential beneficial effects of two doses of RUT in a model of pattern-III lesion of MS, in comparison to the conventional standard drug; dimethyl fumarate (DMF). Demyelination was induced in in male adult C57BL/6 mice by dietary 0.2% (w/w) cuprizone (CPZ) feeding for 6 consecutive weeks. Treated groups received either oral RUT (50 or 100 mg/kg) or DMF (15 mg/kg), along with CPZ feeding, for 6 consecutive weeks. Mice were then tested for behavioral changes, followed by biochemical analyses and histological examinations of the corpus callosum (CC). Results revealed that CPZ caused motor dysfunction, demyelination, and glial activation in demyelinated lesions, as well as significant oxidative stress, and proinflammatory cytokine elevation. Six weeks of RUT treatment significantly improved locomotor activity and motor coordination. Moreover, RUT considerably improved remyelination in the CC of CPZ + RUT-treated mice, as revealed by luxol fast blue staining and transmission electron microscopy. Rutin also significantly attenuated CPZ-induced oxidative stress and inflammation in the CC of tested animals. The effect of RUT100 was obviously more marked than either that of DMF, regarding most of the tested parameters, or even its smaller tested dose. In silico docking revealed that RUT binds tightly within NF-κB at the binding site of the protein-DNA complex, with a good negative score of -6.79 kcal/mol. Also, RUT-Kelch-like ECH-associated protein 1 (Keap1) model clarifies the possible inhibition of Keap1-Nrf2 protein-protein interaction. Findings of the current study provide evidence for the protective effect of RUT in CPZ-induced demyelination and behavioral dysfunction in mice, possibly by modulating NF-κB and Nrf2 signaling pathways. The present study may be one of the first to indicate a pro-remyelinating effect for RUT, which might represent a potential additive benefit in treating MS.
Topics: Male; Animals; Mice; Multiple Sclerosis; Cuprizone; Kelch-Like ECH-Associated Protein 1; Demyelinating Diseases; Neuroprotective Agents; NF-kappa B; Rutin; NF-E2-Related Factor 2; Neurodegenerative Diseases; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38512652
DOI: 10.1007/s10787-024-01442-x -
Scientific Reports Mar 2024This study aimed to investigate the role of autophagy, ferroptosis, and pyroptosis in the antitumour mechanism of harmine (Har) and its crosstalk in ovarian cancer. By...
This study aimed to investigate the role of autophagy, ferroptosis, and pyroptosis in the antitumour mechanism of harmine (Har) and its crosstalk in ovarian cancer. By transmission electron microscopy, we found that compared with those in the control group, the cytoplasm of human ovarian cancer cells (SKOV3) treated with Har showed increased numbers of autophagic vesicles, decreased intracellular mitochondrial volume, increased bilayer membrane density, and decreased cristae. Western blot, immunofluorescence, and monodasylcadaverine (MDC) staining all suggested that Har promoted autophagy in SKOV3 cells. LY294002 and siFOXO3 rescued the inhibition of the PI3K/AKT/mTOR/FOXO3 signalling pathway and the promotion of autophagy by Har. Additionally, the levels of ferroptosis- and pyroptosis-related proteins and the levels of Fe , glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) suggested that Har promoted ferroptosis and pyroptosis in SKOV3 cells. Interestingly, pretreatment with chloroquine (CQ), erastin, rapamycin (Rap), or ferrostatin-1 (Fer-1) increased or reversed the ferroptosis and pyroptosis promoted by Har, respectively. In vivo, the volume of tumours in the Har group was decreased, and immunohistochemistry revealed decreased levels of Ki-67 and GPX4 and increased levels of ATG5 and NARL3. In conclusion, Har exerts its anti-ovarian cancer effect not only by promoting autophagy by regulating the PI3K/AKT/mTOR/FOXO3 signalling pathway but also by promoting ferroptosis and pyroptosis. Additionally, there is complex crosstalk between autophagy, ferroptosis, and pyroptosis in ovarian cancer.
Topics: Female; Humans; Pyroptosis; Harmine; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Ferroptosis; TOR Serine-Threonine Kinases; Ovarian Neoplasms; Autophagy
PubMed: 38499622
DOI: 10.1038/s41598-024-57196-7 -
ACS Omega Mar 2024In recent studies, monoamine oxidase (MAO) inhibitory effects of various thiazolylhydrazone derivatives have been demonstrated. Within the scope of this study, 12 new...
In recent studies, monoamine oxidase (MAO) inhibitory effects of various thiazolylhydrazone derivatives have been demonstrated. Within the scope of this study, 12 new compounds containing thiazolylhydrazone groups were synthesized. The structures of the obtained compounds were elucidated by H NMR, C NMR, and high-resolution mass spectrometry (HRMS) methods. The inhibitory effects of the final compounds on MAO enzymes were investigated by means of in vitro methods. In addition to enzyme inhibition studies, enzyme kinetic studies of compounds with high inhibitory activity were examined, and their effects on substrate-enzyme relations were investigated. Additionaly, cytotoxicity tests were carried out to determine the toxicities of the selected compounds, and the compounds were found to be nontoxic. The interactions of the active compound with the active site of the enzyme were characterized by in silico methods.
PubMed: 38496951
DOI: 10.1021/acsomega.3c07703