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Molecular Biology Reports Jun 2024Cataract contributes to visual impairment worldwide, and diabetes mellitus accelerates the formation and progression of cataract. Here we found that the expression level...
BACKGROUND
Cataract contributes to visual impairment worldwide, and diabetes mellitus accelerates the formation and progression of cataract. Here we found that the expression level of miR-204-5p was diminished in the lens epithelium with anterior lens capsule of cataract patients compared to normal donors, and decreased more obviously in those of diabetic cataract (DC) patients. However, the contribution and mechanism of miR-204-5p during DC development remain elusive.
METHODS AND RESULT
The mitochondrial membrane potential (MMP) was reduced in the lens epithelium with anterior lens capsule of DC patients and the H2O2-induced human lens epithelial cell (HLEC) cataract model, suggesting impaired mitochondrial functional capacity. Consistently, miR-204-5p knockdown by the specific inhibitor also attenuated the MMP in HLECs. Using bioinformatics and a luciferase assay, further by immunofluorescence staining and Western blot, we identified IGFBP5, an insulin-like growth factor binding protein, as a direct target of miR-204-5p in HLECs. IGFBP5 expression was upregulated in the lens epithelium with anterior lens capsule of DC patients and in the HLEC cataract model, and IGFBP5 knockdown could reverse the mitochondrial dysfunction in the HLEC cataract model.
CONCLUSIONS
Our results demonstrate that miR-204-5p maintains mitochondrial functional integrity through repressing IGFBP5, and reveal IGFBP5 may be a new therapeutic target and prognostic factor for DC.
Topics: MicroRNAs; Humans; Cataract; Mitochondria; Insulin-Like Growth Factor Binding Protein 5; Epithelial Cells; Diabetes Complications; Membrane Potential, Mitochondrial; Lens, Crystalline; Male; Female; Middle Aged
PubMed: 38874707
DOI: 10.1007/s11033-024-09701-4 -
Brain and Behavior Jun 2024Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various...
BACKGROUND
Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various aspects of memory performance, anxiety, and oxidative stress in an AD rat model induced by intracerebroventricular injection of amyloid beta (Aβ).
METHODS
Oral administration of SEL at a dose of 0.5 mg/kg/day was performed for 30 consecutive days. Following the 30 days, several tests, including the open-field, elevated plus-maze, novel object recognition, Morris water maze, and passive avoidance learning were conducted to assess locomotor activity, anxiety-like behavior, recognition memory, spatial memory, and passive avoidance memory, respectively.
RESULTS
The results indicate that the induction of AD in rats led to recognition memory, spatial memory, and passive avoidance memory impairments, as well as increased anxiety. Additionally, the AD rats exhibited a decrease in total antioxidant capacity and an increase in total oxidant status levels, suggesting an imbalance in oxidative-antioxidant status. However, the administration of SEL improved memory performance, reduced anxiety, and modulated oxidative-antioxidant status in AD rats.
CONCLUSIONS
These findings provide evidence that SEL may alleviate anxiety-like behavior and cognitive deficits induced by Aβ through modulation of oxidative-antioxidant status.
Topics: Animals; Amyloid beta-Peptides; Anxiety; Rats; Male; Selegiline; Memory Disorders; Oxidative Stress; Alzheimer Disease; Disease Models, Animal; Avoidance Learning; Peptide Fragments; Spatial Memory; Maze Learning; Rats, Wistar; Recognition, Psychology; Behavior, Animal; Neuroprotective Agents; Antioxidants
PubMed: 38873869
DOI: 10.1002/brb3.3599 -
Animal Models and Experimental Medicine Jun 2024Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as...
BACKGROUND
Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis; therefore, inhibition of ASK1 kinase activity can protect cells from pathological injury. In this study, we designed and synthesized a novel selective ASK1 inhibitor, CS17919, and investigated its pharmacological effects in various animal models of metabolic injury.
METHODS
First, we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib (GS-4997), a phase III ASK1 inhibitor. We then conducted pharmacokinetic (PK) studies in mice. Finally, we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH).
RESULTS
Compared to GS-4997, CS17919 demonstrated comparable inhibition of ASK1 in vitro, exhibited lower toxicity, and provided greater protection in palmitic acid-treated LO2 cells. CS17919 also showed pronounced pharmacokinetic properties such as a high plasma concentration. In the unilateral ureteral obstruction model (UUO), CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis. In the diabetic kidney disease (DKD) model, CS17919 significantly improved serum creatinine and glomerular sclerosis. In the NASH model, the combination of CS17919 and a THRβ agonist (CS27109) was found to significantly improve liver inflammation and substantially reduced liver fibrosis.
CONCLUSIONS
CS17919 showed cell protective, anti-inflammatory, and antifibrotic effects in vitro and in vivo, suggesting its therapeutic potential for metabolic-related kidney and liver diseases.
PubMed: 38873818
DOI: 10.1002/ame2.12437 -
Molecular Biology Reports Jun 2024The present study aimed to elucidate the potential anticancer activity and mechanism of P. harmala's alkaloid extract, harmine (HAR), and harmaline (HAL) in HCT-116...
BACKGROUND
The present study aimed to elucidate the potential anticancer activity and mechanism of P. harmala's alkaloid extract, harmine (HAR), and harmaline (HAL) in HCT-116 colorectal cancer cells.
METHODS AND RESULTS
P. harmala's alkaloid was extracted from harmala seeds. HCT-116 cells were treated with P. harmala's alkaloid extract, HAR and HAL. Cytotoxicity was determined by MTT assay, apoptotic activity detected via flow cytometry and acridine orange (AO)/ethidium bromide (EB) dual staining, and cell cycle distribution analyzed with flow cytometry. The mRNA expression of Bcl-2-associated X protein (Bax) and glycogen synthase kinase-3 beta (GSK3β) was measured by real-time PCR. Furthermore, the expression of Bax, Bcl-2, GSK3β and p53 proteins, were determined by western blotting. The findings indicated that, P. harmala's alkaloids extract, HAR and HAL were significantly cytotoxic toward HCT116 cells after 24 and 48 h of treatment. We showed that P. harmala's alkaloid extract induce apoptosis and cell cycle arrest at G2 phase in the HCT116 cell line. Downregulation of GSK3β and Bcl-2 and upregulation of Bax and p53 were observed.
CONCLUSION
The findings of this study indicate that the P. harmala's alkaloid extract has anticancer activity and may be further investigated to develop future anticancer chemotherapeutic agents.
Topics: Humans; Peganum; HCT116 Cells; Apoptosis; Colonic Neoplasms; Seeds; Harmine; Glycogen Synthase Kinase 3 beta; bcl-2-Associated X Protein; Plant Extracts; Alkaloids; Harmaline; Antineoplastic Agents, Phytogenic; Tumor Suppressor Protein p53; Proto-Oncogene Proteins c-bcl-2; Cell Proliferation
PubMed: 38872006
DOI: 10.1007/s11033-024-09655-7 -
Biomacromolecules Jun 2024Acute myeloid leukemia (AML) is often associated with poor prognosis and survival. Small molecule inhibitors, though widening the treatment landscape, have limited...
Acute myeloid leukemia (AML) is often associated with poor prognosis and survival. Small molecule inhibitors, though widening the treatment landscape, have limited monotherapy efficacy. The combination therapy, however, shows suboptimal clinical outcomes due to low bioavailability, overlapping systemic toxicity and drug resistance. Here, we report that CXCR4-mediated codelivery of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor sorafenib (SOR) via T22 peptide-tagged disulfide cross-linked polymeric micelles (TM) achieves synergistic treatment of FLT3-ITD AML. TM-VS with a VEN/SOR weight ratio of 1/4 and T22 peptide density of 20% exhibited an extraordinary inhibitory effect on CXCR4-overexpressing MV4-11 AML cells. TM-VS at a VEN/SOR dosage of 2.5/10 mg/kg remarkably reduced leukemia burden, prolonged mouse survival, and impeded bone loss in orthotopic MV4-11-bearing mice, outperforming the nontargeted M-VS and oral administration of free VEN/SOR. CXCR4-mediated codelivery of BCL-2 and FLT3 inhibitors has emerged as a prospective clinical treatment for FLT3-ITD AML.
PubMed: 38869359
DOI: 10.1021/acs.biomac.4c00561 -
PloS One 2024The present study aims to investigate the specific protective effects and underlying mechanisms of Ganshuang granule (GSG) on dimethylnitrosamine (DMN)-induced hepatic...
OBJECTIVE
The present study aims to investigate the specific protective effects and underlying mechanisms of Ganshuang granule (GSG) on dimethylnitrosamine (DMN)-induced hepatic fibrosis in rat models.
METHODS
Hepatic fibrosis was experimentally evoked in rats by DMN administration, and varying dosages of GSG were employed as an intervention. Hepatocellular damage was assessed by measuring serum levels of aminotransferase and bilirubin, accompanied by histopathological examinations of hepatic tissue. The hepatic concentrations of platelet-derived growth factor (PDGF) and transforming growth factor-β1 (TGF-β1) were quantitated via enzyme-linked immunosorbent assay (ELISA). The expression of α-smooth muscle actin (α-SMA) within hepatic tissue was evaluated using immunohistochemical techniques. The levels of hepatic interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and a spectrum of interleukins (IL-2, IL-4, IL-6, IL-10) were quantified by quantitative real-time PCR (qRT-PCR). Additionally, hepatic stellate cells (HSCs) were cultured in vitro and exposed to TNF-α in the presence of naringin, a principal component of GSG. The gene expression levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metallopeptidase-1 (MMP-1) in these cells were also quantified by qRT-PCR. Proliferative activity of HSCs was evaluated by the Cell Counting Kit-8 assay. Finally, alterations in Smad protein expression were analyzed through Western blotting.
RESULTS
Administration of GSG in rats with fibrosis resulted in reduced levels of serum aminotransferases and bilirubin, along with alleviation of histopathological liver injury. Furthermore, the fibrosis rats treated with GSG exhibited significant downregulation of hepatic TGF-β1, PDGF, and TNF-α levels. Additionally, GSG treatment led to increased mRNA levels of IFN-γ, IL-2, and IL-4, as well as decreased expression of α-SMA in the liver. Furthermore, treatment with naringin, a pivotal extract of GSG, resulted in elevated expression of MMP-1 and decreased levels of TIMP-1 in TNF-α-stimulated HSCs when compared to the control group. Additionally, naringin administration led to a reduction in Smad expression within the HSCs.
CONCLUSION
GSG has the potential to mitigate fibrosis induced by DMN in rat models through the regulation of inflammatory and fibrosis factors. Notably, naringin, the primary extract of GSG, may exert a pivotal role in modulating the TGF-β-Smad signaling pathway.
Topics: Animals; Liver Cirrhosis; Signal Transduction; Flavanones; Male; Rats; Smad Proteins; Hepatic Stellate Cells; Drugs, Chinese Herbal; Rats, Sprague-Dawley; Dimethylnitrosamine; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1; Platelet-Derived Growth Factor; Liver; Actins
PubMed: 38857261
DOI: 10.1371/journal.pone.0304185 -
Theranostics 2024It has been emergingly recognized that apoptosis generates plenty of heterogeneous apoptotic vesicles (apoVs), which play a pivotal role in the maintenance of organ and...
It has been emergingly recognized that apoptosis generates plenty of heterogeneous apoptotic vesicles (apoVs), which play a pivotal role in the maintenance of organ and tissue homeostasis. However, it is unknown whether apoVs influence postnatal ovarian folliculogenesis. Apoptotic pathway deficient mice including Fas mutant ( ) and Fas ligand mutant ( ) mice were used with apoV replenishment to evaluate the biological function of apoVs during ovarian folliculogenesis. Ovarian function was characterized by morphological analysis, biochemical examination and cellular assays. Mechanistical studies were assessed by combinations of transcriptomic and proteomic analysis as well as molecular assays. mice was established to verify the role of WNT signaling during ovarian folliculogenesis. Polycystic ovarian syndrome (PCOS) mice and 15-month-old mice were used with apoV replenishment to further validate the therapeutic effects of apoVs based on WNT signaling regulation. We show that systemic administration of mesenchymal stem cell (MSC)-derived apoptotic vesicles (MSC-apoVs) can ameliorate impaired ovarian folliculogenesis, PCOS phenotype, and reduced birth rate in and mice. Mechanistically, transcriptome analysis results revealed that MSC-apoVs downregulated a number of aberrant gene expression in mice, which were enriched by kyoto encyclopedia of genes and genomes (KEGG) pathway analysis in WNT signaling and sex hormone biosynthesis. Furthermore, we found that apoptotic deficiency resulted in aberrant WNT/β-catenin activation in theca and mural granulosa cells, leading to responsive action of dickkopf1 (DKK1) in the cumulus cell and oocyte zone, which downregulated WNT/β-catenin expression in oocytes and, therefore, impaired ovarian folliculogenesis NPPC/cGMP/PDE3A/cAMP cascade. When WNT/β-catenin was specially activated in theca cells of mice, the same ovarian impairment phenotypes observed in apoptosis-deficient mice were established, confirming that aberrant activation of WNT/β-catenin in theca cells caused the impairment of ovarian folliculogenesis. We firstly revealed that apoVs delivered WNT membrane receptor inhibitor protein RNF43 to ovarian theca cells to balance follicle homeostasis through vesicle-cell membrane integration. Systemically infused RNF43-apoVs down-regulated aberrantly activated WNT/β-catenin signaling in theca cells, contributing to ovarian functional maintenance. Since aging mice have down-regulated expression of WNT/β-catenin in oocytes, we used MSC-apoVs to treat 15-month-old mice and found that MSC-apoVs effectively ameliorated the ovarian function and fertility capacity of these aging mice through rescuing WNT/β-catenin expression in oocytes. Our studies reveal a previously unknown association between apoVs and ovarian folliculogenesis and suggest an apoV-based therapeutic approach to improve oocyte function and birth rates in PCOS and aging.
Topics: Animals; Female; Polycystic Ovary Syndrome; Mice; Wnt Signaling Pathway; Mesenchymal Stem Cells; Apoptosis; Ovarian Follicle; Ovary; Disease Models, Animal; Aging; Fas Ligand Protein
PubMed: 38855175
DOI: 10.7150/thno.94943 -
Journal of Ethnopharmacology Jun 2024Qiju Dihuang Pill (QDP) is a traditional Chinese medicine prescription for the treatment of eye diseases. Novel literature reports that copper-induced cell death, called...
ETHNOPHARMACOLOGICAL RELEVANCE
Qiju Dihuang Pill (QDP) is a traditional Chinese medicine prescription for the treatment of eye diseases. Novel literature reports that copper-induced cell death, called as cuproptosis, is a copper-dependent and differs distinctly from other types of cell death.
AIM OF THE STUDY
The present study aims to investigate whether QDP could protect lens epithelial cells via alleviating copper-induced death in diabetic cataract.
MATERIALS AND METHODS
The different concentration of QDP medicated serum was administrated on high glucose (HG)-induced human lens epithelial cells (HLECs). The copper concentration was tested using Elabscience Copper Assay kit. The proliferation was detected using CCK-8 and EdU assays. The molecular binding was identified using RIP-PCR and luciferase reporter assay.
RESULTS
Results indicated that HG culture condition triggered the copper concentration and repressed the proliferation of HLECs. Then, the elesclomol-Cu (Es-Cu) administration up-regulated the copper concentration and inhibited the proliferation, and cuproptosis inhibitor tetrathiomolybdate (TTM) could specifically reverse the consequence. QDP treatment reduced the copper concentration and cuproptosis-related genes (SLC31A1, FDX1). MeRIP-Seq and RIP-PCR confirmed that QDP reduced the stability of SLC31A1 mRNA through mA modified site, and copper actually synergized the molecular binding efficiency. Rescue assay verified the role of QDP and SLC31A1 on HLECs' cuproptosis characteristic.
CONCLUSION
This research identified the protective role of QDP on HG-induced HLECs in DC through decreasing mA/SLC31A1-mediated cuproptosis in DC. This finding provides novel insights into mechanisms for QDP and sheds light on the multifaceted role of traditional prescription on DC.
PubMed: 38851473
DOI: 10.1016/j.jep.2024.118444 -
Open Medicine (Warsaw, Poland) 2024Rheumatoid arthritis (RA) is a chronic inflammatory and disabling disease that imposes significant economic and social costs. Hook F (TwHF) has a long history of use in...
BACKGROUND
Rheumatoid arthritis (RA) is a chronic inflammatory and disabling disease that imposes significant economic and social costs. Hook F (TwHF) has a long history of use in traditional Chinese medicine for treating joint disorders, and it has been shown to be cost-effective in treating RA, but its exact mechanism is unknown.
OBJECTIVE
The goal of the network pharmacology analysis and molecular docking was to investigate the potential active compounds and associated anti-RA mechanisms of TwHF.
METHODS
TCMSP and UniProt databases were searched for active compounds and related targets of TwHF. PharmGKB, DrugBank, OMIM, TTD, and the Human Gene Databases were used to identify RA-related targets. The intersected RA and TwHF targets were entered into the STRING database to create a protein-protein interaction network. R software was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking technology was used to analyze the optimal effective components from TwHF for docking with the selected target gene.
RESULTS
Following screening and duplicate removal, a total of 51 active compounds and 96 potential targets were chosen. The PPI network revealed that the target proteins are CXCL8, CXCL6, STAT3, STAT1, JUN, PPARG, TP53, IL14, MMP9, VEGFA, RELA, CASP3, PTGS2, IFNG, AKT1, FOS, ICAM1, and MAPK14. The results of the GO enrichment analysis focused primarily on the response to lipopolysaccharide, the response to molecules of bacterial origin, and the response to drugs. The KEGG results indicated that the mechanisms were closely related to lipid and atherosclerosis, chemical carcinogenesis-receptor activation, Kaposi sarcoma-associated, herpesvirus infection, hepatitis B, fluid shear stress and atherosclerosis, IL-17 signaling pathways, Th17-cell differentiation, and so on, all of which are involved in angiogenesis, immune cell chemotaxis, and inflammatory responses. Molecular docking results suggested that triptolide was the appropriate PTGS1, PTGS2, and TNF inhibitors.
CONCLUSION
Our findings provide an essential role and basis for further immune inflammatory studies into the molecular mechanisms of TwHF and PTGS1, PTGS2, and TNF inhibitor development in RA.
PubMed: 38841174
DOI: 10.1515/med-2024-0967 -
European Journal of Medicinal Chemistry Aug 2024Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development...
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development of novel scaffolds for human monoamine oxidase B (hMAO-B) inhibitors with reversible properties represents an important strategy to improve the efficacy and safety for PD treatment. In the current work, we have devised and assessed two innovative derivative series serving as hMAO-B inhibitors. These series have utilized benzimidazole as a scaffold and strategically incorporated a primary amide group, which is recognized as a pivotal pharmacophore in subsequent activity screening and reversible mode of action. Among these compounds, 16d has emerged as the most potent hMAO-B inhibitor with an IC value of 67.3 nM, comparable to safinamide (IC = 42.6 nM) in vitro. Besides, 16d demonstrated good selectivity towards hMAO-B isoenzyme with a selectivity index over 387. Importantly, in line with the design purpose, 16d inhibited hMAO-B in a competitive and reversible manner (K = 82.50 nM). Moreover, 16d exhibited a good safety profile in both cellular and acute toxicity assays in mice. It also displayed ideal pharmacokinetic properties and blood-brain barrier permeability in vivo, essential prerequisites for central nervous system medicines. In the MPTP-induced PD mouse model, 16d significantly alleviated the motor impairment, especially muscle relaxation and motor coordination. Therefore, 16d, serving as a lead compound, holds instructive significance for subsequent investigations regarding its application in the treatment of PD.
Topics: Monoamine Oxidase Inhibitors; Monoamine Oxidase; Humans; Animals; Structure-Activity Relationship; Mice; Benzimidazoles; Parkinson Disease; Molecular Structure; Drug Discovery; Dose-Response Relationship, Drug; Male; Mice, Inbred C57BL; Antiparkinson Agents
PubMed: 38838545
DOI: 10.1016/j.ejmech.2024.116566