Journal of cellular biochemistry最新文献

In the current study, new pyrazolo[3,4-b]pyridine esters, hydrazides, and Schiff bases have been synthesized starting from 3-methyl-1-phenyl-1H-pyrazol-5-amine. The first step involved solvent-free synthesis of pyrazolo[3,4-b]pyridine-6-carboxylate derivatives (2a-d) with 55%-70% yield in the minimum time frame compared with the conventional refluxing method, which was followed by the synthesis of corresponding hydrazides (3a-d) and hydrazones (4a-e). The structures of the synthesized derivatives were confirmed using element analysis, FT-IR, ¹H NMR, ¹³C NMR, and LC-MS techniques. Synthesized hydrazides (3a-d) and hydrazones (4a-e) were also tested for their in-vitro antidiabetic activity and found that all the compounds exhibited significant antidiabetic activity, while 3c (IC₅₀ = 9.6 ± 0.5 μM) among the hydrazides and 4c (IC₅₀ = 13.9 ± 0.7 μM) among the hydrazones were found to be more active in comparison to other synthesized derivatives. These in-vitro results were further validated via docking studies against the α-amylase enzyme using the reference drug acarbose (200.1 ± 10.0 μM). The results were greatly in agreement with their in-vitro studies and these derivatives can be encouraging candidates for further in-vivo studies in mice models.

Plants are rich sources of therapeutic compounds that often lack the side effects commonly found in synthetic chemicals. Researchers have effectively synthesized pharmaceuticals from natural sources, taking inspiration from traditional medicine, in their pursuit of modern drugs. This study aims to evaluate the phenolic and flavonoid content of Solanum virginianum seeds using different solvent extracts, enzymatic assays including 2,2-diphenyl-1-picrylhydrazyl activity, reducing power, and superoxide activity. Our phytochemical screening identified active compounds, such as phenols, flavonoids, tannins, and alkaloids. The methanol extract notably possesses higher levels of total phenolic and flavonoid content in comparison to the other extracts. The results highlight the superior antioxidant activity of methanol-extracted leaves, demonstrated by their exceptional IC₅₀ values, which surpass the established standard. In this study, molecular docking techniques were used to assess the binding affinity and to predict the binding conformation of the compounds. Quercetin 3-O beta-d-galactopyranoside displayed a binding energy of -8.35 kcal/mol with several important amino acid residues, PHE222, TRP440, ILE184, LEU192, VAL221, LEU218, SER185, and ALA188. Kaempferol 3-O-beta-l-glucopyranoside exhibited a binding energy of -8.33 kcal/mol, interacting with specific amino acid residues including ALA 441, VAL318, VAL322, MET307, ILI409, GLY442, and PHE439. The results indicate that the methanol extract has a distinct composition of biologically active constituents compared to the other extracts. Overall, seeds exhibit promise as natural antioxidants and potential agents for combating cancer. This study highlights the significance of utilizing the therapeutic capabilities of natural compounds and enhancing our comprehension of their pharmacological characteristics.

Acute lung injury (ALI) is a destructive respiratory disease characterized by alveolar structural destruction and excessive inflammation responses. Aerobic glycolysis of macrophages plays a crucial role in the pathophysiology of ALI. Previous studies have shown that the expression of the key rate-limiting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in inflammatory cells is significantly increased, which promotes an increase in the rate of glycolysis in inflammatory cells. However, little is known about the biological functions of PFKFB3 in macrophage inflammation and ALI. In this study, we identified that PFKFB3 is markedly increased in lipopolysaccharide (LPS)-induced ALI mice and macrophages. Knockdown of pfkfb3 attenuated LPS-induced glycolytic flux, decreased the release of pro-inflammatory cytokines, and inactivated NF-κB signaling pathway in macrophages. Subsequently, we found that dehydrocostus lactone (DL), a natural sesquiterpene lactone, significantly decreased both the mRNA and protein levels of PFKFB3. Furthermore, it reduced the release of inflammatory cytokines and inactivated NF-κB pathways in vitro. Accordingly, DL alleviated LPS-induced pulmonary edema and reduced the infiltration of inflammatory cells in mouse lung tissue. In summary, our study reveals the vital role of PFKFB3 in LPS-induced inflammation and discovers a novel molecular mechanism underlying DL's protective effects on ALI.

Extensive research has focused on cellular cholesterol and its regulation, primarily due to its crucial physiological roles and its association with numerous diseases resulting from dysregulated homeostasis. Consequently, investigating cholesterol metabolism and the network of regulating proteins remains an ongoing challenge for biomedical research seeking new molecular targets to manage aberrant cholesterol levels in pathologic conditions. There is evidence that Sigma-2/TMEM97 receptor regulates cholesterol metabolism. However, the mechanisms remain incompletely understood to date. Therefore, this study aimed to employ a pharmacological approach based on selective Sigma-2/TMEM97 agonists, rimcazole and siramesine, to uncover the contribution of this receptor to cholesterol homeostasis. Our results indicate that Sigma-2/TMEM97 activation modulates cholesterol uptake by altering key proteins involved in, leading to free cholesterol and neutral lipids accumulation. This sheds light on potential mechanisms implied, contributing a new piece to the intricate puzzle of cholesterol metabolism homeostasis.

Defect in membrane repair contributes to the development of muscular dystrophies such as limb girdle muscular dystrophy (LGMD) type R2 or R12. Nevertheless, many other muscular dystrophies may also result from a defect in this process. Identifying these pathologies requires the development of specific methods to inflict sarcolemma damage on a large number of cells and rapidly analyze their response. We adapted a protocol hitherto used to study the behavior of cancer cells to mechanical constraint. This method is based on forcing the passage of cells through a thin needle, which induces shear stress. Due to size considerations, this method requires working with mononuclear muscle cells instead of myotubes or muscle fibers. Although functional sarcolemma repair was thought to be restricted to myotubes and muscle fibers, we show here that 24h-differentiated myoblasts express a complete machinery capable of addressing membrane damage. At this stage, muscle cells do not yet form myotubes, revealing that the membrane repair machinery is set up early throughout the differentiation process. When submitted to the shear-stress assay, these cells were observed to repair membrane damage in a Ca²⁺-dependent manner, as previously reported. We show that this technique is able to identify the absence of membrane resealing in muscle cells from patient suffering from LGMDR2. The proposed technique provides therefore a suitable method for identifying cellular dysregulations in membrane repair of dystrophic human muscle cells.

Diabetic Kidney Disease (DKD), a frequent consequence of diabetes, has substantial implications for both morbidity and mortality rates, prompting the exploration of new metabolic biomarkers due to limitations in current methods like creatinine and albumin measurements. Pentraxin 3 (PTX3) shows promise for assessing renal inflammation in DKD. This study investigates how DKD metabolites could influence PTX3 expression through molecular docking, ADMET profiling, and dynamic simulation. Network and pathway analyses were conducted to explore metabolite interactions with DKD genes and their contributions to DKD pathogenesis. Thirty-three DKD-associated metabolites were screened, using pentoxifylline (PEN) as a reference. The pharmacokinetic properties of these compounds were evaluated through molecular docking and ADMET profiling. Molecular dynamics simulations over 200 ns assessed the stability of PTX3 (apo), the PRE-PTX3 complex, and PEN-PTX3 across multiple parameters. Cytoscape identified 1082 nodes and 1381 edges linking metabolites with DKD genes. KEGG pathway analysis underscored PTX3's role in inflammation. Molecular docking revealed pregnenolone sulfate (PRE) with the highest binding affinity (-6.25 kcal/mol), followed by hydrocortisone (-6.03 kcal/mol) and 2-arachidonoylglycerol (-5.92 kcal/mol), compared to PEN (-5.35 kcal/mol). ADMET profiling selected PRE for dynamic simulation alongside PEN. Analysis of RMSD, RMSF, RG, SASA, H-bond, PCA, FEL, and MM-PBSA indicated stable complex behavior over time. Our findings suggest that increasing PRE levels could be beneficial in managing DKD, potentially through isolating PRE from fungal sources, synthesizing it as dietary supplements, or enhancing endogenous PRE synthesis within the body.

Septins are a class of proteins with diverse and vital roles in cell biology. Structurally, they form hetero-oligomeric complexes and assemble into filaments, contributing to the organization of cells. These filaments act as scaffolds, aiding in processes like membrane remodeling, cytokinesis, and cell motility. Functionally, septins are essential to cell division, playing essential roles in cytokinetic furrow formation and maintaining the structural integrity of the contractile ring. They also regulate membrane trafficking and help organize intracellular organelles. In terms of physiology, septins facilitate cell migration, phagocytosis, and immune responses by maintaining membrane integrity and influencing cytoskeletal dynamics. Septin dysfunction is associated with pathophysiological conditions. Mutations in septin genes have been linked to neurodegenerative diseases, such as hereditary spastic paraplegias, underscoring their significance in neuronal function. Septins also play a role in cancer and infectious diseases, making them potential targets for therapeutic interventions. Septins serve as pivotal components of intracellular signaling networks, engaging with diverse proteins like kinases and phosphatases. By modulating the activity of these molecules, septins regulate vital cellular pathways. This integral role in signaling makes septins central to orchestrating cellular responses to environmental stimuli. This review mainly focuses on the human septins, their structural composition, regulatory functions, and implication in pathophysiological conditions underscores their importance in fundamental cellular biology. Moreover, their potential as therapeutic targets across various diseases further emphasizes their significance.