Cell Biochemistry and Biophysics最新文献

Wuzi Yanzong Pill (WZYZP) is a traditional Chinese medicine formula extensively used in China to treat male reproductive dysfunction, with a specific focus on invigorating the kidney. Despite its observed efficacy, the exact mechanisms and therapeutic targets remain unclear. The primary goal of this study is to elucidate the potential molecular targets and underlying mechanisms of WZYZP in the treatment of asthenozoospermia (AZS). It will be achieved through the integration of network pharmacology and bioinformatics analyses in a comprehensive and systematic approach. This study employed bioinformatics analysis and network pharmacology methodologies, encompassing: construction of protein-protein interaction (PPI) networks; development of 'Ingredients-Potential Target Genes-Signaling Pathways' (IPS) networks; Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis; differential gene analysis; molecular docking; and molecular dynamics simulations (MDS). Through network pharmacology analysis, we identified 485 potential targets of WZYZP. Cross-referencing with disease databases resulted in 57 intersecting targets pertinent to both WZYZP and AZS. Construction of the IPS network further determined eight core candidate targets: PIK3R1, MAPK3, GSK3B, AKT1, MAPK14, ESR1, ESR2, and CYP17A1. GO and KEGG pathway enrichment analyses highlighted significant involvement in prolactin signaling, endocrine resistance, and estrogen signaling pathways. Molecular docking and MDS confirmed stable binding of WZYZP components to all eight core targets. Our findings suggest that WZYZP may exert therapeutic effects in AZS by targeting eight pivotal genes (PIK3R1, MAPK3, GSK3B, AKT1, MAPK14, ESR1, ESR2, and CYP17A1). This is achieved through modulation of prolactin signaling, estrogen signaling, and endocrine resistance, thereby inhibiting inflammatory damage, antagonizing apoptotic signaling, maintaining hormonal homeostasis, and restoring metabolic imbalance.

Adenylate kinases (ADK) maintain cellular energy homeostasis and catalyse a reversible reaction that converts two molecules of ADP into ATP and AMP. ATP in Chlamydomonas reinhardtii flagella is utilised by dynein to generate flagellar beating. ATP must be constantly supplied and maintained; however, the constricted nature of flagella restricts the localisation of mitochondria in vicinity. We show that C. reinhardtii flagella carry conserved ADK domain-containing proteins that are large in number and longer than their cytosolic counterparts. Six of the eight flagellar ADKs are enriched in the central pair apparatus (CPA). Upon flagellar regeneration and resorption, the ADK activity changes, suggesting a shift in the energy demands for the two processes. The total ADK activity in regenerating flagella increased, and resorbing flagella showed an equal but reverse effect. ADKs help regenerate ATP locally and act as phosphotransfer agents that spatially direct the transfer of nucleotides. The ADP to ATP ratio during reflagellation and resorption suggests a role for ADKs in maintaining the nucleotide levels. To the best of our knowledge, this is the first study providing evidence for the role of ADK domain-containing proteins in maintaining ATP homeostasis in response to flagella regeneration and resorption.

The management of brain abscesses, particularly with Escherichia coli (E. coli) in immunocompromised patients, remains contentious. This study evaluates the bioactive potential of Ficus benghalensis extracts against brain abscess pathogens, including multidrug-resistant E. coli and Staphylococcus aureus (S. aureus), through phytochemical, pharmacological, and computational analyses. High yields (75-85%) were obtained from polar solvent extraction (acetone, methanol, ethyl acetate). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 30 bioactive compounds, including myricetin, naringenin-7-O-rutinoside, and harpagoside. Methanol extracts exhibited potent antimicrobial activity with inhibition zones of 18.2 mm (E. coli) and 17.9 mm (S. aureus) and minimum inhibitory concentration (MIC) values of 210-250 µg/mL. Ex vivo assays on clinical isolates showed dose-dependent inhibition (MIC50 = 150 µg/mL). Molecular docking indicated quercetin (-7.5 kcal/mol) and kaempferol (-7.8 kcal/mol) targeting E. coli FimH and OmpA, while lupeol (-9.1 kcal/mol) and ellagic acid (-8.7 kcal/mol) targeted S. aureus PBP2a and Hla. Pharmacokinetic analysis revealed quercetin and gallic acid as lead candidates with 100% gastrointestinal (GI) absorption and bioavailability (0.55-0.56), but limited blood-brain barrier (BBB) permeability (brain score: 0.24). Three-dimensional quantitative structure-activity relationship (3D-QSAR) comparative molecular field analysis (CoMFA) models (R² = 0.111, Q² = 0.00) emphasized steric and electrostatic interactions (84%) in bioactivity. These findings suggest that Ficus benghalensis holds potential as a multitarget antimicrobial agent for brain abscess therapy, with further optimization for central nervous system (CNS) delivery needed.

Royal jelly (RJ) is a natural product that reduces toxic effects and has anti-proliferative effects. The aim of the study is to increase the anticancer effect of Paclitaxel (PAX), which is used in cancer treatment, and to reduce its toxic effect with RJ in oral squamous carcinoma cells. Cytotoxicity tests of RJ and PAX substances were tested on healthy gingival HGF cells and their anti-proliferative effects on UPCI-SCC-131 cells with real-time cell analyzer (xCELLigence RTCA). Their anti-migratory properties were observed with wound healing assay. Glycolysis stress test was performed with Seahorse XFe24 to measure the glycolytic capacity. Total RNA-seq libraries were created and sequenced with NovaSeq 6000. Transcriptome profiles were created with bioinformatic analyses and functional enrichment analyses were performed. Results demonstrate that both RJ and PAX exhibit significant anti-proliferative effects against oral squamous cell carcinoma cells, as quantified by real-time cell analysis. Notably, RJ co-treatment mitigated PAX-induced cytotoxicity in healthy human gingival fibroblasts, suggesting a protective role against chemotherapy-associated toxicity. While both compounds inhibited cancer cell proliferation, PAX particularly displayed potent anti-migratory properties in wound healing assays, significantly impairing OSCC cell motility. Metabolic profiling revealed that the RJ-PAX combination therapy substantially reduced glycolytic capacity in OSCC cells, indicating disruption of their energy metabolism. Transcriptomic analysis identified downregulation of critical cell cycle regulators (MCM2, CDC25A, CCNE2) and DNA replication factors (RFC2, PCNA), along with modulation of MYC and E2F pathways, providing insights into the observed anti-cancer effects.

Cancer is one of the prominent causes of death, and brain cancer accounts for about 2% of this figure, with glioma being the major type. This study aims to identify biomarker candidates for glioma subtypes, specifically glioblastoma (GBM) and oligodendroglioma (ODG), as well as to disclose repurposed drug candidates common to these brain tumors. Gene expression profiles were analyzed and integrated with data from proteomics interactions as well as miRNA regulation. 23 mutual core DEGs (differentially expressed genes) were identified. Correlation networks and protein interaction networks were constructed from these core DEGs. Hubs of the protein interaction networks (CALM1), miRNA - core DEG interaction network (SOX4, MTHFD2, and CALM1), and correlation networks such as ABCA2, TPPP, PPP1R16B, SPOCK3, and SPARC, as well as central miRNAs (hsa-miR-1-3p, hsa-miR-19b-3p, and hsa-miR-335-5p) were identified. Furthermore, candidate therapeutic agents were revealed. Docking-based virtual screening suggests that budesonide, sirolimus, cephaeline, etoposide, and staurosporine may target proteins upregulated in GBM and ODG, such as APOC, MTHFD2, and LPL, in addition to their actual targets. Particularly, sirolimus and protriptyline exhibited comparable binding affinities against MTHFD2 (-11.23 kcal/mol) and LPL (-7.45 kcal/mol), respectively, compared to their actual targets. The holistic network-based approach applied in this study may be advantageous in the illumination of these subtypes and may aid in the design of improved therapeutics in treatment of the studied gliomas.

The purpose of this research was to assess oxidative stress levels in colon cancer patients and examine their association with disease onset and progression. 176 individuals were recruited, comprising 106 colon cancer patients and 70 healthy controls. Serum oxidative stress marker levels of protein carbonyl (PCO), ischemia-modified albumin (IMA), malondialdehyde (MDA), and glutathione-S-transferase (GST) and antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) were quantified. The tumor markers carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA 19.9) were also evaluated. The levels of PCO, IMA, MDA, and GST were significantly increased (P < 0.01 for each) with a significant decrease in GPX and SOD levels (P < 0.01) when compared to the control group. No significant difference was noted in CAT levels. The tumor markers CEA and CA 19.9 were significantly increased in the patient group (P < 0.01). These results suggest an imbalance of oxidative/antioxidant status in favor of oxidative stress in patients with colon cancer. The study identifies oxidative stress as a major factor in the pathogenesis of colon cancer. Clinically, biomarkers such as IMA with more than 80% sensitivity can be powerful secondary aids to early detection or monitoring disease progression. The findings suggest that modulating oxidative stress would be therapeutic in the treatment of colon cancer.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, with limited therapeutic options and adverse effects associated with long-term pharmacological treatments. This study investigated the neuroprotective potential of Bryophyllum pinnatum (B. pinnatum) through integrative in silico and in vivo approaches. Network pharmacology and pathway enrichment analyses (KEGG, Cytoscape 3.10.1) were used to identify compound-target network association. Molecular docking using AutoDock Vina and molecular dynamics (MD) simulations for 200 ns using GROMACS were executed to assess the stability of the key ligands and targets. Cognitive impairment was induced in Wistar rats using scopolamine (1 mg/kg, i.p.). Animals were treated with B. pinnatum hydroalcoholic leaf extract (200 and 400 mg/kg, p.o.) and donepezil (3 mg/kg, i.p.) for 30 days. Cognitive and motor functions were evaluated via Morris water maze, elevated plus maze, locomotor activity, and grip strength tests. Biochemical assays measured acetylcholinesterase (ACHE) activity, β-amyloid (Aβ) levels, glutathione, and lipid peroxidation. Histopathological analysis of brain tissue assessed neuronal integrity. In silico analyses identified multiple phytoconstituents involved in AD-relevant pathways, including MAPK, PI3K-Akt, and cholinergic signaling. Diosmin exhibited high binding affinities to ACHE (-10.3 kcal/mol) and MAO-B (-11.2 kcal/mol), with stable binding confirmed via MD simulations. In vivo, B. pinnatum significantly improved cognitive performance, motor coordination, and antioxidant status while reducing Aβ aggregation and ACHE activity (p < 0.05). Histological findings showed reduced neuronal degeneration and neuroinflammation. These results highlight the multitarget neuroprotective potential of B. pinnatum, with diosmin emerging as a promising plant-derived candidate for AD therapeutics.