BioFactors最新文献

Pancreatic adenocarcinoma accounts for 90% of pancreatic cancer cases, the deadliest kind. PC patients' poor immunotherapy, chemotherapy, and other responses lead to a generally failed treatment strategy. Thus, understanding molecular processes is essential for creating novel PC therapies. The natural chemical andrographolide (ADG) from Andrographis paniculata shows anticancer properties against various cancer types. The method by which ADG fights pancreatic cancer is unknown. In PC cell lines, ADG inhibited cell proliferation and migration, caused G0/G1 phase arrest, and caused cell death due to reactive oxygen species, iron accumulation, malondialdehyde production, and glutathione (GSH) exhaustion. Ferrostatin-1 inhibited ADG-induced cell death. A molecular docking investigation demonstrated that ADG directly binds to heat shock protein 90 (HSP90). ADG suppresses HSP90 expression, and tanespimycin prevents ADG-induced cytotoxicity, showing that HSP90 is ADG's main target in activating intracellular activities. Tests using immunoprecipitation, degradation, and in vitro ubiquitination showed that the ADG-HSP90 pair targeted and broke down glutathione peroxidase 4 (GPX4), allowing it to be tagged for destruction. ADG also reduced cell development, caused apoptosis, increased reactive oxygen species and iron, synthesized malondialdehyde, depleted glutathione, and ubiquitinated and degraded GPX4. In subcutaneous in vivo tumors, ferroptosis caused by ADG inhibits tumor development. HSP90 is a new ADG target. After connecting to and complexing with HSP90, ADG targeted and deleted GPX4, triggering ferroptosis in PC. The findings strongly suggest that ADG may treat PC. ADG's pharmacokinetics and other effects must be studied in patients' clinical trials to make it a pancreatic cancer therapy option.

Exosomes are nano-sized extracellular vesicles that contain specific proteins, nucleic acids, and lipids. These small vesicles are significant in a wide range of physiological and pathological conditions. Circular RNAs (circRNAs) are a subclass of noncoding RNAs that are expressed differently in many tissues and play essential roles in biological function. circRNAs are remarkably stable and prevalent in exosomes. These properties make them ideal candidates for biomedical research. Exosomal circRNAs function as pathogenic regulators, biomarkers, and therapy candidates in various diseases, including metabolic syndrome. Metabolic syndrome is a multifaceted condition distinguished by disruptions in the body's metabolism, encompassing obesity, insulin resistance, diabetes, nonalcoholic fatty liver disease, hyperlipidemia, and atherosclerosis. This syndrome is linked to a high risk of type 2 diabetes, cardiovascular disease, cancer, and mortality. In this review, we provide a comprehensive overview of the roles of exosomal circRNAs in metabolic syndrome, providing recent perspectives on the pathogenesis, diagnosis, and treatment of these complicated disorders.

The role of mitochondrial dysfunction underlying increased susceptibility to cerebrovascular disease in hypertension, previously detected in stroke-prone spontaneously hypertensive rats (SHR-SP) fed with a high-salt stroke-permissive Japanese-style diet (JD), was studied for the first time at the molecular level. The Complex I (CI) (dis)assembly in the supramolecular organization of respiratory supercomplexes (SCs) has emerged as the main component impairing the kinetic activity and SCs organization of mitochondrial respiration in SHR-SP compared with the SHR-stroke resistant (SR) strain upon the same dietary condition. The leak of substrate channeling and SCs arrangement in CI-dependent NADH oxidation in JD-fed SHR-SP was not detected in SHR-SR upon the same dietary regimen. Our results highlight that SCs association linked to CI dynamic and stability protects from stroke manifestation.

Bromelain, a combination of pineapple-derived enzymes, has demonstrated neuroprotective effects owing to its antioxidant and anti-inflammatory attributes. The current study intended to explore bromelain's neuroprotective impact against 3-nitropropionic acid (3-NP)-induced Huntington's disease (HD)-like symptoms in rats. Four groups of rats were randomly allocated: group 1 received saline; bromelain (40 mg/kg/i.p.) was given to groups 2 and 4 daily, whereas groups 3 and 4 received daily doses of 3-NP (10 mg/kg/i.p.) for 14 days. On the molecular level, bromelain administration resulted in upregulation of striatal SIRT-1, PGC-1α, TFAM and Nrf2 expression, enhancement of Akt phosphorylation, elevation of FOXO3a deacetylation and lessening of striatal oxidative stress damage by lowering MDA concentrations as well as raising the levels of NQO1, TAC, SOD and GSH. These effects were further substantiated by improvements in muscle strength, locomotor coordination, cognitive performance, and neuronal integrity. In conclusion, bromelain could be a beneficial neuroprotective candidate against HD-like aberrations experimentally induced by 3-NP.

Central nervous system (CNS) diseases occur in the context of inflammation and demyelination. Demyelination is a pathological process in which myelin sheaths are lost from around axons, while remyelination is the restoration of myelin sheaths by oligodendrocytes. TGFβ is an anti-inflammatory cytokine that participates in the immune response, favors the oligodendroglial cell fate of adult neural precursor cells, and induces oligodendrocyte precursor cell (OPC) differentiation and maturation. To evaluate TGFβ participation in remyelination, in vivo experiments were performed in control and cuprizone (CPZ)-treated rats intracranially injected (IC) with either TGFβ or vehicle and analyzed after 7 days, or intraperitoneally injected (IP) TGFβ before toxin removal from the diet. After IC, TGFβ induced an increase in phagocytic microglia in control and demyelinated animals and in MAG+ cells in demyelinated animals. Likewise, IP TGF in CPZ-demyelinated animals showed lesser microgliosis and higher IL10 transcript levels in TGFβ-treated demyelinated animals. These anti-inflammatory effects coincided with an increase in myelin-associated glycoprotein (MAG)+ cells and MAG transcript expression. On the other hand, in vitro experiments were performed on primary microglial cultures and OPCs. In microglial cultures, TGFβ treatment reduced iNOS, IL1β, TNFα, and IL10 transcript levels and increased those of Arg1. TGFβ also reduced microglial phagocytic capacity after LPS exposure. In OPC cultures, TGFβ produced no changes in platelet derived growth factor receptor alpha (PDGFRα)+ and myelin basic protein (MBP)+ cells but promoted morphological complexity in OPCs and mature oligodendrocytes. These results suggest that TGFβ might have a positive action in remyelination by modulating microglial reactivity and promoting OPC maturation.

Prolonged use of conventional chemotherapy has led to adverse side effects and drug resistance, leading to therapeutic failure in colon cancer patients. An alternative therapy involving natural products with least toxicity can show promising results in cancer therapeutics. A bioactive alkaloid Piperlongumine (PIP), found in our culinary spice, exhibits potential pharmacological relevance, especially regarding its anticancer effects. This study is an original research work examining the anticancer efficacy of PIP and its related molecular mechanisms in human colon cancer cells. The results revealed that PIP induces selective cytotoxicity against colon cancer cells while inhibiting proliferation, migration and invasion. PIP also builds up reactive oxygen species (ROS) that increase the oxidative stress of the cells leading to disruption of the mitochondrial membrane and loss of mitochondrial membrane potential. In addition, PIP induces cell cycle arrest at the G₂/M phase of the cell cycle and impedes the epithelial-to-mesenchymal transition in colon cancer cells. Further, PIP-mediated elevated intracellular ROS induces DNA damage and activates the caspase-dependent apoptotic pathway in colon cancer cells. PIP also reports an anti-tumorigenic effect on the multicellular tumor spheroids of colon cancer cells. Collectively, these findings validate that PIP shows promising anticancer potential towards colon cancer cells and is a potential candidate for use in combination with existing anticancer drugs.

Nootkatone, a valuable sesquiterpene with broad bioactivities and application potential, faces yield limitations in microbial synthesis due to metabolic and enzymatic inefficiencies. In this study, we present an advanced strategy combining metabolic engineering and deep learning-guided enzyme design to optimize nootkatone production in Pichia pastoris. By systematically modifying the mevalonate pathway, optimizing cofactor supply, and minimizing competing metabolic pathways, a robust yeast strain producing 702.15 mg/L valencene was developed. To facilitate the efficient conversion of valencene to nootkatone, we applied ancestral sequence reconstruction (ASR) to identify hotspot amino acid residues, guiding the design of a variant library. The deep learning model DLKcat was then used to conduct virtual saturation mutagenesis screening on library sites, predicting their enzyme turnover number (k_cat). The engineered cytochrome P450 (HPO) variant H54A exhibited the highest activity, with catalytic performance 2.3 times that of the initial. Furthermore, the implementation of intermittent feeding fermentation significantly elevated the final nootkatone yield to 3365.36 mg/L, the highest reported to date. This study provided a green platform for an alternative sustainable access of high-value nootkatone, and exemplifies the potential of machine learning in optimizing metabolic pathway enzymes for efficient biosynthesis of other bioactive terpenoids in microbial systems.