Ping Shi

Disrupted protein homeostasis is a shared characteristic in ageing, obesity‐induced lipotoxicity and neurodegenerative diseases. The accumulation of misfolded or unfolded proteins within the cell triggers endoplasmic reticulum (ER) stress. In response, the unfolded protein response (UPR) and ER‐associated degradation (ERAD) pathways are activated. A key mechanism to alleviate intracellular protein aggregation involves ubiquitination of substrates and their subsequent degradation by the proteasome. The ubiquitin–proteasome system (UPS) is indispensable for cellular protein quality control, and its dysfunction contributes to various proteopathies. However, the crosstalk between the proteasome subunit Rpt3 and the Ire1‐Hac1 pathway appears to be rarely reported. In Saccharomyces cerevisiae , growth curve and spotting assay demonstrated that overexpression of Rpt3 reduced the sensitivity of ire1 Δ or hac1 Δ to ER stressors. The growth‐promoting effect of Rpt3 is not a common feature of the BASE subunits, as overexpression of Rpt6 failed to rescue the growth inhibition. Deletion of hac1 resulted in stoichiometric imbalance among proteasomal subunits, which may be key for Rpt3‐mediated rescue of hac1 Δ growth, as deletion of the proteasome transcriptional factor Rpn4 impedes Rpt3 from restoring the growth of hac1 Δ from ER stress. Overexpression of Rpt3 enhanced proteasome assembly and activity, reducing intracellular ubiquitin levels in hac1 Δ. Moreover, Rpt3 increased the protein level of Hac1, and its alleviation of proteotoxic stress was dependent on the collaboration of ubiquitinating enzymes and chaperones. Western blot and proteasome activity assay in human cells confirmed the cross‐species conservation of Rpt3 function. These results highlight a dual role for Rpt3 in proteostasis: beyond enhancing proteasomal activity, Rpt3 upregulates Hac1 protein abundance, thereby ensuring proteostasis maintenance.

This work presents a LQM core that, for the first time, allows in situ ˙OH-specific photogeneration from H ₂ O. This breakthrough in O ₂ -independent photocatalytic therapy is enabled via a “H ₂ O–O ₂ –˙OH” oxygen-chain cascade pathway.

Due to its hydrophilicity and biocompatibility, PEGylated graphene oxide (GO-PEG) has been reported as a potential nanocarrier for anticancer therapeutic agents. Alpha lipoic acid (α-LA), a cofactor in multienzyme complexes, plays a central role in mitochondrial energy metabolism. In this study, we first observed that GO-PEG could rapidly enter rat cardiomyocyte H9C2 cells and colocalize with mitochondria by confocal laser microscopy using Rhodamine B (RhB) as a probe. Next, α-LA was loaded onto GO-PEG-RhB through π-π stacking and hydrophobic interactions, forming a GO-PEG-RhB/α-LA complex with a 21.4% loading rate and 42.8% encapsulation efficiency. In vitro assays showed that GO-PEG-RhB/α-LA significantly mitigated mitochondrial dysfunction compared with free α-LA in a hypoxia-induced H9C2 cell model treated with CoCl₂ via the regulation of mitochondrial dynamics and biogenesis signaling pathways. GO-PEG-RhB/α-LA clearly showed better mitochondrial targeting and α-LA release in mitochondria than free α-LA. After oral administration in a hypoxia-induced mouse model, GO-PEG-RhB/α-LA again showed a better recovery effect on hypoxia-induced mitochondrial dysfunction than free α-LA. Taken together, our data demonstrate the feasibility of GO-PEG as a nanocarrier for mitochondrial-targeted drugs. This work broadens the application of graphene-based nanocarriers in biomedical fields.

Aim: The objective of this study is to ascertain the antimicrobial and anticancer properties of dry Morinda citrifolia L. (noni) pulp hydroalcoholic extracts. Methods: In this study, dry noni samples were immersed in hydro-alcoholic solvents, ethanol (EtOH) and methanol (MeOH). Using the intelligent-flash extractor (KBE-I5) and freeze-vacuum dryer, noni ethanol (NE) and noni methanol (NM) extracts were obtained for antimicrobial testing against bacterial and fungal strains via disc diffusion assay. Cell viability was assessed using the cell counting kit-8 (CCK-8) assay, acridine orange (AO) staining, and western blotting to evaluate anticancer effects on human cancer cells. Novel phytoconstituents were identified using dual-mode ultra-performance liquid chromatography quadrupole exactive orbitrap-tandem mass spectrometer (UPLC-Q-exactive orbitrap-MS/MS) analysis. Results: Extraction yielded 16.8% for NE and 25.8% for NM. NE minimum inhibitory concentrations (MICs) against Escherichia coli (EC), Saccharomyces cerevisiae (SC), Staphylococcus aureus (SA), and Streptococcus thermophilus (ST) being 177, 52, 388, and 283 mg/mL. NM MICs values were 105, 47, 312, and 135 mg/mL, respectively. Anticancer half inhibitory concentrations (IC50s) for NE against human colon adenocarcinoma cell (HT-29) and human bladder cancer cell lines (UMUC-3) were 758 and 899 µg/mL. For NM, IC50s were 1,231 (HT-29) and 1,173 (UMUC-3) µg/mL. Cell death indicators include organelle deformities, AO fluorescence, and autophagy protein expression. In dual ion-scan mode UPLC analysis, 17 distinct phytoconstituents were identified, including 2-Hydroxycinnamic acid, 4-Hydroxycinnamic acid, and riboflavin, known for treating cancer, metabolic dysfunctions, and COVID-19. The 14 constituents were discovered in noni fruit for the first time. Conclusions: Noni fruit extracts show antimicrobial/anticancer activity and therapeutic potential, establishing noni fruit as a promising food and medicinal source based on composition.

Alzheimer's disease (AD), the most common form of dementia, has gotten considerable attention. Previous studies have demonstrated that clioquinol (CQ) as a metal chelator is a potential drug for the treatment of AD. However, the mode of action of CQ in AD is still unclear. In our study, the antioxidant effects of CQ on yeast cells expressing Aβ42 were investigated. We found that CQ could reduce Aβ42 toxicity by alleviating reactive oxygen species (ROS) generation and lipid peroxidation level in yeast cells. These alterations were mainly attributable to the increased reduced glutathione (GSH) content and independent of activities of superoxide dismutase (SOD) and/or catalase (CAT). CQ could affect antioxidant enzyme activity by altering the transcription level of related genes. Interestingly, it was noted for the first time that CQ could combine with antioxidant enzymes to reduce their enzymatic activities by molecular docking and circular dichroism spectroscopy. In addition, CQ restored Aβ42‐mediated disruption of GSH homeostasis via regulating YAP1 expression to protect cells against oxidative stress. Our findings not only improve the current understanding of the mechanism of CQ as a potential drug for AD treatment but also provide ideas for subsequent drug research and development.