Mitochondria are essential organelles that perform important roles in cell biologies such as ATP synthesis, metabolic regulation, immunomodulatory, and apoptosis. Parkinson's disease (PD) is connected with mitochondrial neuronal damage related to mitochondrial unfolded protein response (mtUPR). Rosmarinic acid (RA) is a naturally occurring hydroxylated polyphenolic chemical found in the Boraginaceae and the Labiatae subfamily Nepetoideae. This study looked into RA's protective effect against mitochondrial loss in the substantia nigra (SN) caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the underlying mechanism associated with the mtUPR. Pretreatment with RA reduced motor impairments and dopaminergic neuronal degeneration in the SN of a mouse model injected with MPTP. Pretreatment of SH-SY5Y cells from cell viability loss, morphological damage, and oxidative stress. Furthermore, RA pre-injection suppressed MPTP-induced mtUPR, lowered the expression of HSPA9, HSPE1, CLPP, LONP1, and SIRT 4, and protected the MPTP-mice and SH-SY5Y cells from mitochondrial failure. These findings imply that RA can prevent Parkinson's disease by preventing mitochondrial damage in dopaminergic neurons in Parkinson's disease via alleviating mitochondrial unfolded protein response.

Acute myeloid leukemia (AML) is a common type of hematological malignancy that can progress rapidly. AML has a poor prognosis and a high incidence of relapse due to therapeutic resistance. Azelaic acid (AZA), a small molecular compound is known to exhibit antitumor effect on various tumor cells. This study aimed to evaluate the antiproliferative and immunoregulatory effects of AZA against AMLviathe activation of the notch signaling pathway. We found that AZA can inhibit the proliferation of AML cells. In addition, laser confocal microscopy showed AZA-treated AML cells began to swelling and undergo cytoplasmic vacuolization. Importantly, AZA promoted the proliferation of NK and T cells and increased the secretion of TNF-αand IFN-γ. AZA also increased the expression levels of CD107a and TRAIL in NK cells, and CD25 and CD69 in T cells to influence their activation and cytotoxic ability. AZA-treated NK cells can kill AML cells more efficiently at the single-cell level as observed under the microfluidic chips. Further mechanistic analysis using protein mass spectrometry analysis and Notch signaling reporter assay demonstrated that Notch1and Notch2 were up-regulated and the Notch signaling pathway was activated. Moreover, combining AZA with the Notch inhibitor, RO4929097, decreased the expression of Notch1and Notch2, and downstream HES1 and HEY1, which rendered AML cells insensitive to AZA-induced apoptosis and alleviated AZA-mediated cytotoxicity in AML. In vivo, AZA relieved the leukemic spleen infiltration and extended the survival. The percentage of CD3-CD56+NK cells and CD4+CD8+T cells as well as the secretion of cytotoxic cytokines was increased after the treatment of AZA. The overall findings reveal that AZA is a potential Notch agonist against AML in activating the Notch signaling pathway.

Introduction: The majority of individuals diagnosed with advanced colorectal cancer (CRC) will ultimately acquire resistance to 5-FU treatment. An increasing amount of evidence indicates that aerobic glycolysis performs a significant function in the progression and resistance of CRC. Nevertheless, the fundamental mechanisms remain to be fully understood. Methods: Proteomic analysis of 5-FU resistant CRC cells was implemented to identify and determine potential difference expression protein. Results: These proteins may exhibit resistance mechanisms that are potentially linked to the process of aerobic glycolysis. Herein, we found that nucleolar protein 58 (NOP58) has been overexpressed within two 5-FU resistant CRC cells, 116-5FuR and Lovo-5FuR. Meanwhile, the glycolysis rate of drug-resistant cancer cells has increased. NOP58 knockdown decreased glycolysis and enhanced the sensitivity of 116-5FuR and Lovo-5FuR cells to 5FU. Conclusion: The proteomic analysis of chemoresistance identifies a new target involved in the cellular adaption to 5-FU and therefore highlights a possible new therapeutic strategy to overcome this resistance.

The p53 gene has the highest mutation frequency in tumors, and its inactivation can lead to malignant transformation, such as cell cycle arrest and apoptotic inhibition. Persistent high-risk human papillomavirus (HR-HPV) infection is the leading cause of cervical cancer. P53 was inactivated by HPV oncoprotein E6, promoting abnormal cell proliferation and carcinogenesis. To study the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer by restoring p53 expression and inactivating HPV oncoprotein, and to verify the effectiveness of nano drugs based on nucleic acid delivery in cancer treatment, we developed poly (beta-amino ester)537, to form biocompatible and degradable nanoparticles with plasmids (expressing p53 and targeting E7). In vitro and in vivo experiments show that nanoparticles have low toxicity and high transfection efficiency. Nanoparticles inhibited the growth of xenograft tumors and successfully reversed HPV transgenic mice's cervical intraepithelial neoplasia. Our work suggests that the restoration of p53 expression and the inactivation of HPV16 E7 are essential for blocking the development of cervical cancer. This study provides new insights into the precise treatment of HPV-related cervical lesions.