Fe-BPsalan Complex-Catalyzed Asymmetric [4 + 2] Cycloaddition of Cyclopentadiene with α,ß-Unsaturated Heterocycles.

An efficient iron-catalyzed asymmetric [4 + 2] cycloaddition of cyclopentadiene with α,ß-unsaturated acyl imidazoles or 2-cinnamoylisoindoline-1,3-dione derivatives was developed to afford the addition products in high yield and selectivity. Interestingly, the absolute structures of the addition products were controlled by the auxiliaries via different coordination modes with the same type of catalyst.

Sirtuin 3 is required for the protective effect of Resveratrol on Manganese-induced disruption of mitochondrial biogenesis in primary cultured neurons.

Chronic manganese (Mn) exposure can disturb mitochondrial homeostasis leading to mitochondrial dysfunction, which is involved in Mn-induced neurodegenerative diseases. Resveratrol (RSV), as a promoter of mitochondrial biogenesis, plays a significant role against mitochondrial dysfunction. However, whether RSV can relieve Mn-induced neuronal injury and mitochondrial dysfunction remains unknown. Sirtuin 3 (SIRT3), a main mitochondrial sirtuin, is an important regulator of mitochondria to maintain mitochondrial homeostasis. Therefore, this study investigated whether SIRT3 was required for RSV alleviating Mn-induced mitochondrial dysfunction in primary cultured neurons from C57BL/6 mice. Here, we showed that Mn (100 and 200 µM) exposure for 24 hr caused significant neuronal damage and mitochondrial dysfunction through increasing mitochondrial ROS, reducing mitochondrial membrane potential and adenosine triphosphate level, and leading to mitochondrial network fragmentation, which could be ameliorated by RSV pretreatment in primary cultured neurons. Additionally, our results also indicated that RSV could activate the SIRT1/PGC-1α signaling pathway and alleviate Mn-induced disruption of mitochondrial biogenesis by increasing SIRT1 expression and activity, enhancing deacetylation of PGC-1α. Furthermore, SIRT3 over-expression increased deacetylation of mitochondrial transcription factor A and mitochondrial DNA (mtDNA) copy number. Oppositely, silencing SIRT3 increased acetylation of mitochondrial transcription factor A and decreased mtDNA copy number. Our results showed SIRT3 was required for the protective effect of RSV in mitochondrial biogenesis. In conclusion, our findings demonstrated that RSV could ameliorate Mn-induced neuronal injury and mitochondrial dysfunction in primary cultured neurons through activating the SIRT1/ PGC-1α signaling pathway, and that SIRT3 is required for promoting mitochondrial biogenesis and attenuating Mn-induced mitochondrial dysfunction.

Cationic Polymeric Nanoparticle Delivering CCR2 siRNA to Inflammatory Monocytes for Tumor Microenvironment Modification and Cancer Therapy.

Accumulating evidence has confirmed that malignant tumors have a complex microenvironment, which consists of a heterogeneous collection of tumor cells and other cell subsets (including the full gamut of immune cells). Tumor-associated macrophages (TAMs), derived from circulating Ly6Chi monocytes, constitute the most substantial fraction of tumor-infiltrating immune cells in nearly all cancer types and contribute to tumor progression, vascularization, metastasis, immunosuppression, and therapeutic resistance. Interrupting monocyte recruitment to tumor tissues by disturbing pivotal signaling pathways (such as CCL2-CCR2) is viewed as one of the most promising avenues for tumor microenvironment manipulation and cancer therapy. One critical issue for monocyte-based therapy is to deliver therapeutic agents into monocytes efficiently. In the present study, we systematically investigated the relationship between the surface potential and the biodistribution of polymeric nanoparticles in monocytes in vivo, aiming to screen and identify an appropriate delivery system for monocyte targeting, and we found that cationic nanoparticles have a higher propensity to accumulate in monocytes compared with their neutral counterparts. We further demonstrated that siCCR2-encapsulated cationic nanoparticle (CNP/siCCR2) could modify immunosuppressive tumor microenvironment more efficiently and exhibit superior antitumor effect in an orthotopic murine breast cancer model.

Spatial Targeting of Tumor-Associated Macrophages and Tumor Cells with a pH-Sensitive Cluster Nanocarrier for Cancer Chemoimmunotherapy.

Chemoimmunotherapy, which combines chemotherapeutics with immune-modulating agents, represents an appealing approach for improving cancer therapy. To optimize its therapeutic efficacy, differentially delivering multiple therapeutic drugs to target cells is desirable. Here we developed an immunostimulatory nanocarrier (denoted as BLZ-945SCNs/Pt) that could spatially target tumor-associated macrophages (TAMs) and tumor cells for cancer chemoimmunotherapy. BLZ-945SCNs/Pt undergo supersensitive structure collapse in the prevascular regions of tumor tissues and enable the simultaneous release of platinum (Pt)-prodrug conjugated small particles and BLZ-945, a small molecule inhibitor of colony stimulating factor 1 receptor (CSF-1R) of TAMs. The released BLZ-945 can be preferentially taken up by TAMs to cause TAMs depletion from tumor tissues, while the small particles carrying Pt-prodrug enable deep tumor penetration as well as intracellularly specific drug release to kill more cancer cells. Our studies demonstrate that BLZ-945SCNs/Pt outperform their monotherapy counterparts in multiple tumor models. The underlying mechanism studies suggest that the designer pH-sensitive codelivery nanocarrier not only induces apoptosis of tumor cells but also modulates the tumor immune environment to eventually augment the antitumor effect of CD8+ cytotoxic T cells through TAMs depletion.

Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy.

Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an 'adaptor' while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.

Resveratrol ameliorates disorders of mitochondrial biogenesis and mitophagy in rats continuously exposed to benzo(a)pyrene from embryonic development through adolescence.

Exposure to benzo(a)pyrene (BaP) is associated with poor neurodevelopment in children and memory impairment in adults. Previous research has demonstrated that mitochondrial damage plays an important role in BaP-induced neurotoxicity. Of interest, increasing evidence has suggested that resveratrol (RSV) can alleviate nerve cell damage, however the exact mechanisms of biological activity in mitochondria are not fully understood. In the current study, Wistar rats were exposed to BaP (1, 2, 4 mg/kg) and/or RSV (15, 30 mg/kg) during embryonic development and adolescence, and learning and memory ability, mitochondrial damage, and the expression of proteins associated with mitochondrial biogenesis and mitophagy were evaluated. These studies indicated that 2 and 4 mg/kg BaP could induce disorders of mitochondrial biogenesis and mitophagy, which leads to abnormal nerve cell development. However, pretreatment with 30 mg/kg RSV alleviated cell damage and the disorder of mitochondrial biogenesis by activating the AMPK/PGC-1α signaling pathway and promoting mitophagy. These findings suggested that RSV had utility in promoting mitochondrial homeostasis against BaP-induced nerve cell damage in the hippocampus of rats.

Resveratrol prevents benzo(a)pyrene-induced disruption of mitochondrial homeostasis via the AMPK signaling pathway in primary cultured neurons.

Exposure to benzo(a)pyrene (BaP) has been shown to cause mitochondrial dysfunction and injury to neural cells. Resveratrol (RSV) has been studied as an antioxidant, anti-inflammatory, anti-apoptotic, and anticancer agent and can modulate mitochondrial function in vitro and in vivo. However, the molecular mechanisms underlying RSV's protection against mitochondrial dysfunction have not been fully elucidated. To investigate whether RSV can effectively prevent BaP-induced mitochondrial dysfunction, we tested the effects of RSV in primary neuronal models. Our results confirmed that neurons exhibited mitochondrial dysfunction and apoptosis in the mitochondrial pathway after BaP-treatment, and that pretreatment with RSV could reduce that dysfunction. Further, our results indicated that RSV pretreatment enhanced mitochondrial biogenesis via the AMPK/PGC-1α pathway and activated mitophagy via the PINK1-Parkin and AMPK/ULK1 pathways, thereby coordinating mitochondrial homeostasis. We also found that RSV could alleviate mitochondrial network fragmentation caused by BaP. This work provided insights into the role of RSV in preventing BaP-induced primary neuronal apoptosis in the mitochondrial pathway, mainly via regulation of mitochondrial biogenesis and mitophagy through AMPK pathway, thus maintaining the integrity of the mitochondrial network.

Promoting tumor penetration of nanoparticles for cancer stem cell therapy by TGF-ß signaling pathway inhibition.

Cancer stem cells (CSCs), which hold a high capacity for self-renewal, play a central role in the development, metastasis, and recurrence of various malignancies. CSCs must be eradicated to cure instances of cancer; however, because they can reside far from tumor vessels, they are not easily targeted by drug agents carried by nanoparticle-based drug delivery systems. We herein demonstrate that promoting tumor penetration of nanoparticles by transforming growth factor ß (TGF-ß) signaling pathway inhibition facilitates CSC therapy. In our study, we observed that although nanoparticles carrying siRNA targeting the oncogene polo-like kinase 1 (Plk1) efficiently killed breast CSCs derived from MDA-MB-231 cells in vitro, this intervention enriched CSCs in the residual tumor tissue following systemic treatment. However, inhibition of the TGF-ß signaling pathway with LY364947, an inhibitor of TGF-ß type I receptor, promoted the penetration of nanoparticles in tumor tissue, significantly ameliorating the intratumoral distribution of nanoparticles in MDA-MB-231 xenografts and further leading to enhanced internalization of nanoparticles by CSCs. As a result, synergistic treatment with a nanoparticle drug delivery system and LY364947 inhibited tumor growth and reduced the proportion of CSCs in vivo. This study suggests that enhanced tumor penetration of drug-carrying nanoparticles can enhance CSCs clearance in vivo and consequently provide superior anti-tumor effects.