Common neural deficits across reward functions in major depression: a meta-analysis of fMRI studies.

Major depressive disorder (MDD) is characterized by deficient reward functions in the brain. However, existing findings on functional alterations during reward anticipation, reward processing, and learning among MDD patients are inconsistent, and it was unclear whether a common reward system implicated in multiple reward functions is altered in MDD. Here we meta-analyzed 18 past studies that compared brain reward functions between adult MDD patients (N = 477, mean age = 26.50 years, female = 59.40%) and healthy controls (N = 506, mean age = 28.11 years, females = 55.58%), and particularly examined group differences across multiple reward functions. Jack-knife sensitivity and subgroup meta-analyses were conducted to test robustness of findings across patient comorbidity, task paradigm, and reward nature. Meta-regression analyses assessed the moderating effect of patient symptom severity and anhedonia scores. We found during reward anticipation, MDD patients showed lower activities in the lateral prefrontal-thalamus circuitry. During reward processing, patients displayed reduced activities in the right striatum and prefrontal cortex, but increased activities in the left temporal cortex. During reward learning, patients showed reduced activity in the lateral prefrontal-thalamic-striatal circuitry and the right parahippocampal-occipital circuitry but higher activities in bilateral cerebellum and the left visual cortex. MDD patients showed decreased activity in the right thalamus during both reward anticipation and learning, and in the right caudate during both reward processing and learning. Larger functional changes in MDD were observed among patients with more severe symptoms and higher anhedonia levels. The thalamic-striatal circuitry functional alterations could be the key neural mechanism underlying MDD patients overarching reward function deficiencies.

Selective stabilization of multiple promoter G-quadruplex DNA by using 2-phenyl-1H-imidazole-based tanshinone IIA derivatives and their potential suppressing function in the metastatic breast cancer.

The G-quadruplex (G4) DNA, which has been developed as a potential anticancer target in drug screening and design, plays a crucial role in the oncogene transcription and translation. Tanshinone IIA derivatives with a planar heterocycle structure may function as G4 stabilizers. We present an innovative case of imidazole-based tanshinone IIA derivatives (1-8) especially compound 4 that improve the selectivity and the binding affinity with G4 DNA and enhance the target tumor inhibition. Cellular and in vivo experiments indicate that the tanshinone IIA derivative 4 inhibits the growth, metastasis, and angiogenesis of triple-negative breast cancer cells possibly through the stabilization of multiple G4 DNAs (e.g., c-myc, K-ras, and VEGF) to induce DNA damage. Further investigation of the intermolecular interaction and the molecular docking indicates that tanshinone IIA derivatives have better selective binding capability to various G4 DNAs than to double-stranded DNA. These findings provide guidance in modifying the molecular structures of tanshinone IIA derivatives and reveal their potential to function as specific G4 stabilizers.

Polypyridyl Ruthenium(II) complex-induced mitochondrial membrane potential dissipation activates DNA damage-mediated apoptosis to inhibit liver cancer.

In this study, four polypyridyl ruthenium(II) complexes, namely, [(L1)2RuL2]·2ClO4 (1: L1 = phen, L2 = o-TFPIP, 2: L1 = bpy, L2 = o-TFPIP, 3: L1 = phen, L2 = o-MOPIP, and 4: L1 = bpy, L2 = o-MOPIP), were synthesized with different phenanthroimidazole derivatives, and their inhibitory activities were tested against various cancer cells. Among the Ru(II) complexes, 1 excellently inhibited the proliferation and induced the apoptosis of HepG2 cell. Importantly, 1 was mainly distributed in the cell mitochondria and markedly induced the dissipation of mitochondrial membrane potential, possibly attributing to DNA damage induced by the Ru(II) complexes. Synthetic Ru(II) complexes can suppress the growth of tumor cells in zebrafish xenograft model with low toxicity at effective concentrations. These results inspired us to further develop polypyridyl ruthenium(II) complexes as potential potent inhibitors against liver cancer.

Nucleus-enriched Ruthenium Polypyridine Complex Acts as a Potent Inhibitor to Suppress Triple-negative Breast Cancer Metastasis In vivo.

Polypyridine Ru(II) complexes have long been deemed to excellent antitumor agents that inhibit the proliferation of breast cancer cells. Nevertheless, their effects on the metastatic potency of breast cancer cells need further research. Herein, a class of polypyridine Ru(II) complexes coordinated with phenazine derivates (DPPZ) ([Ru(bpy)2(DPPZ-R)](ClO4)2, Ru(bpy) 2 DPPZ: R = -H, Ru(bpy) 2 BrDPPZ: R = -Br, Ru(bpy) 2 MDPPZ: R = -CH3, Ru(bpy)2BnDPPZ: R = -acene, Ru(bpy) 2 BEDPPZ: R = -C ≡ C(C6H5)) was synthesized by introducing different substituent groups to regulate the electron cloud density and planarity of the main ligands. Results indicated that this class of DPPZ-based Ru(II) complexes exhibited promising inhibitory effect against MDA-MB-231 triple-negative breast cancer cells, especially for Ru(bpy) 2 BEDPPZ, which is comparable with that of cisplatin. In addition, Ru(bpy) 2 BEDPPZ effectively inhibited the migration and invasion of MDA-MB-231 cells in vitro and suppressed focal adhesion and stress fiber formation. Moreover, it effectively blocked MDA-MB-231 cell metastasis in blood vessels and restrained angiogenesis formation in a zebrafish xenograft breast cancer model. Further studies showed that the mechanisms may involve DNA damage-mediated apoptosis probably due to Ru(bpy) 2 BEDPPZ, which was enriched in the cell nucleus and induced DNA damage. All these results suggested that the DPPZ-based Ru(II) complexes can act as potent anti-metastasis agents.

Tissue regeneration promotion effects of phenanthroimidazole derivatives through pro-inflammatory pathway activation.

A chemotherapeutic drug exerts favorable antitumor activity and simultaneously exhibits expectable inhibition on wound healing process. Phenanthroimidazole derivatives possess potent anticancer activity. However, only a few studies focused on the discovery of its potential effects on promoting tissue regeneration. In this study, four novel phenanthroimidazole derivatives were synthesized and characterized, and they exhibited evident inhibition on different tumor cells; compound 3 is the most active one. Moreover, 3 can promote wound healing of zebrafish in a dose-dependent manner. Further study demonstrated that 3 promoted the recruitment of inflammatory cells, formation of angiogenesis, and generation of reactive oxygen species and also influenced the motor behavior of zebrafish. Results indicated that 3 can accelerate the occurrence of pro-inflammation, angiogenesis, oxidative stress, and innervation, which play key roles in the facilitation of wound healing. Therefore, 3 can act as a bifunctional drug in inhibiting tumor and promoting tissue regeneration.