Nanoscopic evaluation on mitochondrial ultrastructures by regulating reactive oxygen species productivity within terpyridyl Zn(II) complexes with different alkyl chain lengths.

Mitochondria targeting complexes are widely utilized as photosensitizers in photodynamic therapy. However, the mechanisms by which they regulate reactive oxygen species (ROS) production at the molecular level and their influence on intracellular mitochondrial signaling and ultrastructures remain rarely studied. Herein, we present two terpyridyl Zn(II) complexes with different side alkyl chain lengths (Zn-2C and Zn-6C) that lead to low and high ROS productivities in vitro, respectively. Both complexes could enter live cells effectively with minimal dark toxicity and accumulate preferably in the mitochondria. We also demonstrated that Zn-6C, with more efficient ROS productivity, could significantly downregulate the caspase signaling pathway but showed no evident influence on mitochondrial membrane proteins. We also highlighted and compared the mitochondrial ultrastructural variations during such a process by stimulated emission depletion (STED) super-resolution nanoscopy.

Preparation and application of pH-responsive drug delivery systems.

Microenvironment-responsive drug delivery systems (DDSs) can achieve targeted drug delivery, reduce drug side effects and improve drug efficacies. Among them, pH-responsive DDSs have gained popularity since the pH in the diseased tissues such as cancer, bacterial infection and inflammation differs from a physiological pH of 7.4 and this difference could be harnessed for DDSs to release encapsulated drugs specifically to these diseased tissues. A variety of synthetic approaches have been developed to prepare pH-sensitive DDSs, including introduction of a variety of pH-sensitive chemical bonds or protonated/deprotonated chemical groups. A myriad of nano DDSs have been explored to be pH-responsive, including liposomes, micelles, hydrogels, dendritic macromolecules and organic-inorganic hybrid nanoparticles, and micron level microspheres. The prodrugs from drug-loaded pH-sensitive nano DDSs have been applied in research on anticancer therapy and diagnosis of cancer, inflammation, antibacterial infection, and neurological diseases. We have systematically summarized synthesis strategies of pH-stimulating DDSs, illustrated commonly used and recently developed nanocarriers for these DDSs and covered their potential in different biomedical applications, which may spark new ideas for the development and application of pH-sensitive nano DDSs.

Immunogenic Cell Death Activates the Tumor Immune Microenvironment to Boost the Immunotherapy Efficiency.

Tumor immunotherapy is only effective in a fraction of patients due to a low response rate and severe side effects, and these challenges of immunotherapy in clinics can be addressed through induction of immunogenic cell death (ICD). ICD is elicited from many antitumor therapies to release danger associated molecular patterns (DAMPs) and tumor-associated antigens to facilitate maturation of dendritic cells (DCs) and infiltration of cytotoxic T lymphocytes (CTLs). The process can reverse the tumor immunosuppressive microenvironment to improve the sensitivity of immunotherapy. Nanostructure-based drug delivery systems (NDDSs) are explored to induce ICD by incorporating therapeutic molecules for chemotherapy, photosensitizers (PSs) for photodynamic therapy (PDT), photothermal conversion agents for photothermal therapy (PTT), and radiosensitizers for radiotherapy (RT). These NDDSs can release loaded agents at a right dose in the right place at the right time, resulting in greater effectiveness and lower toxicity. Immunotherapeutic agents can also be combined with these NDDSs to achieve the synergic antitumor effect in a multi-modality therapeutic approach. In this review, NDDSs are harnessed to load multiple agents to induce ICD by chemotherapy, PDT, PTT, and RT in combination of immunotherapy to promote the therapeutic effect and reduce side effects associated with cancer treatment.

Cortical thickness abnormalities in patients with bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: An increasing number of neuroimaging studies report alterations of cortical thickness (CT) related to the neuropathology of bipolar disorder (BD). We provide here a whole-brain vertex-wise meta-analysis, which may help improve the spatial precision of these identifications. METHODS: A comprehensive meta-analysis was performed to investigate the differences in CT between patients with BD and healthy controls (HCs) by using a newly developed mask for CT analysis in seed-based d mapping (SDM) meta-analytic software. We used meta-regression to explore the effects of demographics and clinical characteristics on CT. This meta-review was conducted in accordance with PRISMA guideline. RESULTS: We identified 21 studies meeting criteria for the systematic review, of which 11 were eligible for meta-analysis. The meta-analysis comprising 649 BD patients and 818 HCs showed significant cortical thinning in the left insula extending to left Rolandic operculum and Heschl gyrus, the orbital part of left inferior frontal gyrus (IFG), the medial part of left superior frontal gyrus (SFG) as well as bilateral anterior cingulate cortex (ACC) in BD. In meta-regression analyses, mean patient age was negatively correlated with reduced CT in the left insula. LIMITATIONS: All enrolled studies were cross-sectional; we could not explore the potential effects of medication and mood states due to the limited data. CONCLUSIONS: Our results suggest that BD patients have significantly thinner frontoinsular cortex than HCs, and the results may be helpful in revealing specific neuroimaging biomarkers of BD patients.

Dysconnectivity of the amygdala and dorsal anterior cingulate cortex in drug-naive post-traumatic stress disorder.

Convergent studies have highlighted the amygdala-based and dorsal anterior cingulate cortex (dACC)-based circuit or network dysfunction in post-traumatic stress disorder (PTSD). However, previous studies are often complicated by various traumatic types, psychiatric comorbidities, chronic illness duration, and medication effect on brain function. Besides, little is known whether the functional integration with amygdala-dACC interaction disrupted or not in PTSD. Here, we investigated effective connectivity (EC) between the amygdala-dACC and rest of the cortex by applying psycho-physiological interaction (PPI) approach to resting-state functional magnetic resonance imaging data of 63 drug-naive PTSD patients and 74 matched trauma-exposed non-PTSD controls. Pearson correlation analysis was performed between EC values extracted from regions with between-group difference and clinical profiles in PTSD patients. We observed distinct amygdala-dACC interaction pattern between PTSD group and the control group, which is composed primarily by positive EC in the former and negative in the latter. In addition, compared with non-PTSD controls, PTSD patients showed increased EC between amygdala-dACC and the prefrontal cortex, left inferior parietal lobule, and bilateral ventral occipital cortex, and decreased EC between amygdala-dACC and the left fusiform gyrus. The EC increase between amygdala-dACC and the right middle frontal gyrus was negatively correlated with the clinician-administered PTSD scale scores in PTSD patients. Aberrent communication between amgydala-dACC and brain regions involved in central executive network and visual systems might be associated with the pathophysiology of PTSD. Further, these findings suggested that dysconnectivity of the amygdala and dACC could be adapted as a relatively early course diagnostic biomarker of PTSD.

Cortical thickness abnormalities in patients with first episode psychosis: a meta-analysis of psychoradiologic studies and replication in an independent sample.

BACKGROUND: Abnormalities of cortical thickness (CTh) in patients with their first episode psychosis (FEP) have been frequently reported, but findings are inconsistent. OBJECTIVE: To define the most consistent CTh changes in patients with FEP by meta-analysis of published whole-brain studies. METHODS: The meta-analysis used seed-based d mapping (SDM) software to obtain the most prominent regional CTh changes in FEP, and meta-regression analyses to explore the effects of demographics and clinical characteristics. The meta-analysis results were verified in an independent sample of 142 FEP patients and 142 age- and sex-matched healthy controls (HCs), using both a vertex-wise and a region of interest analysis, with multiple comparisons correction. RESULTS: The meta-analysis identified lower CTh in the right middle temporal cortex (MTC) extending to superior temporal cortex (STC), insula, and anterior cingulate cortex (ACC) in FEP compared with HCs. No significant correlations were identified between CTh alterations and demographic or clinical variables. These results were replicated in the independent dataset analysis. CONCLUSION: This study identifies a robust pattern of cortical abnormalities in FEP and extends understanding of gray matter abnormalities and pathological mechanisms in FEP.