Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data ...analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.
Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and few molecularly targeted anticancer therapies have been developed to treat it. Thus, the identification of new therapeutic ...targets is urgent. Metabolic reprogramming is an important hallmark of cancer. However, how ubiquitin ligases are involved in the regulation of cancer metabolism remains poorly understood.
RT-PCR, western blot and IHC were used to determine ZFP91 expression. RNAi, cell proliferation, colony formation and transwell assays were used to determine the
functions of ZFP91. Mouse xenograft models were used to study the
effects of ZFP91. Co-IP together with mass spectrometry or western blot was utilized to investigate protein-protein interaction. Ubiquitination was analyzed using IP together with western blot. RNA splicing was assessed by using RT-PCR followed by restriction digestion. Lactate production and glucose uptake assays were used to analyze cancer metabolism.
We identified that an E3 ligase zinc finger protein 91 (ZFP91) suppressed HCC metabolic reprogramming, cell proliferation and metastasis
and
. Mechanistically,
promoted the Lys48-linked ubiquitination of the oncoprotein hnRNP A1 at lysine 8 and proteasomal degradation, thereby inhibiting hnRNP A1-dependent PKM splicing, subsequently resulting in higher PKM1 isoform formation and lower PKM2 isoform formation and suppressing HCC glucose metabolism reprogramming, cell proliferation and metastasis. Moreover, HCC patients with lower levels of ZFP91 have poorer prognoses, and ZFP91 is an independent prognostic factor for patients with HCC.
Our study identifies ZFP91 as a tumor suppressor of hepatocarcinogenesis and HCC metabolism reprogramming and proposes it as a novel prognostic biomarker and therapeutic target of HCC.
The potential of marine natural products as effective drugs for osteoporosis treatment is an understudied area. In this study, we investigated the ability of lead compounds from deep-sea-derived ...Penicillium solitum MCCC 3A00215 to promote bone formation in vitro and in vivo. We found that penicopeptide A (PPA) promoted osteoblast mineralization among bone marrow mesenchymal stem cells (BMSCs) in a concentration-dependent manner, and thus, we selected this natural peptide for further testing. Our further experiments showed that PPA significantly promoted the osteogenic differentiation of BMSCs while inhibiting their adipogenic differentiation and not affecting their chondrogenic differentiation. Mechanistic studies showed that PPA binds directly to the AKT and GSK-3β and activates phosphorylation of AKT and GSK-3β, resulting in the accumulation of β-catenin. We also evaluated the therapeutic potential of PPA in a female mouse model of ovariectomy-induced systemic bone loss. In this model, PPA treatment prevented decreases in bone volume and trabecular thickness. In conclusion, our in vitro and in vivo results demonstrated that PPA could promote osteoblast-related bone formation via the AKT, GSK-3β, and β-catenin signaling pathways, indicating the clinical potential of PPA as a candidate compound for osteoporosis prevention.
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The thermal insulating performance of plasma-sprayed thermal barrier coatings (PS-TBCs) depends dominantly on inter-splat pores, which would be inevitably healed during high temperature exposure. The ...sintering kinetics of TBCs appears to be highly stage-sensitive. However, the ultrafast sintering kinetics during the initial sintering stage is not yet well understood. In this study, the sintering behavior of PS-TBCs was investigated in a scale-progressive (from nano- to micro-scale) way. Moreover, a novel healing mechanism suitable for lamellar TBCs was proposed based on a combined-effect of material and pore structure. Regarding the changing behavior of material, nano-scale roughening can be found at the as-deposited smooth pore surface after thermal exposure. Regarding the 2D featured inter-splat pores, the roughening behavior facilitates multiple contacts between the counter-surfaces of inter-splat pores. As a result, micro-scale bridge-connection can be observed at the healed parts. This multiple contacts mechanism caused by scale-progressive healing behavior significantly accelerated the matter transfer, resulting in ultrafast sintering kinetics at the initial sintering stage.
Abstract Anhedonia is a hallmark symptom of major depressive disorder (MDD). Preliminary findings suggest that anhedonia is characterized by reduced reward anticipation and motivation of obtaining ...reward. However, relatively little is known about reward-based decision-making in depression. We tested the hypothesis that anhedonia in MDD may reflect specific impairments in motivation on reward-based decision-making and the deficits might be associated with depressive symptoms severity. In study 1, individuals with and without depressive symptoms performed the modified version of the Effort Expenditure for Rewards Task (EEfRT), a behavioral measure of cost/benefit decision-making. In study 2, MDD patients, remitted MDD patients and healthy controls were recruited for the same procedures. We found evidence for decreased willingness to make effort for rewards among individuals with subsyndromal depression; the effect was amplified in MDD patients, but dissipated in patients with remitted depression. We also found that reduced anticipatory and consummatory pleasure predicted decreased willingness to expend efforts to obtain rewards in MDD patients. For individuals with subsyndromal depression, the impairments were correlated with anticipatory anhedonia but not consummatory anhedonia. These data offer novel evidence that motivational deficits in MDD are correlated with depression severity and predicted by self-reported anhedonia.
The nucleus accumbens (NAc) is considered a hub of reward processing and a growing body of evidence has suggested its crucial role in the pathophysiology of major depressive disorder (MDD). However, ...inconsistent results have been reported by studies on reward network-focused resting-state functional MRI (rs-fMRI). In this study, we examined functional alterations of the NAc-based reward circuits in patients with MDD via meta- and mega-analysis. First, we performed a coordinated-based meta-analysis with a new SDM-PSI method for all up-to-date rs-fMRI studies that focused on the reward circuits of patients with MDD. Then, we tested the meta-analysis results in the REST-meta-MDD database which provided anonymous rs-fMRI data from 186 recurrent MDDs and 465 healthy controls. Decreased functional connectivity (FC) within the reward system in patients with recurrent MDD was the most robust finding in this study. We also found disrupted NAc FCs in the DMN in patients with recurrent MDD compared with healthy controls. Specifically, the combination of disrupted NAc FCs within the reward network could discriminate patients with recurrent MDD from healthy controls with an optimal accuracy of 74.7%. This study confirmed the critical role of decreased FC in the reward network in the neuropathology of MDD. Disrupted inter-network connectivity between the reward network and DMN may also have contributed to the neural mechanisms of MDD. These abnormalities have potential to serve as brain-based biomarkers for individual diagnosis to differentiate patients with recurrent MDD from healthy controls.
The PCN-224 with good optical properties have been successfully by using Zr as the metal node and 4,4,4,4-(Porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) (TCPP) as the base ligand. Carrying ...Camptothecin (CPT) and doxorubicin (DOX), the material modified with folic acid (FA) forms a Drug@PCN-224-FA nanomaterial. The average particle size of Drug@PCN-224-FA was less than 200 nm, and it had high drug encapsulation efficiency for both CPT and DOX. At acidic conditions, the release rate of CPT is 46.42% and the release rate of DOX is 40.80%. In 630 nm laser irradiation, Drug@PCN-224-FA can efficiently produce reactive oxygen species (ROS) to kill cancer cells. In vitro cell experiments also show that Drug@PCN-224-FA has good biocompatibility and combined therapeutic effects.
The Drug@PCN-224-FA nano-drug delivery system was constructed for the first time. This study clearly shows that the system can continuously and slowly release loaded anti-cancer drugs under acidic conditions, and can generate 1O2 through light response to achieve the effect of chemotherapy-photodynamic combined therapy. In addition, the surface of the system is modified with FA, which can be targeted to accumulate at the tumor site, thereby enhancing the therapeutic effect. Display omitted
•PCN-224 was successfully modified using FA to make it targeted to tumor cells.•The nano-drug carrier system can release drugs in response to pH.•The nano-drug carrier system shows a good chemotherapy-photodynamic therapy effect.
Ag NPs were generated by reducing silver ions with sodium borohydride and then loaded into a zirconium-based MOF, PCN-222, resulting in a deep purple powder, PCN-222@AgNPs, which exhibited ...photocatalytic activity. The material was characterized and found to have Ag NPs uniformly dispersed in the pores of PCN-222, with a content of 6.0306%. PCN-222@AgNPs had rod-shaped structures of micrometer sizes with irregular spherical Ag NPs on their surfaces, as revealed by scanning electron microscopy and transmission electron microscopy. In experiments on Ag NPs release and reactive oxygen species (ROS) detection, PCN-222@AgNPs effectively released Ag NPs into an aqueous solution and promote ROS generation. Finally, the antibacterial activities of PCN-222@AgNPs against Escherichia coli and Staphylococcus aureus were assessed by in vitro experiments. Results indicated that PCN-222@AgNPs had lower minimum bactericidal concentration (MBC) compared to PCN-222 in both light and dark environments. The MBC further decreased under light conditions due to the enhanced photocatalytic performance of the composite material and the promotion of Ag NPs release by ROS. These findings demonstrate that PCN-222@AgNPs have synergistic antibacterial effects under visible light irradiation.
Antibacterial photodynamic therapy (aPDT) is regarded as one of the most promising antibacterial therapies due to its nonresistance, noninvasion, and rapid sterilization. However, the development of ...antibacterial materials with high aPDT efficacy is still a long-standing challenge. Herein, we develop an effective antibacterial photodynamic composite UiO-66-(SH)2@TCPP@AgNPs by Ag encapsulation and 4,4′,4″,4‴-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) (TCPP) dopant. Through a mix-and-match strategy in the self-assembly process, 2,5-dimercaptoterephthalic acid containing –SH groups and TCPP were uniformly decorated into the UiO-66-type framework to form UiO-66-(SH)2@TCPP. After Ag(I) impregnation and in situ UV light reduction, Ag NPs were formed and encapsulated into UiO-66-(SH)2@TCPP to get UiO-66-(SH)2@TCPP@AgNPs. In the resulting composite, both Ag NPs and TCPP can effectively enhance the visible light absorption, largely boosting the generation efficiency of reactive oxygen species. Notably, the nanoscale size enables it to effectively contact and be endocytosed into bacteria. Consequently, UiO-66-(SH)2@TCPP@AgNPs show a very high aPDT efficacy against Gram-negative and Gram-positive bacteria as well as drug-resistant bacteria (MRSA). Furthermore, the Ag NPs were firmly anchored at the framework by the high density of –SH moieties, avoiding the cytotoxicity caused by the leakage of Ag NPs. By in vitro experiments, UiO-66-(SH)2@TCPP@AgNPs show a very high antibacterial activity and good biocompatibility as well as the potentiality to promote cell proliferation.
It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since ...HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.
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