Inflammation undermines the stability of atherosclerotic plaques, rendering them susceptible to acute rupture, the cataclysmic event that underlies clinical expression of this disease. ...Myeloperoxidase is a central inflammatory enzyme secreted by activated macrophages and is involved in multiple stages of plaque destabilization and patient outcome. We report here that a unique functional in vivo magnetic resonance agent can visualize myeloperoxidase activity in atherosclerotic plaques in a rabbit model.
We performed magnetic resonance imaging of the thoracic aorta of New Zealand White rabbits fed a cholesterol (n=14) or normal (n=4) diet up to 2 hours after injection of the myeloperoxidase sensor bis-5HT-DTPA(Gd) MPO(Gd), the conventional agent DTPA(Gd), or an MPO(Gd) analog, bis-tyr-DTPA(Gd), as controls. Delayed MPO(Gd) images (2 hours after injection) showed focal areas of increased contrast (>2-fold) in diseased wall but not in normal wall (P=0.84) compared with both DTPA(Gd) (n=11; P<0.001) and bis-tyr-DTPA(Gd) (n=3; P<0.05). Biochemical assays confirmed that diseased wall possessed 3-fold elevated myeloperoxidase activity compared with normal wall (P<0.01). Areas detected by MPO(Gd) imaging colocalized and correlated with myeloperoxidase-rich areas infiltrated by macrophages on histopathological evaluations (r=0.91, P<0.0001). Although macrophages were the main source of myeloperoxidase, not all macrophages secreted myeloperoxidase, which suggests that distinct subpopulations contribute differently to atherogenesis and supports our functional approach.
The present study represents a unique approach in the detection of inflammation in atherosclerotic plaques by examining macrophage function and the activity of an effector enzyme to noninvasively provide both anatomic and functional information in vivo.
Regulatory cell death has been a major focus area of cancer therapy research to improve conventional clinical cancer treatment (e.g. chemotherapy and radiotherapy). Ferroptosis, a novel form of ...regulated cell death mediated by iron-dependent lipid peroxidation, has been receiving increasing attention since its discovery in 2012. Owing to the highly iron-dependent physiological properties of cancer cells, targeting ferroptosis is a promising approach in cancer therapy. In this review, we summarised the characteristics of ferroptotic cells, associated mechanisms of ferroptosis occurrence and regulation and application of the ferroptotic pathway in cancer therapy, including the use of ferroptosis in combination with other therapeutic modalities. In addition, we presented the challenges of using ferroptosis in cancer therapy and future perspectives that may provide a basis for further research.
Oral squamous cell carcinoma (OSCC) is one of the most prevalent kinds of cancers. Therefore, there is a pressing need to create a new risk scoring model to personalize the prognosis of OSCC patients ...and screen for patient-specific therapeutic agents and molecular targets.
Firstly, A series of bioinformatics was performed to construct a novel ferroptosis-related prognostic model; Further, drug sensitivity analysis was used to screen for specific therapeutic agents for OSCC; Single-cell analysis was employed to investigate the enrichment of FRDEGs (ferroptosis-related differentially expressed genes) in the OSCC microenvironment; Finally, various experiments were conducted to screen and validate molecular therapeutic targets for OSCC.
In this study, we constructed a novel 10-FRDEGs risk scoring model. Base on the risk scoring model, we founded three potential chemotherapeutic agents for OSCC: 5Z)-7-Oxozeaenol, AT-7519, KIN001-266; In addition, FRDEGs were enriched in the epithelial cells of OSCC. Finally, we found that CA9 and CAV1 could regulate OSCC proliferation, migration and ferroptosis in vitro.
A novel 10-FRDEGs risk scoring model can predict the prognosis of patients with OSCC.Further,5Z)-7-Oxozeaenol, AT-7519, KIN001-266 are potential chemotherapeutic agents for OSCC.Moreover, we identified CA9、CAV1 as potential molecular target for the treatment of OSCC.Our findings provide new directions for prognostic assessment and precise treatment of oral cell squamous carcinoma.
•Previous ferroptosis prognostic models had some limitations.•Novel ferroptosis prognostic models can predict the prognosis accurately.•Three compounds are potential specific chemotherapeutic agents for OSCC.•Ferroptosis genes are mainly enriched in epithelial cells at the single cell level.•CA9 and CAV1 are potential molecular therapeutic targets for OSCC.
Traditional cell lines and xenograft models have been widely recognized and used in research. As a new research model, organoids have made significant progress and development in the past 10 years. ...Compared with traditional models, organoids have more advantages and have been applied in cancer research, genetic diseases, infectious diseases, and regenerative medicine. This review presented the advantages and disadvantages of organoids in physiological development, pathological mechanism, drug screening, and organ transplantation. Further, this review summarized the current situation of vascularization, immune microenvironment, and hydrogel, which are the main influencing factors of organoids, and pointed out the future directions of development.
Ischemic injuries and local hypoxia can result in osteocytes dysfunction and play a key role in the pathogenesis of avascular osteonecrosis. Conventional imaging techniques including magnetic ...resonance imaging (MRI) and computed tomography (CT) can reveal structural and functional changes within bony anatomy; however, characterization of osteocyte behavioral dynamics in the setting of osteonecrosis at the single cell resolution is limited. Here, we demonstrate an optical approach to study real-time osteocyte functions in vivo. Using nicotinamide adenine dinucleotide (NADH) as a biomarker for metabolic dynamics in osteocytes, we showed that NADH level within osteocytes transiently increase significantly after local ischemia through non-invasive photo-induced thrombosis of afferent arterioles followed by a steady decline. Our study presents a non-invasive optical approach to study osteocyte behavior through the modulation of local environmental conditions. Thus it provides a powerful toolkit to study cellular processes involved in bone pathologies in vivo.
Mollusk shell is one kind of potential biomaterial, but its vague mineralization mechanism hinders its further application. Mollusk shell matrix proteins are important functional components that are ...embedded in the shell, which play important roles in shell formation. The proteome of the oyster shell had been determined based on the oyster genome sequence by our group and gives the chance for further deep study in this area. The classical model of shell formation posits that the shell proteins are mantle-secreted. But, in this study, we further analyzed the shell proteome data in combination with organ transcriptome data and we found that the shell proteins may be produced by multiple organs though the mantle is still the most important organ for shell formation. To identify the transport pathways of these shell proteins not in classical model of shell formation, we conducted a shell damage experiment and we determined the shell-related gene set to identify the possible transport pathways from multiple organs to the shell formation front. We also found that there may exist a remodeling mechanism in the process of shell formation. Based on these results along with some published results, we proposed a new immature model, which will help us think about the mechanism of shell formation in a different way.
The amygdala is an important center for emotional behavior, and it influences other cortical regions. Long feedback projections from the amygdala to the primary visual cortex were recently reported ...in the cat and monkey, two animal models for vision research. However, the detailed functional roles of these extensive projections still remain largely unknown. In this study, intrinsic signal optical imaging was used to investigate the visually driven responses of the primary visual cortex of cats as focal drugs were injected into the basal nucleus of the amygdala. Both the visually evoked global signals and differential signals in the functional maps of the primary visual cortex were enhanced or reduced by glutamate-induced activation or GABA-induced deactivation of neurons in the amygdala, respectively. This modulation was found to be non-selective, consistent with the gain control mechanism—both the preferred orientation and its mapped orientation tuning width remained unchanged. The single unit recordings showed similar results supporting the above observations. These results suggest that the distal feedback signals of the amygdala enhance the primary sensory information processing in a non-selective, gain-control fashion. This provides direct neurophysiological evidence and insight for previous studies on emotional-cue related psychological studies.
•Optical imaging was applied in V1 when amygdala was manipulated.•Visually evoked global signals in V1 were up or downregulated by the amygdala.•Orientation specific differential signals in V1 were also regulated by the amygdala.•The feedback effect of the amygdala on V1 is linear gain control amplification.
Severe burn is a serious acute trauma that can lead to significant complications such as sepsis, multiple organ failure, and high mortality worldwide. The gut microbiome, the largest microbial ...reservoir in the human body, plays a significant role in this pathogenic process. Intestinal dysbiosis and disruption of the intestinal mucosal barrier are common after severe burn, leading to bacterial translocation to the bloodstream and other organs of the body, which is associated with many subsequent severe complications. The progression of some intestinal diseases can be improved by modulating the composition of gut microbiota and the levels of its metabolites, which also provides a promising direction for post-burn treatment. In this article, we summarised the studies describing changes in the gut microbiome after severe burn, as well as changes in the function of the intestinal mucosal barrier. Additionally, we presented the potential and challenges of microbial therapy, which may provide microbial therapy strategies for severe burn.
Objective:
This study was conducted to investigate the safety, tolerability and pharmacokinetics (PK) of WXFL10203614 after single and multiple oral doses in healthy Chinese subjects.
Methods:
A ...single-center, randomized, double-blind, placebo-controlled phase Ⅰ study was performed on healthy Chinese subjects. In the single-dose study, Subjects were randomized into 7 dose levels of WXFL10203614 (1 mg group,
n
= 2; 2, 5, 10, 17, 25 and 33 mg groups with placebo, 8 subjects per group, 2 of them given placebo). In the multiple-dose study, subjects received 5 or 10 mg WXFL10203614 once daily (QD), 5 mg twice daily (BID) or placebo for 7 consecutive days. Safety, tolerability and PK of WXFL10203614 were all assessed.
Results:
A total of 592 subjects were screened, 50 subjects were enrolled in the single-dose study and 30 in the multiple-dose study. All adverse events (AEs) were mild or moderate and resolved spontaneously. No Serious Adverse Events (SAEs) or deaths were reported during the study. WXFL10203614 was absorbed rapidly after dosing with T
max
of 0.48–0.98 h, C
max
, AUC
0-t
and AUC
0-∞
were all increased in a dose-related manner over the range of 1–33 mg. Renal excretion was the major route of elimination of WXFL10203614. Steady-state PK parameters (C
max,ss
, AUC
0-t,ss
and AUC
0-∞,ss
) were elevated after once-daily administration of 5–10 mg WXFL10203614 and non- and weak drug accumulations were observed, whereas moderate drug accumulation occurred in the 5 mg BID group.
Conclusion:
WXFL10203614 exhibited good safety, tolerability and favorable PK profiles in healthy Chinese subjects, supporting further clinical development in patients with rheumatoid arthritis.
Clinical Trials Registration Number:
http://www.chinadrugtrials.org.cn/index.html
, #CTR20190069 and CTR20200143.
Although hepatocellular regeneration is the cornerstone of liver homeostasis, current techniques for assessing such regeneration are limited. A method for visualizing the regeneration process would ...provide a means for advanced studies. Therefore, we examined the possibility of using fluorescence ubiquination-based cell cycle indicator (Fucci) mice for direct visualization of hepatocellular regeneration.
We performed a two-thirds partial hepatectomy in conventional and Fucci mice. Fucci animals have orange Cdt1 expressed in the G1 phase and green Geminin expressed in S/G2/M phases. Regenerating livers were procured daily for 7 d. Immunohistochemical staining was performed for proliferative Ki67 and mitotic pHH3 serine 10 (pHH3) markers on formalin-fixed, paraffin-embedded tissue sections from conventional mice. The orange Cdt1 and green Geminin fluorescence indicative of the G1 and S/G2/M phases, respectively, were assessed in liver tissues, in vivo and ex vivo, with two-photon laser scanning microscopy.
Immunostaining with Ki67 and pHH3 revealed a typical profile of hepatocellular regeneration after hepatectomy in conventional mice, although immunostaining required more than a week to process. In contrast, hepatocellular regeneration could be visualized with two-photon microscopy within a few hours in regenerating livers of the Fucci mice. Only orange G1 hepatocytes were seen in the baseline liver specimens; however, multiple bright green and yellow hepatocytes were seen 48 h after hepatectomy, indicating active hepatocytes in the S/G2/M phases of the cell cycle.
Hepatocellular regeneration is readily visualized in regenerating livers of Fucci mice. The Fucci model is an exciting tool for advanced studies of hepatocellular and liver regeneration.
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