Macrophage migration inhibitory factor (MIF) promotes intervertebral disc degeneration through the NF-κB pathway, and the MIF inhibitor CPSI-1306 alleviates intervertebral disc degeneration in a mouse model.

Lumbar intervertebral disc degeneration(IDD) is a prevalent inflammatory disease caused by many proinflammatory factors, such as TNF and IL-1ß. Migration inhibitory factor (MIF) is an upstream inflammatory factor widely expressed in vivo that is associated with a variety of inflammatory diseases or malignant tumors and has potential therapeutic value in many diseases. We explored the role of MIF in intervertebral disc degeneration by regulating the content of exogenous MIF or the expression of MIF in cells. Upon inducing degeneration of nucleus pulposus (NP) cells with IL-1ß, we found that the increase in intracellular and exogenous MIF promoted the catabolism induced by proinflammatory factors in NP cells, while silencing of the MIF gene alleviated the degeneration to some extent. In a mouse model, the intervertebral disc degeneration of MIF-KO mice was significantly less than that of wild-type mice. To explore the treatment of intervertebral disc degeneration, we selected the small-molecular MIF inhibitor CPSI-1306. CPSI-1306 had a therapeutic effect on intervertebral disc degeneration in the mouse model. In summary, we believe that MIF plays an important role in intervertebral disc degeneration and is a potential therapeutic target for the treatment of intervertebral disc degeneration.

A 3D hanging spheroid-filter plate for high-throughput drug testing and CAR T cell cytotoxicity assay.

Tumour spheroids are widely used in immune cell cytotoxicity assays and anticancer drug testing, providing a physiologically relevant model replicating the tumour microenvironment. However, co-culture of immune and tumour cells complicates quantification of immune cell killing efficiency. We present a novel 3D hanging spheroid-filter plate that efficiently facilitates spheroid formation and separates unbound/dead cells during cytotoxicity assays. Optical imaging directly measures the cytotoxic effects of anti-cancer drugs on tumour spheroids, eliminating the need for live/dead fluorescent staining. This approach enables cost-effective evaluation of T-cell cytotoxicity with specific chimeric antigen receptors (CARs), enhancing immune cell-based assays and drug testing in three-dimensional tumour models.

3D hanging spheroid plate for high-throughput CAR T cell cytotoxicity assay.

BACKGROUND: Most high-throughput screening (HTS) systems studying the cytotoxic effect of chimeric antigen receptor (CAR) T cells on tumor cells rely on two-dimensional cell culture that does not recapitulate the tumor microenvironment (TME). Tumor spheroids, however, can recapitulate the TME and have been used for cytotoxicity assays of CAR T cells. But a major obstacle to the use of tumor spheroids for cytotoxicity assays is the difficulty in separating unbound CAR T and dead tumor cells from spheroids. Here, we present a three-dimensional hanging spheroid plate (3DHSP), which facilitates the formation of spheroids and the separation of unbound and dead cells from spheroids during cytotoxicity assays. RESULTS: The 3DHSP is a 24-well plate, with each well composed of a hanging dripper, spheroid wells, and waste wells. In the dripper, a tumor spheroid was formed and mixed with CAR T cells. In the 3DHSP, droplets containing the spheroids were deposited into the spheroid separation well, where unbound and dead T and tumor cells were separated from the spheroid through a gap into the waste well by tilting the 3DHSP by more than 20°. Human epidermal growth factor receptor 2 (HER2)-positive tumor cells (BT474 and SKOV3) formed spheroids of approximately 300-350 µm in diameter after 2 days in the 3DHSP. The cytotoxic effects of T cells engineered to express CAR recognizing HER2 (HER2-CAR T cells) on these spheroids were directly measured by optical imaging, without the use of live/dead fluorescent staining of the cells. Our results suggest that the 3DHSP could be incorporated into a HTS system to screen for CARs that enable T cells to kill spheroids formed from a specific tumor type with high efficacy or for spheroids consisting of tumor types that can be killed efficiently by T cells bearing a specific CAR. CONCLUSIONS: The results suggest that the 3DHSP could be incorporated into a HTS system for the cytotoxic effects of CAR T cells on tumor spheroids.

Recent Progress in Biosensors for Detection of Tumor Biomarkers.

Cancer is a leading cause of death worldwide, with an increasing mortality rate over the past years. The early detection of cancer contributes to early diagnosis and subsequent treatment. How to detect early cancer has become one of the hot research directions of cancer. Tumor biomarkers, biochemical parameters for reflecting cancer occurrence and progression have caused much attention in cancer early detection. Due to high sensitivity, convenience and low cost, biosensors have been largely developed to detect tumor biomarkers. This review describes the application of various biosensors in detecting tumor markers. Firstly, several typical tumor makers, such as neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), squamous cell carcinoma antigen (SCCA), carbohydrate, antigen19-9 (CA19-9) and tumor suppressor p53 (TP53), which may be helpful for early cancer detection in the clinic, are briefly described. Then, various biosensors, mainly focusing on electrochemical biosensors, optical biosensors, photoelectrochemical biosensors, piezoelectric biosensors and aptamer sensors, are discussed. Specifically, the operation principles of biosensors, nanomaterials used in biosensors and the application of biosensors in tumor marker detection have been comprehensively reviewed and provided. Lastly, the challenges and prospects for developing effective biosensors for early cancer diagnosis are discussed.

Simvastatin reverses the harmful effects of high fat diet on titanium rod osseointegration in ovariectomized rats.

INTRODUCTION: The objectives of the present study were to determine whether simvastatin (SIM) could reverse the harmful effects on titanium rod osseointegration in ovariectomized rats fed high-fat diet (HFD). MATERIALS AND METHODS: Ovariectomized female Sprague-Dawley rats were randomly allocated to three groups and received SIM treatment plus HFD for 12 weeks. We then evaluated the microstructure parameters, histological parameters, biomechanical parameters, bone turnover, and blood lipid level. RESULTS: After 12 weeks of treatment, SIM can significantly improve bone formation around the titanium rod and osseointegration including higher values of maximum push-out force, bone area ratio (BAR), bone-to-implant contact (BIC), bone mineral density (BMD), bone volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), mean connective density (Conn.D) when compared with the HFD group. In addition, system administration of SIM showed positive effects on collagen type 1 cross-linked C-telopeptide (CTX-1), procollagen I N-terminal propeptide (PINP), total cholesterol (TC), triglycerides (TGL), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol. Compared with the HFD group, lower values of CTX-1, P1NP, TC, TGL and LDL were observed in the SIM+HFD group (P < 0.05). CONCLUSION: Our findings revealed that HFD may have an adverse effect on osseointegration in osteoporotic conditions, and the harmful effect of HFD on osseointegration could be reversed by SIM.

Nomogram for predicting the overall survival and cancer-specific survival of patients with extremity liposarcoma: a population-based study.

BACKGROUND: Extremity liposarcoma represents 25% of extremity soft tissue sarcoma and has a better prognosis than liposarcoma occurring in other anatomic sites. The purpose of this study was to develop two nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) of patients with extremity liposarcoma. METHODS: A total of 2170 patients diagnosed with primary extremity liposarcoma between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were performed to explore the independent prognostic factors and establish two nomograms. The area under the curve (AUC), C-index, calibration curve, decision curve analysis (DCA), Kaplan-Meier analysis, and subgroup analyses were used to evaluate the nomograms. RESULTS: Six variables were identified as independent prognostic factors for both OS and CSS. In the training cohort, the AUCs of the OS nomogram were 0.842, 0.841, and 0.823 for predicting 3-, 5-, and 8-year OS, respectively, while the AUCs of the CSS nomogram were 0.889, 0.884, and 0.859 for predicting 3-, 5-, and 8-year CSS, respectively. Calibration plots and DCA revealed that the nomogram had a satisfactory ability to predict OS and CSS. The above results were also observed in the validation cohort. In addition, the C-indices of both nomograms were significantly higher than those of all independent prognostic factors in both the training and validation cohorts. Stratification of the patients into high- and low-risk groups highlighted the differences in prognosis between the two groups in the training and validation cohorts. CONCLUSION: Age, sex, tumor size, grade, M stage, and surgery status were confirmed as independent prognostic variables for both OS and CSS in extremity liposarcoma patients. Two nomograms based on the above variables were established to provide more accurate individual survival predictions for extremity liposarcoma patients and to help physicians make appropriate clinical decisions.

Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF-κB signaling pathway.

Current pharmacological intervention for the treatment of osteolytic bone diseases such as osteoporosis focuses on the prevention of excessive osteoclastic bone resorption but does not enhance osteoblast-mediated bone formation. In our study, we have shown that 4-iodo-6-phenylpyrimidine (4-IPP), an irreversible inhibitor of macrophage migration inhibitory factor (MIF), can inhibit receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and potentiate osteoblast-mediated mineralization and bone nodule formation in vitro. Mechanistically, 4-IPP inhibited RANKL-induced p65 phosphorylation and nuclear translocation by preventing the interaction of MIF with thioredoxin-interacting protein-p65 complexes. This led to the suppression of late osteoclast marker genes such as nuclear factor of activated T cells cytoplasmic 1, resulting in impaired osteoclast formation. In contrast, 4-IPP potentiated osteoblast differentiation and mineralization also through the inhibition of the p65/NF-κB signaling cascade. In the murine model of pathologic osteolysis induced by titanium particles, 4-IPP protected against calvarial bone destruction. Similarly, in the murine model of ovariectomy-induced osteoporosis, 4-IPP treatment ameliorated the bone loss associated with estrogen deficiency by reducing osteoclastic activities and enhancing osteoblastic bone formation. Collectively, these findings provide evidence for the pharmacological targeting of MIF for the treatment of osteolytic bone disorders.-Zheng, L., Gao, J., Jin, K., Chen, Z., Yu, W., Zhu, K., Huang, W., Liu, F., Mei, L., Lou, C., He, D. Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF-κB signaling pathway.

Implicitly and explicitly encoded features can guide attention in free viewing.

It is well known that priming, probably by the contents of working memory, can influence subsequent visual task performance. How ubiquitous is this effect? Can incidental exposure to visual stimuli influence the deployment of attention when there is no explicit visual task? Results of two experiments show that a preceding stimulus can influence free-viewing eye movements. A simple change detection task was used as the cover task. The initial memory display was the priming display, while subsequent filler display constituted the free-viewing display of our interest. In Experiment 1, subjects were asked to memorize the number of items in the priming display. Subjects were not explicitly instructed to attend to features, but these might still be implicitly encoded. In Experiment 2, a more complex change detection task required subjects to memorize the number, color, and shape of priming items. Here, prime features were attended and, presumably, explicitly encoded. We were interested to know whether incidentally or explicitly encoded features of prime items would influence attention distribution in the filler display. In both experiments, items sharing color and shape with the prime were attended more often than predicted by chance. Items sharing neither color nor shape were attended less often. Items sharing either color or shape (not both) could also attract attention showing that the priming need not be based on a bound representation of the primed item. Effects were stronger in Experiment 2. No intention or top-down control appears to be needed to produce this priming.

3D Bioprinted Vascularized Tumour for Drug Testing.

An in vitro screening system for anti-cancer drugs cannot exactly reflect the efficacy of drugs in vivo, without mimicking the tumour microenvironment (TME), which comprises cancer cells interacting with blood vessels and fibroblasts. Additionally, the tumour size should be controlled to obtain reliable and quantitative drug responses. Herein, we report a bioprinting method for recapitulating the TME with a controllable spheroid size. The TME was constructed by printing a blood vessel layer consisting of fibroblasts and endothelial cells in gelatine, alginate, and fibrinogen, followed by seeding multicellular tumour spheroids (MCTSs) of glioblastoma cells (U87 MG) onto the blood vessel layer. Under MCTSs, sprouts of blood vessels were generated and surrounding MCTSs thereby increasing the spheroid size. The combined treatment involving the anti-cancer drug temozolomide (TMZ) and the angiogenic inhibitor sunitinib was more effective than TMZ alone for MCTSs surrounded by blood vessels, which indicates the feasibility of the TME for in vitro testing of drug efficacy. These results suggest that the bioprinted vascularized tumour is highly useful for understanding tumour biology, as well as for in vitro drug testing.

A switching role of hard-uptake nanoparticles in microalgae cell electroporation.

The microalgal cell wall is a natural barrier that limits the efficiency of gene delivery in algae genetic engineering. Here, we report the role of hard-uptake nanoparticles (huNPs) in microalgae cell electroporation to enhance the delivery of genes in Chlamydomonas reinhardtii. This role can be divided into two categories: (i) a 'transient state' for short-term behavior under confocal visualization and (ii) a 'steady state' for long-term behavior in cell culture. First, the 'transient' role of gene-huNP complexes was investigated after washing for clear confocal imaging to observe the location of huNPs after electroporation. Second, the 'steady-state' role of the gene-huNP complexes was examined after electroporation by transferring cells to a fresh, medium-rich culture environment without washing to obtain a stable cell culture. For selection of the huNPs, we used two types of nanoparticles (NPs, 250 nm and 530 nm) larger than the threshold size of electroporation uptake to avoid unwanted endocytic uptake of NPs. In the transient state, the visualization results indicate that gene-NP (250 nm) complexes were positioned on the cells and helped to deliver more genes than did the 530 nm NPs. In the steady state, the gene-NP (530 nm) complexes helped stably deliver more genes to the cells by precipitation of NPs due to gravity. We believe that these findings illustrate how gene-NP complexes function in microalgae cell electroporation and could help set up a protocol for enhanced microalgae applications associated with NPs such as environmental waste removal and biofuel production.

Small molecule inhibitor RepSox prevented ovariectomy-induced osteoporosis by suppressing osteoclast differentiation and bone resorption.

Osteoporosis (OP) is a serious metabolic disease that, due to the increased number or function of osteoclasts, results in increased bone brittleness and, therefore, fragile fracture. Some recent studies report the importance of the transforming growth factor ß (TGFß) pathway in bone homeostasis. RepSox is a small molecule inhibitor of TGFßRI that has a wide range of potential application in clinical medicine, except OP. The aim of our study is to evaluate the effects of RepSox on the differentiation and bone resorption of osteoclasts in vitro and in vivo in an ovariectomy (OVX)-induced OP model. An initial analysis showed TGFßRI messenger RNA expression in both bone samples and bone cells. In the in vitro study, RepSox inhibited the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation and bone resorption activity. Real-time polymerase chain reaction (PCR) analysis showed that RepSox suppressed osteoclastic marker gene expression in both dose-dependent and time-dependent manners. In addition, RepSox did not affect osteoblast differentiation, migration or osteoblastic-specific gene expression in vitro. Furthermore, western blot analysis indicated the underlying mechanisms of the RepSox suppression of osteoclastogenesis via the Smad3 and c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) signaling pathways. Finally, our animal experiments revealed that RepSox prevented OVX-induced bone loss in vivo. Together, our data suggest that RepSox regulates osteoclast differentiation, bone resorption, and OVX-induced OP via the suppression of the Smad3 and JNK/AP-1 pathways.

Dependence of cell adhesion on extracellular matrix materials formed on pore bridge boundaries by nanopore opening and closing geometry.

In this study, we report experimental results for characterization of the growth and formation of pore bridge materials that modified the adhesion structures of cells cultured on nanomembranes with opening and closing geometry. To perform the proof-of-concept experiments, we fabricated two types of anodized alumina oxide substrates with single-sided opening (i.e., one side open, but closed at the other side) and double-sided opening (i.e., both sides open). In our experiment, we compared the densities of pores formed and of bridge materials which differently act as connective proteins depending on the size of pores. The results show that the pore opening geometry can be used to promote the net contact force between pores, resulting in the growth and formation of pore bridge materials before and after cell culture. The results also imply that the bridge materials can be used to attract the structural protrusion of filopodia that can promote the adhesion of cell-to-cell and cell-to-pore bridge. It is observed that the shape and size of cellular structures of filopodia depend on the presence of pore bridge materials. Overall, this observation brought us a significant clue that cells cultured on nanopore substrates would change the adhesion property depending on not only the formation of nanopores formed on the surface of topological substrates, but also that of pore bridge materials by its morphological growth.

Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen.

Repeated exposure to cocaine was previously found to cause sensitized behavioral responses and structural remodeling on medium spiny neurons of the nucleus accumbens (NAc) and caudate putamen (CPu). Rac1 has emerged as a key integrator of environmental cues that regulates dendritic cytoskeletons. In this study, we investigated the role of Rac1 in cocaine-induced dendritic and behavioral plasticity in the CPu. We found that Rac1 activation was reduced in the NAc but increased in the CPu following repeated cocaine treatment. Inhibition of Rac1 activity by a Rac1-specific inhibitor NSC23766, overexpression of a dominant negative mutant of Rac1 (T17N-Rac1) or local knockout of Rac1 attenuated the cocaine-induced increase in dendrites and spine density in the CPu, whereas overexpression of a constitutively active Rac1 exert the opposite effect. Moreover, NSC23766 reversed the increased number of asymmetric spine synapses in the CPu following chronic cocaine exposure. Downregulation of Rac1 activity likewise attenuates behavioral reward responses to cocaine exposure, with activation of Rac1 producing the opposite effect. Thus, Rac1 signaling is differentially regulated in the NAc and CPu after repeated cocaine treatment, and induction of Rac1 activation in the CPu is important for cocaine exposure-induced dendritic remodeling and behavioral plasticity.

Three-Dimensional Hanging Drop Spheroid Plates for Easy Chimeric Antigen Receptor (CAR) T Cytotoxicity Assay.

Chimeric antigen receptor (CAR) T cell therapy shows a highly effective therapeutic effect on B-cell malignancies. The tumor microenvironment (TME) of solid tumors in vivo poses a great challenge to CAR T cell therapy due to its complexity. Recently, tumor spheroids have attracted much attention because of their ability to recapitulate TME. However, the use of tumor spheroids for the CAR T cytotoxicity assay involves the difficult task of separating unbound T cells and dead tumor cells from the spheroids. Therefore, we developed a three-dimensional hanging spheroid plate (3DHSP) that facilitates spheroid formation and separation of unbound and dead cells from spheroids during cytotoxicity assays. In this work, detailed steps have been described for fabrication and operation of the 3DHSP. This new 3DHSP device is a 96-well plate in which each well consists of a hanging dripper and a spheroid separation plate. A tumor spheroid forms in a droplet hanging in the dripper and is mixed with CAR T cells. The mixture in the droplet is deposited into the spheroid separation plate by pipetting, and unbound and dead CAR T and tumor cells are detached from the spheroid and moved to the waste well in the plate by tilting the 3DHSP at 20°. The size of the spheroid can be used as a readout for CAR T cell cytotoxicity assay, suggesting that the 3DHSP does not require cumbersome fluorescent staining.

JPEG Quantized Coefficient Recovery via DCT Domain Spatial-Frequential Transformer.

JPEG compression adopts the quantization of Discrete Cosine Transform (DCT) coefficients for effective bit-rate reduction, whilst the quantization could lead to a significant loss of important image details. Recovering compressed JPEG images in the frequency domain has recently garnered increasing interest, complementing the multitude of restoration techniques established in the pixel domain. However, existing DCT domain methods typically suffer from limited effectiveness in handling a wide range of compression quality factors or fall short in recovering sparse quantized coefficients and the components across different colorspaces. To address these challenges, we propose a DCT domain spatial-frequential Transformer, namely DCTransformer, for JPEG quantized coefficient recovery. Specifically, a dual-branch architecture is designed to capture both spatial and frequential correlations within the collocated DCT coefficients. Moreover, we incorporate the operation of quantization matrix embedding, which effectively allows our single model to handle a wide range of quality factors, and a luminance-chrominance alignment head that produces a unified feature map to align different-sized luminance and chrominance components. Our proposed DCTransformer outperforms the current state-of-the-art JPEG artifact removal techniques, as demonstrated by our extensive experiments.

Exploring Long- and Short-Range Temporal Information for Learned Video Compression.

Learned video compression methods have gained various interests in the video coding community. Most existing algorithms focus on exploring short-range temporal information and developing strong motion compensation. Still, the ignorance of long-range temporal information utilization constrains the potential of compression. In this paper, we are dedicated to exploiting both long- and short-range temporal information to enhance video compression performance. Specifically, for long-range temporal information exploration, we propose a temporal prior that can be continuously supplemented and updated during compression within the group of pictures (GOP). With the updating scheme, the temporal prior can provide richer mutual information between the overall prior and the current frame for the entropy model, thus facilitating Gaussian parameter prediction. As for the short-range temporal information, we propose a progressive guided motion compensation to achieve robust and accurate compensation. In particular, we design a hierarchical structure to build multi-scale compensation, and by employing optical flow guidance, we generate pixel offsets as motion information at each scale. Additionally, the compensation results at each scale will guide the next scale's compensation, forming a flow-to-kernel and scale-by-scale stable guiding strategy. Extensive experimental results demonstrate that our method can obtain advanced rate-distortion performance compared to the state-of-the-art learned video compression approaches and the latest standard reference software in terms of PSNR and MS-SSIM. The codes are publicly available on: https://github.com/Huairui/LSTVC.

Toward viewing behavior for aerial scene categorization.

Previous work has demonstrated similarities and differences between aerial and terrestrial image viewing. Aerial scene categorization, a pivotal visual processing task for gathering geoinformation, heavily depends on rotation-invariant information. Aerial image-centered research has revealed effects of low-level features on performance of various aerial image interpretation tasks. However, there are fewer studies of viewing behavior for aerial scene categorization and of higher-level factors that might influence that categorization. In this paper, experienced subjects' eye movements were recorded while they were asked to categorize aerial scenes. A typical viewing center bias was observed. Eye movement patterns varied among categories. We explored the relationship of nine image statistics to observers' eye movements. Results showed that if the images were less homogeneous, and/or if they contained fewer or no salient diagnostic objects, viewing behavior became more exploratory. Higher- and object-level image statistics were predictive at both the image and scene category levels. Scanpaths were generally organized and small differences in scanpath randomness could be roughly captured by critical object saliency. Participants tended to fixate on critical objects. Image statistics included in this study showed rotational invariance. The results supported our hypothesis that the availability of diagnostic objects strongly influences eye movements in this task. In addition, this study provides supporting evidence for Loschky et al.'s (Journal of Vision, 15(6), 11, 2015) speculation that aerial scenes are categorized on the basis of image parts and individual objects. The findings were discussed in relation to theories of scene perception and their implications for automation development.

Experimental Study and Mechanism Analysis of Paraffin/Sisal Composite Phase Change Energy Storage Fiber Prepared by Vacuum Adsorption Method.

Sisal fiber exhibits a fibrous and porous structure with significant surface roughness, making it highly suitable for storing phase change materials (PCMs). Its intricate morphology further aids in mitigating the risk of PCM leakage. This research successfully employs vacuum adsorption to encapsulate paraffin within sisal fiber, yielding a potentially cost-effective, durable, and environmentally friendly phase change energy storage medium. A systematic investigation was carried out to evaluate the effects of sisal-to-paraffin mass ratio, fiber length, vacuum level, and negative pressure duration on the loading rate of paraffin. The experimental results demonstrate that a paraffin loading rate of 8 wt% can be achieved by subjecting a 3 mm sisal fiber to vacuum adsorption with 16 wt% paraffin for 1 h at -0.1 MPa. Through the utilization of nano-CT imaging enhancement technology, along with petrographic microscopy, this study elucidates the mechanism underlying paraffin storage within sisal fiber during vacuum adsorption. The observations reveal that a substantial portion of paraffin is primarily stored within the pores of the fiber, while a smaller quantity is firmly adsorbed onto its surface, thus yielding a durable phase change energy storage medium. The research findings contribute to both the theoretical foundations and the available practical guidance for the fabrication and implementation of paraffin/sisal fiber composite phase change energy storage mediums.

Nitisinone attenuates cartilage degeneration and subchondral osteoclastogenesis in osteoarthritis and concomitantly inhibits the cGAS/STING/NF-κB pathway.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and subchondral bone remodelling. Currently, conservative treatment strategies cannot effectively alleviate the progression of OA. In this study, we used computer network analysis to show that Nitisinone (NTBC) is closely related to extracellular matrix degradation in OA and mainly interferes with the TNF-α signaling pathway. NTBC is an orphan drug used to treat hereditary type I tyrosinemia by altering phenylalanine/tyrosine metabolic flow. In this study, we found that NTBC effectively reduced chondrocyte inflammation and extracellular matrix degradation induced by TNF-α. Mechanistically, NTBC inhibited the cGAS/STING signaling pathway and reduced activation of the STING-dependent NF-κB pathway to alleviate inflammation. In addition, NTBC inhibited osteoclastogenesis and delayed the occurrence of subchondral bone remodelling. In mice with ACLT-induced osteoarthritis, intra-articular injection of NTBC significantly reduced cartilage degradation and subchondral bone remodelling. NTBC showed impressive therapeutic efficacy as a potential pharmaceutical intervention for the treatment of OA.

Exploration of drug resistance mechanisms in triple negative breast cancer cells using a microfluidic device and patient tissues.

Chemoresistance is a major cause of treatment failure in many cancers. However, the life cycle of cancer cells as they respond to and survive environmental and therapeutic stress is understudied. In this study, we utilized a microfluidic device to induce the development of doxorubicin-resistant (DOXR) cells from triple negative breast cancer (TNBC) cells within 11 days by generating gradients of DOX and medium. In vivo chemoresistant xenograft models, an unbiased genome-wide transcriptome analysis, and a patient data/tissue analysis all showed that chemoresistance arose from failed epigenetic control of the nuclear protein-1 (NUPR1)/histone deacetylase 11 (HDAC11) axis, and high NUPR1 expression correlated with poor clinical outcomes. These results suggest that the chip can rapidly induce resistant cells that increase tumor heterogeneity and chemoresistance, highlighting the need for further studies on the epigenetic control of the NUPR1/HDAC11 axis in TNBC.