Inhibition of Caspase-1-dependent pyroptosis alleviates myocardial ischemia/reperfusion injury during cardiopulmonary bypass (CPB) in type 2 diabetic rats.

Cardiovascular complications pose a significant burden in type 2 diabetes mellitus (T2DM), driven by the intricate interplay of chronic hyperglycemia, insulin resistance, and lipid metabolism disturbances. Myocardial ischemia/reperfusion (MI/R) injury during cardiopulmonary bypass (CPB) exacerbates cardiac vulnerability. This study aims to probe the role of Caspase-1-dependent pyroptosis in global ischemia/reperfusion injury among T2DM rats undergoing CPB, elucidating the mechanisms underlying heightened myocardial injury in T2DM. This study established a rat model of T2DM and compared Mean arterial pressure (MAP), heart rate (HR), and hematocrit (Hct) between T2DM and normal rats. Myocardial cell morphology, infarction area, mitochondrial ROS and caspase-1 levels, NLRP3, pro-caspase-1, caspase-1 p10, GSDMD expressions, plasma CK-MB, cTnI, IL-1ß, and IL-18 levels were assessed after reperfusion in both T2DM and normal rats. The role of Caspase-1-dependent pyroptosis in myocardial ischemia/reperfusion injury during CPB in T2DM rats was examined using the caspase-1 inhibitor VX-765 and the ROS scavenger NAC. T2DM rats demonstrated impaired glucose tolerance but stable hemodynamics during CPB, while showing heightened vulnerability to MI/R injury. This was marked by substantial lipid deposition, disrupted myocardial fibers, and intensified cellular apoptosis. The activation of caspase-1-mediated pyroptosis and increased reactive oxygen species (ROS) production further contributed to tissue damage and the ensuing inflammatory response. Notably, myocardial injury was mitigated by inhibiting caspase-1 through VX-765, which also attenuated the inflammatory cascade. Likewise, NAC treatment reduced oxidative stress and partially suppressed ROS-mediated caspase-1 activation, resulting in diminished myocardial injury. This study proved that Caspase-1-dependent pyroptosis significantly contributes to the inflammation and injury stemming from global MI/R in T2DM rats under CPB, which correlate with the surplus ROS generated by oxidative stress during reperfusion.

Targeting ferroptosis as a potential prevention and treatment strategy for aging-related diseases.

Ferroptosis, an emerging paradigm of programmed cellular necrosis posited in recent years, manifests across a spectrum of maladies with profound implications for human well-being. Numerous investigations substantiate that modulating ferroptosis, whether through inhibition or augmentation, plays a pivotal role in the etiology and control of numerous age-related afflictions, encompassing neurological, circulatory, respiratory, and other disorders. This paper not only summarizes the regulatory mechanisms of ferroptosis, but also discusses the impact of ferroptosis on the biological processes of aging and its role in age-related diseases. Furthermore, it scrutinizes recent therapeutic strides in addressing aging-related conditions through the modulation of ferroptosis. The paper consolidates the existing knowledge on potential applications of ferroptosis-related pharmacotherapies and envisages the translational prospects of ferroptosis-targeted interventions in clinical paradigms.

Therapeutic potential: The role of mesenchymal stem cells from diverse sources and their derived exosomes in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetic patients, with its incidence continuously increasing in recent years. DN causes renal tissue damage and functional decline, expedites the aging process of the kidneys, and may ultimately progress leading to end-stage renal disease, severely impacting the patient's quality of life and prognosis. Mesenchymal stem cells (MSCs) are highly valued for their multipotent differentiation, paracrine functions, immunomodulatory effects, and capacity for tissue repair. Particularly, exosomes (Exo) derived from MSCs (MSCs-Exo) are rich in bioactive molecules and facilitate intercellular communication, participating in various physiological and pathological processes. MSCs and MSCs-Exo, in particular, have been demonstrated to have therapeutic effects in DN treatment research by encouraging tissue repair, fibrosis inhibition, and inflammation reduction. Research has shown that MSCs and MSCs-Exo have therapeutic effects in DN treatment by promoting tissue repair, inhibiting fibrosis, and reducing inflammation. Recent studies underscore the potential of MSCs and MSCs-Exo, highlighting their broad applicability in DN treatment. This review aims to provide a comprehensive summary of the scientific developments in treating DN using MSCs and MSCs-Exo from diverse sources, while also exploring their future therapeutic possibilities in detail.

Enhancing osteoporosis treatment with engineered mesenchymal stem cell-derived extracellular vesicles: mechanisms and advances.

As societal aging intensifies, the incidence of osteoporosis (OP) continually rises. OP is a skeletal disorder characterized by reduced bone mass, deteriorated bone tissue microstructure, and consequently increased bone fragility and fracture susceptibility, typically evaluated using bone mineral density (BMD) and T-score. Not only does OP diminish patients' quality of life, but it also imposes a substantial economic burden on society. Conventional pharmacological treatments yield limited efficacy and severe adverse reactions. In contemporary academic discourse, mesenchymal stem cells (MSCs) derived extracellular vesicles (EVs) have surfaced as auspicious novel therapeutic modalities for OP. EVs can convey information through the cargo they carry and have been demonstrated to be a crucial medium for intercellular communication, playing a significant role in maintaining the homeostasis of the bone microenvironment. Furthermore, various research findings provide evidence that engineered strategies can enhance the therapeutic effects of EVs in OP treatment. While numerous reviews have explored the progress and potential of EVs in treating degenerative bone diseases, research on using EVs to address OP remains in the early stages of basic experimentation. This paper reviews advancements in utilizing MSCs and their derived EVs for OP treatment. It systematically examines the most extensively researched MSC-derived EVs for treating OP, delving not only into the molecular mechanisms of EV-based OP therapy but also conducting a comparative analysis of the strengths and limitations of EVs sourced from various cell origins. Additionally, the paper emphasizes the technical and engineering strategies necessary for leveraging EVs in OP treatment, offering insights and recommendations for future research endeavors.

Multiple Tissues Transcriptome of Zig-Zag Eel (Mastacembelus armatus) with Different Growth Rates.

In order to explore the main regulatory genes and related pathways of growth traits, transcriptome sequencing was first performed on the brain, liver, and muscle tissues of 3-month-old M. armatus with different growth rates. By comparative transcriptome analysis of fast-growing and slow-growing groups of M. armatus, a total of 2887 DEGs were screened, of which 59 up-regulated genes and 105 down-regulated genes were detected in the brain, 146 up-regulated genes and 202 down-regulated genes were detected in the liver, and 529 up-regulated genes and 1846 down-regulated genes were detected in muscle, including insulin-like growth factor binding protein 1a (IGFBP1A), insulin-like growth factor binding protein 1b (IGFBP1B), myosin, light chain 1 (MYL1), and myoglobin (MB). Through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we identified a total of 288 significantly enriched GO entries and 68 significantly enriched KEGG pathways related to growth, such as skeletal muscle tissue development, insulin-like growth factor binding, and the mitotic cell cycle. These key genes and signaling pathways may play a key role in regulating the growth of M. armatus. Digging into the regulatory mechanisms of these key genes will provide a theoretical basis for further exploration of the molecular mechanisms related to the growth and development of M. armatus, and help to breed new varieties of M. armatus with rapid growth.

Integrated transcriptomic and proteomic profiling reveals the key molecular signatures of brain endothelial reperfusion injury.

BACKGROUND: Reperfusion therapy after ischemic stroke often causes brain microvascular injury. However, the underlying mechanisms are unclear. METHODS: Transcriptomic and proteomic analyses were performed on human cerebral microvascular endothelial cells following oxygen-glucose deprivation (OGD) or OGD plus recovery (OGD/R) to identify molecules and signaling pathways dysregulated by reperfusion. Major findings were further validated in a mouse model of cerebral ischemia and reperfusion. RESULTS: Transcriptomic analysis identified 390 differentially expressed genes (DEGs) between the OGD/R and OGD group. Pathway analysis indicated that these genes were mostly associated with inflammation, including the TNF signaling pathway, TGF-ß signaling pathway, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and NF-κB signaling pathway. Proteomic analysis identified 201 differentially expressed proteins (DEPs), which were primarily associated with extracellular matrix destruction and remodeling, impairment of endothelial transport function, and inflammatory responses. Six genes (DUSP1, JUNB, NFKBIA, NR4A1, SERPINE1, and THBS1) were upregulated by OGD/R at both the mRNA and protein levels. In mice with cerebral ischemia and reperfusion, brain TNF signaling pathway was activated by reperfusion, and inhibiting TNF-α with adalimumab significantly attenuated reperfusion-induced brain endothelial inflammation. In addition, the protein level of THBS1 was substantially upregulated upon reperfusion in brain endothelial cells and the peri-endothelial area in mice receiving cerebral ischemia. CONCLUSION: Our study reveals the key molecular signatures of brain endothelial reperfusion injury and provides potential therapeutic targets for the treatment of brain microvascular injury after reperfusion therapy in ischemic stroke.

Multi-target antibacterial mechanism of ruthenium polypyridine complexes with anthraquinone groups against Staphylococcus aureus.

Three new Ru(ii) complexes, [Ru(dtb)2PPAD](PF6)2 (Ru-1), [Ru(dmob)2PPAD](PF6)2 (Ru-2) and [Ru(bpy)2PPAD](PF6)2 (Ru-3) (dtb = 4,4'-di-tert-butyl-2,2'-bipyridine, dmob = 4,4'-dimethyl-2,2'-bipyridine, bpy = 2,2'-bipyridine and PPAD = 2-(pyridine-3-yl)-1H-imidazo[4,5f][1.10]phenanthracene-9,10-dione), were synthesized and characterized by 1H NMR and 13C NMR spectroscopy, HRMS and HPLC. Among them, Ru-1 showed excellent antimicrobial activity against Gram-positive bacteria Staphylococcus aureus (minimum inhibitory concentration (MIC) = 1 µg mL-1) and low hemolytic and cytotoxic activity. In addition, Ru-1 showed obviously rapid bactericidal activity, low resistance rate, bacterial biofilm destroying activity and high biosafety in vivo. Moreover, skin infection models and a mouse model of sepsis indicated that the anti-infective efficacy of Ru-1 was comparable to that of vancomycin. Mechanism exploration results showed that the antibacterial behavior is probably related with targeting of the bacterial cell membrane and inhibiting topoisomerase I.

Desferrioxamine Enhances 5-Aminolaevulinic Acid- Induced Protoporphyrin IX Accumulation and Therapeutic Efficacy for Hypertrophic Scar.

Hypertrophic scar is a common problem after skin burns or trauma which brings physical, psychological, and cosmetic problems to patients. Photodynamic therapy with 5-aminolevulinic acid (5-ALA) is a promising therapy for hypertrophic scar. However, clinical applications of 5-ALA are limited because of the low permeability of 5-ALA in the skin stratum corneum and the rapid binding of protoporphyrin IX (PpIX) with iron ions, which lead to insufficient PpIX production in target tissues. Herein, a mixture of 5-ALA and DFO (deferoxamine, a special iron chelator) was applied for the treatment of hypertrophic scar. 5-ALA/DFO could efficiently block the biotransformation of PpIX to heme, thus realizing a significant accumulation of photosensitizer. In addition, injection locally into the lesion was applied, which combined with enhanced photodynamic therapy to destroy hypertrophic scar fibroblasts. In vitro experiments showed that 5-ALA/DFO could increase more ROS generation by increasing the accumulation of PpIX, resulting in the apoptosis of hypertrophic scar fibroblasts. Furthermore, 5-ALA/DFO inhibited the proliferation and migration of hypertrophic scar fibroblasts. In vivo study showed that 5-ALA/DFO could effectively inhibit the formation of proliferative scar. Therefore, 5-ALA/DFO has the potential to enhance the photodynamic therapy of 5-ALA and provides a new treatment strategy for hypertrophic scar.

5-Aminolevulinic Acid-Hyaluronic Acid Complexes Enhance Skin Retention of 5-Aminolevulinic Acid and Therapeutic Efficacy in the Treatment of Hypertrophic Scar.

Hypertrophic scar is a serious skin disorder, which reduces the patient's quality of life. 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy has been used to treat patients with hypertrophic scar. However, the poor skin retention of 5-ALA limited the therapeutic effect. In this study, we constructed the 5-ALA-hyaluronic acid (HA) complex to potentially prolong the skin retention of 5-ALA for improving the therapeutic efficacy. HA is a polysaccharide with viscoelasticity and the carboxyl groups could conjugate with amino groups of 5-ALA via electrostatic interaction. The protoporphyrin IX (PpIX) assay revealed that 5-ALA-HA complexes markedly enhanced the skin retention, resulting in increased generation and accumulation of endogenous photosensitizer PpIX. Furthermore, 5-ALA-HA complexes allowed PpIX to be maintained at a high level for 12 h, much longer than the 3 h of 5-ALA alone. And then, the accumulative PpIX induced by 5-ALA-HA in human hypertrophic scar fibroblasts (HSF) was triggered by laser irradiation to produce sufficient reactive oxygen species, leading to efficient necrosis and apoptosis of HSF. In vivo therapeutic efficacy study indicated that 5-ALA-HA effectively reduced the appearance and scar thickness, and the scar elevation index with 5-ALA-HA treatment was significantly lower than other groups, suggesting that the 5-ALA-HA-treated scar became flattened and was closely matched to the unwounded tissues. Moreover, 5-ALA-HA treatment markedly downregulated the gene expression levels of α-SMA and TGF-ß1, demonstrating attenuated the scar formation and growth. Therefore, the 5-ALA-HA complex enhancing skin retention and PpIX accumulation at the lesion site provide a promising therapeutic strategy for hypertrophic scar.

Endoscopic ultrasonography in the evaluation of condition and prognosis of ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is usually diagnosed through histopathology, enteroscopy, clinical symptoms, and physical findings; however, it is difficult to accurately evaluate disease severity. AIM: To investigate the value of endoscopic ultrasonography (EUS) in the evaluation of the severity and prognosis of UC. METHODS: Patients with UC who were seen in our hospital from March 2019 to December 2020 were eligible, and disease severity was evaluated according to the modified Truelove and Witts and Mayo scores. We performed EUS, calculated the UC endoscopic index of severity (UCEIS) and EUS-UC scores, and administered appropriate treatment. The UCEIS and EUS-UC scores of patients were assessed in relation to disease severity, and the correlations between UCEIS and EUS-UC scores and disease severity was also analyzed. The UCEIS and EUS-UC scores before and after treatment were also compared. RESULTS: A total of 79 patients were included in this study. According to the Mayo Index, 23, 32, and 24 patients had mild, moderate and severe UC, respectively. The UCEIS and EUS-UC scores were higher in moderate cases (4.98 ± 1.04 and 5.01 ± 0.99, respectively) than in mild cases (1.56 ± 0.82 and 1.64 ± 0.91, respectively, P < 0.05). Furthermore, the UCEIS and EUS-UC scores (7.31 ± 1.10 and 7.59 ± 1.02, respectively) were higher in severe cases than in moderate cases (P < 0.05). According to the modified Truelove and Witts scores, 21, 36, and 22 patients were classified as having mild, moderate and severe disease, respectively. The UCEIS and EUS-UC scores were significantly higher in moderate disease (4.79 ± 1.11 and 4.96 ± 1.23, respectively) than in mild disease (1.71 ± 0.78 and 1.69 ± 0.88, respectively, P < 0.05). Additionally, the UCEIS and EUS-UC scores in severe disease (7.68 ± 1.22 and 7.81 ± 0.90, respectively) were significantly higher than in moderate disease (P < 0.05). The UCEIS and EUS-UC scores were significantly and positively correlated with disease severity according to the modified Truelove and Witts score and Mayo score (P < 0.05). The UCEIS and EUS-UC scores after 2 mo of treatment (3.88 ± 0.95 and 4.01 ± 1.14, respectively) and after 6 mo of treatment (1.59 ± 0.63 and 1.64 ± 0.59, respectively) were lower than the respective scores before treatment (5.93 ± 1.79 and 6.04 ± 2.01) (P < 0.05). CONCLUSION: EUS can clarify the status of UC and accurately evaluate the treatment response, providing an objective basis for formulation and adjustment of the treatment plan.

Lithium attenuates blood-brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/ß-catenin signaling-dependent mechanism in mice.

BACKGROUND: Vasogenic cerebral edema resulting from blood-brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation of endothelial Wnt/ß-catenin signaling substantially alleviates BBB breakdown in animals, no agents based on this mechanism are clinically available. Lithium is a medication used to treat bipolar mood disorders and can upregulate Wnt/ß-catenin signaling. METHODS: We evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV-induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt/ß-catenin signaling in mice with endothelial deletion of the Wnt7 coactivator Gpr124. RESULTS: Lithium treatment (3 mmol/kg) significantly decreased the hematoma volume (11.15 ± 3.89 mm3 vs. 19.97 ± 3.20 mm3 in vehicle controls, p = 0.0016) and improved the neurological outcomes of mice following ICH. Importantly, lithium significantly increased the BBB integrity, as evidenced by reductions in the levels of brain edema (p = 0.0312), Evans blue leakage (p = 0.0261), and blood IgG extravasation (p = 0.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt/ß-catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin-5 and ZO-1). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124-mediated endothelial Wnt/ß-catenin signaling. CONCLUSION: Our findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH.

Lane Mark Detection with Pre-Aligned Spatial-Temporal Attention.

Lane mark detection plays an important role in autonomous driving under structural environments. Many deep learning-based lane mark detection methods have been put forward in recent years. However, most of current methods limit their solutions within one single image and do not make use of the de facto successive image input during the driving scene, which may lead to inferior performance in some challenging scenarios such as occlusion, shadows, and lane mark degradation. To address the issue, we propose a novel lane mark detection network which takes pre-aligned multiple successive frames as inputs to produce more stable predictions. A Spatial-Temporal Attention Module (STAM) is designed in the network to adaptively aggregate the feature information of history frames to the current frame. Various structure of the STAM is also studied to ensure the best performance. Experiments on Tusimple and ApolloScape datasets show that our method can effectively improve lane mark detection and achieve state-of-the-art performance.

Simultaneous Semantic Segmentation and Depth Completion with Constraint of Boundary.

As the core task of scene understanding, semantic segmentation and depth completion play a vital role in lots of applications such as robot navigation, AR/VR and autonomous driving. They are responsible for parsing scenes from the angle of semantics and geometry, respectively. While great progress has been made in both tasks through deep learning technologies, few works have been done on building a joint model by deeply exploring the inner relationship of the above tasks. In this paper, semantic segmentation and depth completion are jointly considered under a multi-task learning framework. By sharing a common encoder part and introducing boundary features as inner constraints in the decoder part, the two tasks can properly share the required information from each other. An extra boundary detection sub-task is responsible for providing the boundary features and constructing cross-task joint loss functions for network training. The entire network is implemented end-to-end and evaluated with both RGB and sparse depth input. Experiments conducted on synthesized and real scene datasets show that our proposed multi-task CNN model can effectively improve the performance of every single task.

Regulation of IGFBP-5 expression during tumourigenesis and differentiation of oral keratinocytes.

To identify molecular events involved in the pathogenesis of oral squamous cell carcinoma (OSCC), genes differentially expressed in OSCC and non-cancerous matched tissue (NCMT) samples were analysed using a subtractive hybridization strategy. NCMT-enriching clones that have been linked to suppressor pathway in previous studies were subjected to advanced analyses. Complete absence of insulin-like growth factor binding protein-5 (IGFBP-5) expression at both the mRNA and the protein level was identified in nearly all (5/6) OSCC cell lines with the exception of the SCC25 cell line, which exhibited high IGFBP-5 expression. However, this protein is consistently present in cultured normal human oral keratinocytes (NHOKs). Immunohistochemistry revealed moderate to strong cytoplasmic immunoreactivity of IGFBP-5 in the stratum spinosum and stratum granulosum in the vast majority of NCMT samples. A remarkable reduction in IGFBP-5 immunoreactivity was detected in 56% (26/46) of OSCC samples, compared with the corresponding NCMT (p < 0.0001). Induction of differentiation in both NHOKs and SCC25 up-regulated IGFBP-5 expression. Administration of a green tea compound with anti-cancer properties, (-)-epigallocatechin 3-gallate, at a concentration of 5-20 micro g/ml also up-regulated IGFBP-5 expression in NHOKs in a dose-dependent manner. The findings suggest that IGFBP-5 may be an important factor in the differentiation of oral keratinocytes and that down-regulation of IGFBP-5 may be involved in the neoplastic transformation of oral keratinocytes.