Isofraxidin attenuates dextran sulfate sodium-induced ulcerative colitis through inhibiting pyroptosis by upregulating Nrf2 and reducing reactive oxidative species.

BACKGROUND: Ulcerative colitis (UC), a non-specific gastrointestinal disease, is commonly managed with aminosalicylic acids and immunosuppressive agents to control inflammation and relieve symptoms, despite frequent relapses. Isofraxidin is a coumarin compound extracted from traditional Chinese medicine, exhibiting anti-inflammatory and antioxidant properties; however, its alleviating effect on UC remains unclear. Therefore, we investigated the mechanism of isofraxidin in lipopolysaccharide (LPS)-induced cell inflammation in human intestinal epithelial cell (HIEC) and human colorectal adenocarcinoma cells (Caco-2), as well as in dextran sulfate sodium (DSS)-induced UC in mice. METHODS: We established colitis models in HIEC and Caco-2 cells and mice with LPS and DSS, respectively. Additionally, NLRP3 knockout mice and HIEC cells transfected with NLRP3 silencing gene and ML385 illustrated the role of isofraxidin in pyroptosis and oxidative stress. Data from cells and mice analyses were subjected to one-way analysis of variance or a paired t-test. RESULTS: Isofraxidin significantly alleviated LPS-induced cell inflammation and reduced lactic dehydrogenase release. Isofraxidin also reversed DSS- or LPS-induced pyroptosis in vivo and in vitro, increasing the expression of pyroptosis-related proteins. Moreover, isofraxidin alleviated oxidative stress induced by DSS or LPS, reducing reactive oxidative species (ROS), upregulation nuclear factor erythroid 2-related factor 2 (Nrf2), and promoting its entry into the nucleus. Mechanistically, ML385 reversed the inhibitory effect of isofraxidin on ROS and increased pyroptosis. CONCLUSION: Isofraxidin can inhibit pyroptosis through upregulating Nrf2, promoting its entry into the nucleus, and reducing ROS, thereby alleviating DSS-induced UC. Our results suggest isofraxidin as a promising therapeutic strategy for UC treatment.

Exosome-based regenerative rehabilitation: A novel ice breaker for neurological disorders.

Neurological disorders affect a large population, often leading to different levels of disability and resulting in decreased quality of life. Due to the limited recovery obtained from surgical procedures and other medical approaches, a large number of patients with prolonged dysfunction receive neurorehabilitation protocols to improve their neural plasticity and regeneration. However, the poor neural regeneration ability cannot effectively rebuild the tissue integrity and neural functional networks; consequently, the prognoses of neurorehabilitation remain undetermined. To increase the chances of neural regeneration and functional recovery for patients with neurological disorders, regenerative rehabilitation was introduced with combined regenerative medicine and neurorehabilitation protocols to repair neural tissue damage and create an optimized biophysical microenvironment for neural regeneration potential. With the deepening of exosome research, an increasing number of studies have found that the systemic therapeutic effects of neurorehabilitation approaches are mediated by exosomes released by physically stimulated cells, which provides new insight into rehabilitative mechanisms. Meanwhile, exosome therapy also serves as an alternative cell-free therapy of regenerative medicine that is applied in partnership with neurorehabilitation approaches and formulates exosome-based neurological regenerative rehabilitation. In this study, we review the current state of exosome-associated neurorehabilitation. On the one hand, we focus on presenting the varied mediating effects of exosomes in neurorehabilitation protocols of specific neurological pathologies; on the other hand, we discuss the diverse combinations of exosome therapies and neurorehabilitation approaches in the field of neurological regenerative rehabilitation, aiming to increase the awareness of exosome research and applications in the rehabilitation of neurological disorders.

Autophagy induced by PP121 alleviates MSU crystal-induced acute gouty arthritis via inhibition of the NLRP3 inflammasome.

Acute gouty arthritis (AGA) is a frequent self-limiting inflammatory condition produced by the deposition of monosodium urate (MSU) crystals in the joints and periarticular tissues of patients with hyperuricemia. However, no effective interventional measures currently exist for AGA. Pyroptosis, a kind of pro-inflammatory programmed cell death, plays a crucial role in MSU crystal-induced inflammation and represents a potential treatment target for AGA. Therefore, we determined the therapeutic benefits and mechanism of PP121, a pyroptosis-related compound, on AGA. First, we injected an MSU crystal solution intra-articularly into the left foot pad of C57BL/6 mice to create an AGA mouse model. Subsequent treatment with PP121 substantially decreased tissue damage, pro-inflammatory cytokine release, and inflammatory cell infiltration caused by MSU crystals in the ankle joint. Consistent with these observations, the beneficial effects of PP121 on AGA were cancelled in Beclin1+/-(Becn1+/-) mice. Furthermore, after PP121 treatment, super-resolution microscopy revealed a strong relationship between lysosome-connected membrane protein/light chain 3 positive vesicles and the nucleotide-binding domain of leucine-rich family pyrin domain-containing 3 (NLPR3), demonstrating that PP121 promotes phagocytosis of the NLPR3 inflammasome. In summary, PP121-mediated autophagy can improve degradation of the NLRR3 inflammasome in AGA, which suggests the therapeutic potential of PP121 in AGA.

CC-115 Mediates GSDME-Dependent Pyroptosis in Lung Adenocarcinoma Through the Akt/Bax Pathway.

Chemotherapeutic agents remain the first-line treatment for solid tumors, including lung cancer, but chemotherapy resistance is hampering global efforts to treat this disease. CC-115 is a novel antitumoral compound used in phase I clinical trials. However, it is unclear whether CC-115 is effective against lung adenocarcinoma (LUAD). In the present study, we found that CC-115 induced lytic cell death in A549 and H1650 tumor cells via swelling of cells and formation of large bubbles on the plasma membrane that closely resembled those typical of pyroptosis, a type of programmed cell death linked to chemotherapy. We demonstrated that CC-115 exerts antitumor effects in LUAD through gasdermin E (GSDME)-mediated pyroptosis by acting as a dual inhibitor of DNA-PK and mTOR. CC-115 can inhibit Akt phosphorylation, impairing its inhibitory effect on Bax, thereby inducing pyroptosis via the Bax-mitochondrial intrinsic pathway. CC-115-induced pyroptosis was abrogated by treatment with the Akt activator SC79 or by depletion of Bax. Importantly, CC-115 significantly upregulated the expression of Bax and GSDME-N in a xenograft mouse model, with a reduction in tumor size. Our results revealed that CC-115 suppresses tumor growth by inducing GSDME-mediated pyroptosis through the Akt/Bax-mitochondrial intrinsic pathway, indicating CC-115 as a promising therapeutic agent for LUAD.

Differential regulation and preventive mechanisms of green tea powder with different quality attributes on high-fat diet-induced obesity in mice.

Tea powder has been reported to have some physiological functions. However, there is no report on whether there are differences in the active ingredients of tea powder with different qualities and whether there are different prebiotic mechanisms. This study was aimed to investigate the effects of different qualities of tea powder on preventing obesity from different aspects, namely antioxidation, inflammation, lipid-lowering, and intestinal flora, using an obesity mouse model. The results showed that all three types of tea powder with different qualities could reduce body weight and decrease serum TC, TG, and LDL-C. However, tea powder with different quality attributes exhibited diverse modulatory effects and mechanisms. Tender tea powder contained more tea polyphenols, and it had a better effect on improving oxidative stress. Tender tea powder significantly decreased the abundances of Blautia, Bilophila, and Oscillibacter, and increased the abundances of Alloprevotella, Lachnoclostridium, Romboutsia, and Ruminococcaceae_UCG-004. Coarse tea powder contained more dietary fiber, and had a better effect on reducing the food intake and improving lipid metabolism, which could reduce lipid synthesis and increase lipid ß-oxidation. Coarse tea powder significantly decreased the abundance of Dubosiella and increased the abundances of the Lachnospiraceae_NK4A136 group and Coriobacteriaceae_UCG-002. Our findings provide a theoretical reference for the comprehensive utilization of tea powder.

Increased susceptibility of irradiated mice to Aspergillus fumigatus infection via NLRP3/GSDMD pathway in pulmonary bronchial epithelia.

BACKGROUND: Aspergillus fumigatus infection is difficult to diagnose clinically and can develop into invasive pulmonary aspergillosis, which has a high fatality rate. The incidence of Aspergillus fumigatus infection has increased die to widespread application of radiotherapy technology. However, knowledge regarding A. fumigatus infection following radiation exposure is limited, and the underlying mechanism remains unclear. In this study, we established a mouse model to explore the effect of radiation on A. fumigatus infection and the associated mechanisms. METHODS: In this study, a mouse model of A. fumigatus infection after radiation was established by irradiating with 5 Gy on the chest and instilling 5 × 107/ml Aspergillus fumigatus conidia into trachea after 24 h to explore the effect and study its function and mechanism. Mice were compared among the following groups: normal controls (CON), radiation only (RA), infection only (Af), and radiation + infection (RA + Af). Staining analyses were used to detect infection and damage in lung tissues. Changes in protein and mRNA levels of pyroptosis-related molecules were assessed by western blot analysis and quantitative reverse transcription polymerase chain reaction, respectively. Protein concentrations in the serum and alveolar lavage fluid were also measured. An immunofluorescence colocalization analysis was performed to confirm that NLRP3 inflammasomes activated pyroptosis. RESULTS: Radiation destroyed the pulmonary epithelial barrier and significantly increased the pulmonary fungal burden of A. fumigatus. The active end of caspase-1 and gasdermin D (GSDMD) were highly expressed even after infection. Release of interleukin-18 (IL-18) and interleukin-1ß (IL-1ß) provided further evidence of pyroptosis. NLRP3 knockout inhibited pyroptosis, which effectively attenuated damage to the pulmonary epithelial barrier and reduced the burden of A. fumigatus. CONCLUSIONS: Our findings indicated that the activation of NLRP3 inflammasomes following radiation exposure increased susceptibility to A. fumigatus infection. Due to pyroptosis in lung epithelial cells, it resulted in the destruction of the lung epithelial barrier and further damage to lung tissue. Moreover, we found that NLRP3 knockout effectively inhibited the pyroptosis and reducing susceptibility to A. fumigatus infection and further lung damage. Overall, our results suggest that NLRP3/GSDMD pathway mediated-pyroptosis in the lungs may be a key event in this process and provide new insights into the underlying mechanism of infection. Video abstract.

Current Advances in Structure-Function Relationships and Dose-Dependent Effects of Human Milk Oligosaccharides.

HMOs (human milk oligosaccharides) are the third most important nutrient in breast milk. As complex glycans, HMOs play an important role in regulating neonatal intestinal immunity, resisting viral and bacterial infections, displaying anti-inflammatory characteristics, and promoting brain development. Although there have been some previous reports of HMOs, a detailed literature review summarizing the structure-activity relationships and dose-dependent effects of HMOs is lacking. Hence, after introducing the structures and synthetic pathways of HMOs, this review summarizes and categorizes identified structure-function relationships of HMOs. Differential mechanisms of different structural HMOs utilization by microorganisms are summarized. This review also emphasizes the recent advances in the interactions between different health benefits and the variance of dosage effect based on in vitro cell tests, animal experiments, and human intervention studies. The potential relationships between the chemical structure, the dosage selection, and the physiological properties of HMOs as functional foods are vital for further understanding of HMOs and their future applications.

2'-Fucosyllactose Ameliorates Oxidative Stress Damage in d-Galactose-Induced Aging Mice by Regulating Gut Microbiota and AMPK/SIRT1/FOXO1 Pathway.

The imbalance of reactive oxygen species is the main cause in aging, accompanied by oxidative stress. As the most abundant in human milk oligosaccharides (HMOs), 2'-Fucosyllactose (2'-FL) has been confirmed to have great properties in immunity regulation and anti-inflammatory. The research on 2'-FL is focused on infants currently, while there is no related report of 2'-FL for the elderly. A d-galactose-induced accelerated aging model was established to explore the protective effect of 2'-FL on the intestines and brain in mice. In this study, 2'-FL significantly reduced oxidative stress damage and inflammation in the intestines of aging mice, potentially by regulating the sirtuin1 (SIRT1)-related and nuclear factor E2-related factor 2 (Nrf2) pathways. In addition, 2'-FL significantly improved the gut mucosal barrier function and increased the content of short-chain fatty acids (SCFAs) in the intestine. The gut microbiota analysis indicated that 2'-FL mainly increased the abundance of probiotics like Akkermansia in aging mice. Moreover, 2'-FL significantly inhibited apoptosis in the brains of aging mice, also increasing the expression of SIRT1. These findings provided a basis for learning the benefits of 2'-FL in the aging process.

Prenatal diagnosis of isolated lateral facial cleft by ultrasonography and three-dimensional printing: A case report.

BACKGROUND: Lateral facial clefts are atypical with a low incidence in the facial cleft spectrum. With the development of ultrasonography (US) prenatal screening, such facial malformations can be detected and diagnosed prenatally rather than at birth. Although three-dimensional US (3DUS) can render the fetus' face via 3D reconstruction, the 3D images are displayed on two-dimensional screens without field depth, which impedes the understanding of untrained individuals. In contrast, a 3D-printed model of the fetus' face helps both parents and doctors develop a more comprehensive understanding of the facial malformation by creating more interactive aspects. Herein, we present an isolated lateral facial cleft case that was diagnosed via US combined with a 3D-printed model. CASE SUMMARY: A 31-year-old G2P1 patient presented for routine prenatal screening at the 22nd wk of gestation. The coronal nostril-lip section of two-dimensional US (2DUS) demonstrated that the fetus' bilateral oral commissures were asymmetrical, and left oral commissure was abnormally wide. The left oblique-coronal section showed a cleft at the left oral commissure which extended to the left cheek. The results of 3DUS confirmed the cleft. Furthermore, we created a model of the fetal face using 3D printing technology, which clearly presented facial malformations. The fetus was diagnosed with a left lateral facial cleft, which was categorized as a No. 7 facial cleft according to the Tessier facial cleft classification. The parents terminated the pregnancy at the 24th wk of gestation after parental counseling. CONCLUSION: In the diagnostic course of the current case, in addition to the traditional application of 2D and 3DUS, we created a 3D-printed model of the fetus, which enhanced diagnostic evidence, benefited the education of junior doctors, improved parental counseling, and had the potential to guide surgical planning.

Postoperative discal pseudocyst and its similarities to discal cyst: A case report.

BACKGROUND: Postoperative discal pseudocyst (PDP) is a rare condition that presents after surgery for lumbar disc herniation. Due to the lack of information, the diagnosis and treatment of PDP remain controversial. Herein, we report a PDP case that occurred following percutaneous endoscopic lumbar discectomy and received conservative treatment. Additionally, we review all the published literature regarding PDP and propose our hypothesis regarding PDP pathology. CASE SUMMARY: A 23-year-old man presented with a relapse of low back pain and numbness in his left lower extremity after undergoing percutaneous endoscopic lumbar discectomy for lumbar disc herniation. Repeat magnetic resonance imaging demonstrated a cystic lesion at the surgical site with communication with the inner disc. The patient was diagnosed as having PDP. The patient received conservative treatment, which resulted in rapid improvement and spontaneous regression of the lesion, and had a favorable outcome in follow-up. CONCLUSION: PDP and discal cyst (DC) exhibit similarities in both histological and epidemiological characteristics, which indicates the same pathological origin of PDP and DC. The iatrogenic annular injury during discectomy might accelerate the pathological progression of DC. For patients with mild to moderate symptoms, conservative treatment can lead to great improvement, even inducing spontaneous regression. However, surgical cystectomy is necessary in patients with neurological deficits and where conservative treatment is ineffective.

Malignant solitary fibrous tumor of the greater omentum: A case report and review of literature.

BACKGROUND: Malignant solitary fibrous tumors (SFTs) account for 15%-20% of all SFTs, and malignant SFTs arising from the greater omentum are extremely rare. Most malignant SFTs of the greater omentum are diagnosed via pathological examinations after surgery. In this study, we report a case of malignant omental SFT and review the published literature on this rare malignancy. CASE SUMMARY: A 64-year-old female presented with an abdominal mass, and underwent exploratory surgery, during which a huge tumor originating from the greater omentum and intraperitoneal implants were identified and resected. The results of the pathological examination, immunohistochemistry staining, and gene sequencing led to the diagnosis of malignant SFT of the greater omentum. The patient died one and a half years later due to tumor recurrence and metastasis. CONCLUSION: This is the first report of the application of gene sequencing in the diagnosis of malignant SFTs of the greater omentum.

LncRNA DLEU2 promotes tumour growth by sponging miR-337-3p in human osteosarcoma.

According to statistics, abnormal regulation of lncRNAs pivotally influences multiple malignant tumours. DLEU2, as one of these lncRNAs, is detected to be related to growth and development of tumours. The molecular mechanisms of DLEU2 in osteosarcoma, however, are still unknown. QRT-PCR was adopted to analyse the correlations of clinicopathological features and prognosis of osteosarcoma cases with DLEU2. The influences of DLEU2 on cell migration and viability were evaluated independently by experiments in vitro and in vivo. Bioinformatics analysis, RNA immunoprecipitation (RIP) assay, and dual luciferase reporter gene assay confirmed the specific binding of DLEU2 to miR-337-3p. Moreover, rescue experiments were carried out to further evaluate the regulatory association between miR-337-3p expression and DLEU2. In osteosarcoma tissues and cells, DLEU2 expression level was raised remarkably in comparison with that in para-carcinoma normal tissues, and DLEU2 high expression had associations with poor prognosis, tumour stages, and TS of osteosarcoma cases. Cell migration ability and viability were blocked by DLEU2 knockdown but enhanced by ectopic DLEU2 expression in vitro and in vivo. Additionally, DLEU2 was found to sponge miR-337-3p and trigger the stimulating effect in osteosarcoma cells, which would be suppressed by miR-337-3p mimics. Furthermore, a negative correlation existed between miR-337-3p expression and DLEU2 in osteosarcoma tissues. This study manifests that DLEU2 sponges miR-337-3p to accelerate tumour growth and is confirmed to be a factor for poor prognosis of osteosarcoma cases. SIGNIFICANCE OF THE STUDY: LncRNA DLEU2 has been reported to be dysregulated in many tumours; however, the functions and underlying mechanism of DLEU2 in osteosarcoma pathogenesis are still unknown. This study is the first to demonstrate the roles of DLEU2 in osteosarcoma and revealed that DLEU2 may serve as a ceRNA to sponge miR-337-3p and then promote the progression of osteosarcoma, providing a potential therapeutic target for osteosarcoma.

Effect of glial cells on remyelination after spinal cord injury.

Remyelination plays a key role in functional recovery of axons after spinal cord injury. Glial cells are the most abundant cells in the central nervous system. When spinal cord injury occurs, many glial cells at the lesion site are immediately activated, and different cells differentially affect inflammatory reactions after injury. In this review, we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process. Activated astrocytes influence proliferation, differentiation, and maturation of oligodendrocyte precursor cells, while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury. Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.

Thymosin Beta-4 Recombinant Adeno-associated Virus Enhances Human Nucleus Pulposus Cell Proliferation and Reduces Cell Apoptosis and Senescence.

BACKGROUND: Thymosin beta-4 (TB-4) is considered key roles in tissue development, maintenance and pathological processes. The study aimed to prove TB-4 positive biological function on nucleus pulposus (NP) cell apoptosis and slowing the process of cell aging while increasing the cell proliferation. METHODS: TB-4 recombinant adeno-associated virus (AAV) was constructed and induced to human NP cells. Cell of same group were cultured without gene modification as controlled group. Proliferation capacity and cell apoptosis were observed during 6 passages of the cells. Morphology and expression of the TB-4 gene were documented as parameter of cell activity during cell passage. RESULTS: NP cells with TB-4 transfection has normal TB-4 expression and exocytosis. NP cells with TB-4 transfection performed significantly higher cell activity than that at the control group in each generation. TB-4 recombinant AAV-transfected human NP cells also show slower cell aging, lower cell apoptosis and higher cell proliferation than control group. CONCLUSIONS: TB-4 can prevent NP cell apoptosis, slow NP cell aging and promote NP cell proliferation. AAV transfection technique was able to highly and stably express TB-4 in human NP cells, which may provide a new pathway for innovation in the treatment of intervertebral disc degenerative diseases.