Exerkine FNDC5/irisin-enriched exosomes promote proliferation and inhibit ferroptosis of osteoblasts through interaction with Caveolin-1.

Postmenopausal osteoporosis is a prevalent metabolic bone disorder characterized by a decrease in bone mineral density and deterioration of bone microstructure. Despite the high prevalence of this disease, no effective treatment for osteoporosis has been developed. Exercise has long been considered a potent anabolic factor that promotes bone mass via upregulation of myokines secreted by skeletal muscle, exerting long-term osteoprotective effects and few side effects. Irisin was recently identified as a novel myokine that is significantly upregulated by exercise and could increase bone mass. However, the mechanisms underlying exercise-induced muscle-bone crosstalk remain unclear. Here, we identified that polyunsaturated fatty acids (arachidonic acid and docosahexaenoic acid) are increased in skeletal muscles following a 10-week treadmill exercise programme, which then promotes the expression and release of FNDC5/irisin. In osteoblasts, irisin binds directly to Cav1, which recruits and interacts with AMP-activated protein kinase α (AMPKα) to activate the AMPK pathway. Nrf2 is the downstream target of the AMPK pathway and increases the transcription of HMOX1 and Fpn. HMOX1 is involved in regulating the cell cycle and promotes the proliferation of osteoblasts. Moreover, upregulation of Fpn in osteoblasts enhanced iron removal, thereby suppressing ferroptosis in osteoblasts. Additionally, we confirmed that myotube-derived exosomes are involved in the transportation of irisin and enter osteoblasts through caveolae-mediated endocytosis. In conclusion, our findings highlight the crucial role of irisin, present in myotube-derived exosomes, as a crucial regulator of exercise-induced protective effects on bone, which provides novel insights into the mechanisms underlying exercise-dependent treatment of osteoporosis.

Single-Cell Transcriptomics Reveals the Heterogeneity of the Immune Landscape of IDH-Wild-Type High-Grade Gliomas.

Isocitrate dehydrogenase (IDH)-wild-type (WT) high-grade gliomas, especially glioblastomas, are highly aggressive and have an immunosuppressive tumor microenvironment. Although tumor-infiltrating immune cells are known to play a critical role in glioma genesis, their heterogeneity and intercellular interactions remain poorly understood. In this study, we constructed a single-cell transcriptome landscape of immune cells from tumor tissue and matching peripheral blood mononuclear cells (PBMC) from IDH-WT high-grade glioma patients. Our analysis identified two subsets of tumor-associated macrophages (TAM) in tumors with the highest protumorigenesis signatures, highlighting their potential role in glioma progression. We also investigated the T-cell trajectory and identified the aryl hydrocarbon receptor (AHR) as a regulator of T-cell dysfunction, providing a potential target for glioma immunotherapy. We further demonstrated that knockout of AHR decreased chimeric antigen receptor (CAR) T-cell exhaustion and improved CAR T-cell antitumor efficacy both in vitro and in vivo. Finally, we explored intercellular communication mediated by ligand-receptor interactions within the tumor microenvironment and PBMCs and revealed the unique cellular interactions present in the tumor microenvironment. Taken together, our study provides a comprehensive immune landscape of IDH-WT high-grade gliomas and offers potential drug targets for glioma immunotherapy.

Bioinspired total synthesis and biological activity of Pegaharine A.

BACKGROUND: Phytopathogens cause various diseases by parasitizing crops, reducing crop yield and resulting in substantial economic losses in agricultural production. A novel type isolated from the perennial herbaceous Peganum harmala L. seeds, ß-carboline alkaloids pegaharine A (PA), has become a hot topic in developing plant-originated green pesticides owing to their significant physiological activities. RESULTS: A scalable bioinspired total synthesis of PA is accomplished in the present work. The systematical biological assay study showed that PA exhibited moderate inhibitory activity against nine tested plant pathogenic fungi and showed significant inhibitory activity in vitro against the three tested plant pathogenic bacteria. Most noteworthy is the inhibitory rates of PA on Xanthomonas oryzae pv. oryzae (Xoo), X. oryzae pv. oryzicola (Xoc) and X. axonopodis pv. citri (Xac) of 93.6%, 92.1% and 86.1%, respectively, which are better than the control drug, bismerthiazol (63.4%, 61.2% and 53.7% at 100 µg mL-1 concentration). Furthermore, the EC50 value of PA against Xoo, Xoc and Xac was 52.2, 60.0 and 65.1 µg mL-1 , respectively, superior to 72.9, 64.2 and 70.1 µg mL-1 of the control drug. Moreover, the anti-Xoo mechanistic studies revealed that PA exerted its antibacterial effects by increasing the permeability of the bacterial membrane, reducing the extracellular polysaccharide content and inducing morphological changes in bacterial cells. CONCLUSION: A novel ß-carboline alkaloid, PA, was prepared by biomimetic total synthesis. Its significant antibacterial activity was closely related to the permeation of bacterial cell membranes, which was confirmed by anti-Xoo mechanistic studies. More importantly, the structure could be regarded as a model for developing novel bactericides. © 2023 Society of Chemical Industry.

Total Synthesis of Natural Terpenoids Enabled by Cobalt Catalysis.

Transition metal catalysis plays an essential role in the total synthesis of natural products. Cobalt-mediated asymmetric catalysis has successfully been used as a primary or a secondary step in the total synthesis of natural products, especially terpenoids. Terpenoids represent one of the most prominent families among various categories of natural products, attracting immense attention due to their promising physiological activities. This review summarizes the recent advances toward the total synthesis of terpenoids by cobalt-mediated asymmetric catalysis, which may shed some light on their future synthetic efforts toward natural pesticides such as celanguline, azadirachtin, etc.

KIF26B Is Overexpressed in Medulloblastoma and Promotes Malignant Progression by Activating the PI3K/AKT Pathway.

Medulloblastoma is one of the most common malignant tumors of the central nervous system in children. Although KIF2B was reported as an oncogene in several malignant tumor types, its role in medulloblastoma has not been studied so far. The PCR results of our study showed that KIF26B is highly expressed in medulloblastoma, and its high expression is associated with a high clinical stage. Knockdown the expression of KIF26B could significantly impair the proliferation and migration of medulloblastoma cells. KIF26B promotes the malignant progression of medulloblastoma by affecting the expression of phosphorylation of key proteins in the PI3K/AKT signaling pathway. With the help of 740 Y-P, activating the pi3k signaling pathway can partially rescue the phenotype. Therefore, our experimental results suggest that KIF26B is a potential target for medulloblastoma.

A Synthetic View on Momilactones and Related 9ß-H Pimarane Skeleton Diterpenoids.

Allelochemicals are secondary metabolites produced from plants and used to prevent and control the invasion of other plants and microorganisms, with broad application prospects in crop protection. Structurally, momilactones belong to 9ß-H pimarane diterpenoids, one of rice's significant allelochemicals with anti-weeds and antibacterial activity. Rare studies have been reported with the synthesis challenges of the unique 9ß-H pimarane skeleton. Hence, synthetic strategies of momilactones and related 9ß-H pimarane skeleton are reviewed from 1984 to 2021.

Solitary fibrous tumor of the pineal region with delayed ectopic intracranial metastasis: A case report and review of the literature.

RATIONALE: Solitary fibrous tumors of central nervous system are rare spindle-cell mesenchymal tumors. Although most are benign in nature, malignant transformation and extracranial metastasis have been reported. Up to now, only one case of CSF dissemination was described. Here we described an extremely rare case of intracranial Solitary fibrous tumors arising from the pineal region with a delayed ectopic metastasis. PATIENT CONCERNS: A 35-year-old female presented with double vision, memory disturbance and unsteady gait was referred to our center. MRI showed an irregular mass in the pineal region. DIAGNOSES: The patient was diagnosed as pineal tumor, with unknown pathology. INTERVENTIONS: Gross total resection was achieved and the pathologic studies confirmed a solitary fibrous tumor. Thirty-nine months later local recurrence occurred and gamma-knife radiotherapy was offered. Seven months later, MRI found a metastasis in the left temporal lobe. Surgical resection was conducted and pathological analysis revealed changes in cell morphology, counts and Ki-67 level, confirmed the diagnosis of solitary fibrous tumor/hemangiopericytoma (WHO Grade III). The patient received post-operational radiotherapy. OUTCOMES: The patient was followed up for 7 months with no signs of recurrence. LESSONS: Here, we report an extremely rare case of primary solitary fibrous tumor of pineal region with delayed intracranial ectopic metastasis, together with literature review of metastatic solitary fibrous tumors. Strict surveillance is strongly recommended, considering the malignant potential of this seemingly benign disease entity. Complete resection of the tumor is the treatment of first choice and radiotherapy might be an effective adjuvant therapy for high grade SFT/HPCs.

Relationship between plasma high mobility group box-1 protein levels and clinical outcomes of aneurysmal subarachnoid hemorrhage.

BACKGROUND: High-mobility group box 1 (HMGB1), originally described as a nuclear protein that binds to and modifies DNA, is now regarded as a central mediator of inflammation by acting as a cytokine. However, the association of HMGB1 in the peripheral blood with disease outcome and cerebrovasospasm has not been examined in patients with aneurysmal subarachnoid hemorrhage. METHODS: In this study, 303 consecutive patients were included. Upon admission, plasma HMGB1 levels were measured by ELISA. The end points were mortality after 1 year, in-hospital mortality, cerebrovasospasm and poor functional outcome (Glasgow Outcome Scale score of 1 to 3) after 1 year. RESULTS: Upon admission, the plasma HMGB1 level in patients was statistically significantly higher than that in healthy controls. A multivariate analysis showed that the plasma HMGB1 level was an independent predictor of poor functional outcome and mortality after 1 year, in-hospital mortality and cerebrovasospasm. A receiver operating characteristic curve showed that plasma HMGB1 level on admission statistically significantly predicted poor functional outcome and mortality after 1 year, in-hospital mortality and cerebrovasospasm of patients. The area under the curve of the HMGB1 concentration was similar to those of World Federation of Neurological Surgeons (WFNS) score and modified Fisher score for the prediction of poor functional outcome and mortality after 1 year, and in-hospital mortality, but not for the prediction of cerebrovasospasm. In a combined logistic-regression model, HMGB1 improved the area under the curve of WFNS score and modified Fisher score for the prediction of poor functional outcome after 1 year, but not for the prediction of mortality after 1 year, in-hospital mortality, or cerebrovasospasm. CONCLUSIONS: HMGB1 level is a useful, complementary tool to predict functional outcome and mortality after aneurysmal subarachnoid hemorrhage. However, HMGB1 determination does not add to the accuracy of prediction of the clinical outcomes.

Delayed intracerebral hemorrhage secondary to ventriculoperitoneal shunt: two case reports and a literature review.

Ventriculoperitoneal (VP) shunt has become a popular operation to achieve cerebrospinal fluid (CSF) diversion, but is associated with many complications. Postoperative delayed intracerebral hemorrhage is a kind of rare but severe event, which has not thus far been reported in retrospective case analyses. Here we present two cases of delayed intracerebral hemorrhage, along the path of the ventricular catheter, which occurred on postoperative days 3 and 5. We also provide a literature review regarding this rare complication.

Detection of copeptin in peripheral blood of patients with aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Copeptin has been proposed as a prognostic marker in acute illness. This study investigated the ability of copeptin to predict the disease outcome and cerebrovasospasm in the patients with aneurysmal subarachnoid hemorrhage. METHODS: In this retrospective study, 303 consecutive patients were included. Upon admission, plasma copeptin levels were measured by enzyme-linked immunosorbent assay. The end points were mortality after 1 year, in-hospital mortality, cerebrovasospasm and poor functional outcome (Glasgow Outcome Scale score of 1-3) after 1 year. RESULTS: Upon admission, plasma copeptin level in patients was statistically significantly higher than that in healthy controls. A multivariate analysis showed that plasma copeptin level was an independent predictor of poor functional outcome and mortality after 1 year, in-hospital mortality and cerebrovasospasm. A receiver operating characteristic curve showed that plasma copeptin level on admission predicted poor functional outcome and mortality after 1 year, in-hospital mortality and cerebrovasospasm of patients statistically significantly. The area under curve of the copeptin concentration was similar to those of World Federation of Neurological Surgeons (WFNS) score and modified Fisher score for the prediction of poor functional outcome and mortality after 1 year, and in-hospital mortality, but not for the prediction of cerebrovasospasm. In a combined logistic-regression model, copeptin improved the area under curve of WFNS score and modified Fisher score for the prediction of poor functional outcome after 1 year, but not for the prediction of mortality after 1 year, in-hospital mortality, and cerebrovasospasm. CONCLUSIONS: Copeptin level is a useful, complementary tool to predict functional outcome and mortality after aneurysmal subarachnoid hemorrhage.