GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression.

BACKGROUND: Lactate has emerged as a critical regulator within the tumor microenvironment, including glioma. However, the precise mechanisms underlying how lactate influences the communication between tumor cells and tumor-associated macrophages (TAMs), the most abundant immune cells in glioma, remain poorly understood. This study aims to elucidate the impact of tumor-derived lactate on TAMs and investigate the regulatory pathways governing TAM-mediated tumor-promotion in glioma. METHODS: Bioinformatic analysis was conducted using datasets from TCGA and CGGA. Single-cell RNA-seq datasets were analyzed by using UCSC Cell Browser and Single Cell Portal. Cell proliferation and mobility were evaluated through CCK8, colony formation, wound healing, and transwell assays. Western blot and immunofluorescence staining were applied to assess protein expression and cell distribution. RT-PCR and ELISA were employed to identify the potential secretory factors. Mechanistic pathways were explored by western blotting, ELISA, shRNA knockdown, and specific inhibitors and activators. The effects of pathway blockades were further assessed using subcutaneous and intracranial xenograft tumor models in vivo. RESULTS: Elevated expressions of LDHA and MCT1 were observed in glioma and exhibited a positive correlation with M2-type TAM infiltration. Lactate derived from glioma cells induced TAMs towards M2-subtype polarization, subsequently promoting glioma cells proliferation, migration, invasion, and mesenchymal transition. GPR65, highly expressed on TAMs, sensed lactate-stimulation in the TME, fueling glioma cells malignant progression through the secretion of HMGB1. GPR65 on TAMs triggered HMGB1 release in response to lactate stimulation via the cAMP/PKA/CREB signaling pathway. Disrupting this feedback loop by GPR65-knockdown or HMGB1 inhibition mitigated glioma progression in vivo. CONCLUSION: These findings unveil the intricate interplay between TAMs and tumor cells mediated by lactate and HMGB1, driving tumor progression in glioma. GPR65, selectively highly expressed on TAMs in glioma, sensed lactate stimulation and fostered HMGB1 secretion via the cAMP/PKA/CREB signaling pathway. Blocking this feedback loop presents a promising therapeutic strategy for GBM.

Application of endoport-assisted neuroendoscopic techniques in lateral ventricular tumor surgery.

Objective: The objective of this study was to investigate the clinical experience and therapeutic efficiency of Endoport-assisted neuroendoscopic surgery for resection of lateral ventricular tumors. The key points and application value of this surgical technique were additionally discussed. Methods: A retrospective analysis was conducted on the clinical and follow-up data of 16 patients who underwent endoport-assisted neuroendoscopic surgery for lateral ventricular tumors at the Department of Neurosurgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, between January 2018 and September 2020. The surgical procedures, complications and outcomes were analyzed. Results: The study included a total of 16 patients (5 males and 11 females) with lateral ventricular tumors, with a mean age of 43.2 years (18-70 years old). The tumors were distributed as follows: 5 cases involved the body of the lateral ventricle, 3 involved the frontal horn and body, 3 involved the occipital horn, 2 involved the trigone, 2 involved the frontal horn, and 1 case involved the occipital horn and body. Perioperative complications were analyzed, revealing 1 case of intraoperative acute epidural hematoma intraoperative and 2 cases of postoperative obstructive hydrocephalus. All complications were promptly managed. Postoperative MRI revealed that 14 cases (88%) achieved total resection, while 2 cases (12%) achieved subtotal resection. During the follow-up of 6-38 months, no recurrence was observed. The patient diagnosed with glioblastoma died 16 months after surgery (GOS=1), while the remaining patients have successfully resumed to normal daily life with a GOS score of 5. Conclusion: In conclusion, endoport-assisted neuroendoscopic surgery proved to be a minimally invasive and effective technique for resecting lateral ventricular tumors, with acceptable complications. It effectively utilizes the benefits of close observation, comprehensive exposure, and reduced tissue damage. Therefore, endoport-assisted neuroendoscopic surgery is suitable for the resection of lateral ventricular tumors.

Endoscopic far-lateral supracerebellar infratentorial approach for resection of dumbbell-shaped trigeminal schwannoma: surgical techniques and preliminary results.

BACKGROUND: Trigeminal schwannomas (TSs) are mostly benign tumors. However, dumbbell-shaped TSs are most challenging for surgeons and pose a high surgical risk. OBJECTIVE: We describe the technique of the purely endoscopic far-lateral supracerebellar infratentorial approach (EFL-SCITA) for removing dumbbell-shaped TSs and further discuss the feasibility of this approach and our experience. METHODS: EFL-SCITA was performed for resection of 5 TSs between January 2020 and March 2023. The entire procedure was performed endoscopically with the goal of total tumor resection. During the operation, the tumor was exposed in close proximity and multiple angles under the endoscope, and the peri-tumor nerves were carefully identified and protected, especially the normal trigeminal fiber bundles around the tumor. RESULTS: All the tumors of 5 patients involved the middle and posterior cranial fossa, of which total removal was achieved in 2 patients and near-total removal in 3 patients. The most common preoperative symptoms were relieved after surgery. Two patients had postoperative mild facial paralysis (House-Brackmann grade II), and 1 patient had abducens palsy; both recovered during the follow-up period. Two patients experienced new postoperative facial hypesthesia, and 1 experienced mastication weakness, which did not recover. There was no tumor recurrence or residual tumor growth during the follow-up period in any of the patients. CONCLUSION: EFL-SCITA is a new and effective alternative for the surgical treatment of TSs. For dumbbell-shaped TSs, this approach provides sufficient surgical field exposure and freedom of operation.

Can leaf drought tolerance predict species abundance and its changes in tropical-subtropical forests?

Climate change has resulted in an increase in drought severity in the species-rich tropical and subtropical forests of southern China. Exploring the spatiotemporal relationship between drought-tolerance trait and tree abundance provides a means to elucidate the impact of droughts on community assembly and dynamics. In this study, we measured the leaf turgor loss point (πtlp) for 399 tree species from three tropical forest plots and three subtropical forest plots. The plot area was 1 ha and tree abundance was calculated as total basal area per hectare according to the nearest community census data. The first aim of this study was to explore πtlp abundance relationships in the six plots across a range of precipitation seasonality. Additionally, three of the six plots (two tropical forests and one subtropical forest) had consecutive community censuses data (12-22 years) and the mortality ratios and abundance year slope of tree species were analyzed. The second aim was to examine whether πtlp is a predictor of tree mortality and abundance changes. Our results showed that tree species with lower (more negative) πtlp were more abundant in the tropical forests with relative high seasonality. However, πtlp was not related to tree abundance in the subtropical forests with low seasonality. Moreover, πtlp was not a good predictor of tree mortality and abundance changes in both humid and dry forests. This study reveals the restricted role of πtlp in predicting the response of forests to increasing droughts under climate change.

Tree growth is correlated with hydraulic efficiency and safety across 22 tree species in a subtropical karst forest.

Karst forests are habitats in which access to soil water can be challenging for plants. Therefore, safe and efficient xylem water transport and large internal water storage may benefit tree growth. In this study, we selected 22 tree species from a primary subtropical karst forest in southern China and measured their xylem anatomical traits, saturated water content (SWC), hydraulic conductivity (Ks) and embolism resistance (P50). Additionally, we monitored growth of diameter at breast height (DBH) in 440 individual trees of various sizes over three consecutive years. Our objective was to analyze the relationships between xylem structure, hydraulic efficiency, safety, water storage and growth of karst tree species. The results showed significant differences in structure but not in hydraulic traits between deciduous and evergreen species. Larger vessel diameter, paratracheal parenchyma and higher SWC were correlated with higher Ks. Embolism resistance was not correlated with the studied anatomical traits, and no tradeoff with Ks was observed. In small trees (5-15 cm DBH), diameter growth rate (DGR) was independent of hydraulic traits. In large trees (>15 cm DBH), higher Ks and more negative P50 accounted for higher DGR. From lower to greater embolism resistance, the size-growth relationship shifted from growth deceleration to acceleration with increasing tree size in eight of the 22 species. Our study highlights the vital contributions of xylem hydraulic efficiency and safety to growth rate and dynamics in karst tree species; therefore, we strongly recommend their integration into trait-based forest dynamic models.

Case report: A rare case of thyrotropin-secreting pituitary macroadenoma with diffuse calcification presenting with hyperthyroidism and literature review.

Background: Thyroid-stimulating hormone (TSH)-secreting pituitary adenomas (TSHomas) are rare and usually present with hyperthyroidism. Calcification in pituitary tumors is an infrequent finding. Herein, we report an extremely rare case of TSHoma with diffuse calcification. Case description: A 43-year-old man was admitted to our department with a complaint of palpitations. An endocrinological examination revealed elevated serum levels of TSH, free triiodothyronine (FT3), and free thyroxin, whereas the physical examination revealed no obvious abnormality. Computerized tomography (CT) showed a sellar mass with diffuse calcification. Contrast-enhanced T1-weighted images revealed a less-enhancing tumor without obvious suprasellar or parasellar expansion. The tumor was completely removed via endoscopic transnasal-sphenoidal surgery. Microscopically, nests of cells were inconspicuous among the diffuse psammoma bodies. Expression of TSH was patchy, and only several TSH-positive cells were observed. Postoperatively, the serum levels of TSH, FT3, and FT4 decreased to their normal range. Follow-up MR images showed no evidence of residual tumor or regrowth after the resection. Conclusions: Herein, we report a rare case of TSHoma with diffuse calcification that presented with hyperthyroidism. A correct and early diagnosis was made according to the European Thyroid Association guidelines. This tumor was completely removed via endoscopic transnasal-transsphenoidal surgery (eTSS), and thyroid function was normalized after the operation.

Rab32 promotes glioblastoma migration and invasion via regulation of ERK/Drp1-mediated mitochondrial fission.

The highly widespread and infiltrative nature of glioblastoma multiforme (GBM) makes complete surgical resection hard, causing high recurrence rate and poor patients' prognosis. However, the mechanism underlying GBM migration and invasion is still unclear. In this study, we investigated the role of a Ras-related protein Rab32 on GBM and uncovered its underlying molecular and subcellular mechanisms that contributed to GBM aggressiveness. The correlation of Rab32 expression with patient prognosis and tumor grade was investigated by public dataset analysis and clinical specimen validation. The effect of Rab32 on migration and invasion of GBM had been evaluated using wound healing assay, cell invasion assay, as well as protein analysis upon Rab32 manipulations. Mitochondrial dynamics of cells upon Rab32 alterations were detected by immunofluorescence staining and western blotting. Both the subcutaneous and intracranial xenograft tumor model were utilized to evaluate the effect of Rab32 on GBM in vivo. The expression level of Rab32 is significantly elevated in the GBM, especially in the most malignant mesenchymal subtype, and is positively correlated with tumor pathological grade and poor prognosis. Knockdown of Rab32 attenuated the capability of GBM's migration and invasion. It also suppressed the expression levels of invasion-related proteins (MMP2 and MMP9) as well as mesenchymal transition markers (N-cadherin, vimentin). Interestingly, Rab32 transported Drp1 to mitochondrial from the cytoplasm and modulated mitochondrial fission in an ERK1/2 signaling-dependent manner. Furthermore, silencing of Rab32 in vivo suppressed tumor malignancy via ERK/Drp1 axis. Rab32 regulates ERK1/2/Drp1-dependent mitochondrial fission and causes mesenchymal transition, promoting migration and invasion of GBM. It serves as a novel therapeutic target for GBM, especially for the most malignant mesenchymal subtype. Schematic of Rab32 promotes GBM aggressiveness via regulation of ERK/Drp1-mediated mitochondrial fission. Rab32 transports Drp1 from the cytoplasm to the mitochondria and recruits ERK1/2 to activate the ser616 site of Drp1, which in turn mediates mitochondrial fission and promotes mesenchymal transition, migration and invasion of GBM.

Comparison of the preoperative diagnostic accuracy of BIPSS versus MRI for Cushing disease: a single-centre experience.

BACKGROUND: Cushing disease (CD) arises due to a pituitary corticotroph adenoma, which is the most common cause of Cushing syndrome (CS). Bilateral inferior petrosal sinus sampling (BIPSS) is a safe method for differentiating CD from ectopic adrenocorticotropic hormone (ACTH)-dependent CS. Enhanced high-resolution magnetic resonance imaging (MRI) can localize tiny pituitary lesions. The aim of this study was to compare the preoperative diagnostic accuracy of BIPSS versus MRI for CD in CS patients. We performed a retrospective study of patients who underwent BIPSS and MRI between 2017 and 2021. Low- and high-dose dexamethasone suppression tests were performed. Blood samples were collected simultaneously from the right and left catheter and femoral vein before and after desmopressin stimulation. MRI images were obtained, and endoscopic endonasal transsphenoidal surgery (EETS) was performed in confirmed CD patients. Dominant sides of ACTH secretion during BIPSS and MRI were compared with surgical findings. RESULTS: Twenty-nine patients underwent BIPSS and MRI. CD was diagnosed in 28 patients, 27 of whom received EETS. Localizations of microadenomas by MRI and BIPSS agreed with the EETS findings in 96% and 93% of the cases, respectively. BIPSS and EETS were successfully performed on all patients. CONCLUSION: BIPSS was the most accurate method (gold standard) for establishing a preoperative diagnosis of pituitary-dependent CD and was more sensitive than MRI in diagnosing microadenoma. High-resolution MRI with enhancement had an advantage over BIPSS in microadenoma lateralization diagnostics. The combined use of MRI and BIPSS could improve the preoperative diagnosis accuracy in ACTH-dependent CS patients.

Initial Experience With Transoral Endoscopic Thyroidectomy via the Submental and Vestibular Approach for the Treatment of Thyroid Cancer: A Retrospective Cohort Study.

Background: Transoral endoscopic thyroidectomy vestibular approach is feasible and safe but has some unavoidable limitations, such as sensory changes in the center of the chin region. We aim to report our initial experience in performing transoral endoscopic thyroidectomy via the submental and vestibular approach for the treatment of thyroid cancer. Patients and Methods: This retrospective cohort study included patients with thyroid cancer confirmed by fine-needle aspiration who underwent endoscopic thyroidectomy and central lymph node dissection via the submental and vestibular approaches between November 2019 and January 2020. Patients' clinicopathological characteristics, operation details, and postoperative complications were analyzed. Results: Fifteen surgeries were performed successfully. The mean ± standard deviation age of the patients was 37 ± 10.8 years, the average duration of surgery was 146.5 ± 34.6 min, and the median intraoperative blood loss was 11.1 ± 6.3 mL. None of the surgeries were converted to open thyroidectomy. According to postoperative pathology, all cases involved papillary thyroid carcinoma or papillary thyroid microcarcinoma. One patient developed transient recurrent laryngeal nerve paralysis. No patient developed skin numbness at the center of the chin region. Conclusions: Transoral endoscopic thyroidectomy via the submental and vestibular approach is effective and safe in patients with thyroid cancer and does not lead to skin numbness at the center of the chin region. This technique is beneficial for surgeons less experienced in performing transoral thyroid surgery as it involves using a short and direct route to the thyroid gland, which can reduce the difficulty in establishing the first operative space to some extent.

Neuroprotective effects of mild hypothermia against traumatic brain injury by the involvement of the Nrf2/ARE pathway.

BACKGROUND: Traumatic brain injury (TBI) is the leading cause of death and disability worldwide. Mild hypothermia (32-35°C) has been found to show neuroprotective effects against TBI. However, the specific mechanism is still elusive. In the current study, we explored the relationship between oxidative damage after TBI and treatment with mild hypothermia as well as the underlying molecular mechanisms. METHODS: We used the closed cortex injury model to perform the brain injury and a temperature monitoring and control system to regulate the body temperature of mice after injury. Adult male C57BL/6 mice were adopted in this study and divided into four experimental groups. Tissue samples were harvested 24 h after injury. RESULTS: First, our results showed that treatment with mild hypothermia significantly improved neurobehavioral dysfunction and alleviated brain edema after TBI. Moreover, treatment with mild hypothermia enhanced the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase and reduced the accumulation of lipid peroxidation malondialdehyde. Importantly, the expression and activation of the nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) pathway were upregulated by mild hypothermia after TBI. Finally, treatment with hypothermia significantly decreased the cell apoptosis induced by TBI. CONCLUSION: Our results showed that the protective effects of mild hypothermia after TBI may be achieved by the upregulation of the Nrf2-ARE pathway and revealed Nrf2 as a potentially important target to improve the prognosis of TBI.

Oridonin attenuates hind limb ischemia-reperfusion injury by modulating Nrf2-mediated oxidative stress and NLRP3-mediated inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Oridonin (Ori), extracted from Isodon rubescens (Hemsl.) H.Hara, is a well-known traditional Chinese herbal medicinal product that possesses antioxidant and anti-inflammatory activities. Oxidative stress and inflammation are the main pathophysiological mechanisms in hindlimb IR injury. However, whether Ori has a protective effect on hind limb IR injury is unknown. AIM OF THE STUDY: The present study was designed to determine the effect of Ori on hindlimb IR injury and its relationship with oxidative stress and inflammation. MATERIALS AND METHODS: The hind limb IR injury model in mice was used to evaluate the protective effect and related mechanisms of Ori. Forty-eight C57BL/6 mice (n = 12 per group) were randomly divided into four groups: Sham group; IR group; IR + Ori (10 mg/kg) group and IR + Ori (20 mg/kg) group. Mice in the IR and IR + Ori groups were subjected to hindlimb IR injury, while mice in the Sham group were subjected to no hindlimb IR injury. HE staining, Masson's staining, TTC staining, DHE staining, TUNEL staining, western blotting analysis and quantitative real-time PCR were employed to explore the mechanisms by which Ori exerts a protective effect on a classical hindlimb IR model in mice. RESULTS: We found that Ori pretreatment prevented muscle damage and decreased cell apoptosis levels compared with the vehicle control. Moreover, the SOD2, CAT, MDA and ROS levels in muscle showed that Ori could significantly reduce oxidative stress in hindlimb IR mice, while the IL-1ß and TNF-α levels in muscle showed that Ori could significantly attenuate IR-induced inflammation. We also found that Ori could increase the expression of Nrf2 and its downstream protein HO-1 and inhibit the expression levels of NLRP3-related proteins (NLRP3, ASC and Caspase-1) in vivo. CONCLUSIONS: Our study suggested that Ori has a protective effect on hindlimb IR injury, which may be related to Nrf2-mediated oxidative stress and NLRP3-mediated inflammasome activation.

Neuroprotective Effect of Oridonin on Traumatic Brain Injury via Inhibiting NLRP3 Inflammasome in Experimental Mice.

NLRP3 inflammasome has been considered as an important contributor to inflammation and neuronal death after traumatic brain injury (TBI). Oridonin (Ori), the major active ingredient of Chinese herbal medicine Rabdosia rubescens, has been proved to be a covalent NLRP3 inhibitor with strong anti-inflammation activity. The purpose of this study was to investigate the effect of Ori on inflammation and brain injury induced by TBI. Adult male C57BL/6 mice were subjected to closed-head injury using Hall's weight-dropping method. Ori was injected directly intraperitoneally at a dose of 10 mg/kg within 30 min after TBI and injected once daily until the experiments ended. Our results showed that NLRP3 inflammasome was activated within 24 h post-TBI. The expression of NLRP3 inflammasome components (NLRP3, ASC, and caspase-1) was significantly decreased after treatment with Ori. Besides, the secretion of IL-1ß and IL-18, downstream inflammatory factors of activated caspase-1, was reduced by Ori treatment. Importantly, Ori administration further protected the blood-brain barrier, alleviated brain edema, reduced cortical lesion volume, decreased cell death, and attenuated neurological deficits after TBI. Our findings indicate that NLRP3 inflammasome participated in the secondary injury after TBI and the application of Ori may provide neuroprotection via inhibiting NLRP3 inflammasome in animal models, suggesting that Ori might be a promising candidate for patients with TBI.

Leaf hydraulic safety margin and safety-efficiency trade-off across angiosperm woody species.

Leaf hydraulic conductance and the vulnerability to water deficits have profound effects on plant distribution and mortality. In this study, we compiled a leaf hydraulic trait dataset with 311 species-at-site combinations from biomes worldwide. These traits included maximum leaf hydraulic conductance (Kleaf), water potential at 50% loss of Kleaf (P50leaf), and minimum leaf water potential (Ψmin). Leaf hydraulic safety margin (HSMleaf) was calculated as the difference between Ψmin and P50leaf. Our results indicated that 70% of the studied species had a narrow HSMleaf (less than 1 MPa), which was consistent with the global pattern of stem hydraulic safety margin. There was a positive relationship between HSMleaf and aridity index (the ratio of mean annual precipitation to potential evapotranspiration), as species from humid sites tended to have larger HSMleaf. We found a significant relationship between Kleaf and P50leaf across global angiosperm woody species and within each of the different plant groups. This global analysis of leaf hydraulic traits improves our understanding of plant hydraulic response to environmental change.