The chemometrics analysis and integrated pharmacology approach to decipher the effect and mechanism between raw and processed cistanche tubulosa.

ETHNOPHARMACOLOGICAL RELEVANCE: Cistanche tubulosa (CT) is the dried fleshy stem with scaly leaves of Cistanche tubiflora (Schenk) Wight, which has the effects of tonifying the kidney-yang, benefiting the vital essence and blood, and moisturizing the intestines and laxatives. There are differences in the activity of CT before and after processing, but the mechanism of processing is not clear. AIM OF THE STUDY: The study aimed to compare the strength of action of CT before and after yellow-wine processing in the treatment of constipation and kidney yang deficiency and to identify the active ingredients responsible for the differences in activity before and after yellow-wine processing. MATERIALS AND METHODS: This study established the fingerprints of CT and PCT using HPLC to identify their shared components. Then efficacy of KYDS and FC were carried out to compare the differences between CT and PCT in terms of efficacy. Next, this study established the spectrum-effect relationship between the shared chemical components and the medical effects of CT and PCT using the gray correlation analysis and entropy methods. Ultimately, the activity of the analyzed chemical components was verified using the zebrafish model. RESULTS: CT was more effective than PCT in promoting intestinal peristalsis, regulating gastrointestinal hormone levels, and thus treating FC. PCT was more effective than CT in improving the level of hormone indexes of the hypothalamus-pituitary-target gland axis, replenishing blood, and enhancing immunity. Through the analysis of the spectrum-effect relationship, it was finally found that 5, 6, 12 (tubuloside A), and 13 (isoacteoside) might be more closely related to the activity of tonifying kidney yang, and peaks 9, 10, and 11 (acteoside) are more closely associated with the treatment of constipation, and peaks 3 (salidroside), 4, 1, 2 (geniposidic acid), and 8 (echinacoside) were associated with both kidney yang tonic and treatment of constipation. At the same time, an activity verification experiment showed that echinacoside, geniposidic acid, and salidroside were effective in the treatment of FC and KYDS, while acteoside was very effective in the treatment of FC, and tubuloside A was significant in supplementing the blood, which validated the spectrum-effect relationship analysis. CONCLUSION: This study proved that the raw CT had a better laxative effect, while the yellow-wine processed CT had a better kidney-yang tonic effect; moreover, spectrum-effect relationships were established to analyze the chemical components leading to changes in the activity of CT before and after yellow-wine processing.

Dexmedetomidine Prevents Chronic Incisional Pain After Brain Tumor Resection: A Secondary Analysis of the Randomized Control Trial.

BACKGROUND: Dexmedetomidine was reported to reduce postoperative acute pain after neurosurgery. However, the efficacy of dexmedetomidine for preventing chronic incisional pain is uncertain. METHODS: This article is a secondary analysis of a randomized, double-blind, placebo-controlled trial. Eligible patients were randomly allocated to either the dexmedetomidine group or the placebo group. Patients assigned to the dexmedetomidine group were given a 0.6 µg kg -1 dexmedetomidine bolus followed by a 0.4 µg kg -1 h -1 maintenance dose until dural closure; placebo patients were given comparable amounts of normal saline. The primary end point was the incidence of incisional pain at 3 months after craniotomy evaluated by numerical rating scale scores and defined as any score >0. The secondary end points were postoperative acute pain scores, sleep quality, and Short-Form McGill Pain Questionnaire (SF-MPQ-2) at 3 months after craniotomy. RESULTS: From January 2021 to December 2021, a total of 252 patients were included in the final analysis: the dexmedetomidine group (n = 128) and the placebo group (n = 124). The incidence of chronic incisional pain was 23.4% (30 of 128) in the dexmedetomidine group versus 42.7% (53 of 124) in the placebo group (risk ratio, 0.55; 95% confidence interval, 0.38-0.80; P = .001). The overall severity of chronic incisional pain was mild in both groups. Patients in the dexmedetomidine group had lower acute pain severity on movement than those in the placebo group for the first 3 days after surgery (all adjusted P < .01). Sleep quality did not differ between groups. However, the SF-MPQ-2 total sensory ( P = .01) and neuropathic pain descriptor ( P = .023) scores in the dexmedetomidine group were lower than those in the placebo group. CONCLUSIONS: Prophylactic intraoperative dexmedetomidine infusion reduces the incidence of chronic incisional pain as well as acute pain score after elective brain tumor resections.

The effect of tranexamic acid on intraoperative blood loss in patients undergoing brain meningioma resections: Study protocol for a randomized controlled trial.

INTRODUCTION: Tranexamic acid (TXA) has been proven to prevent thrombolysis and reduce bleeding and blood transfusion requirements in various surgical settings. However, the optimal dose of TXA that effectively reduce intraoperative bleeding and blood product infusion in patients undergoing neurosurgical resection of meningioma with a diameter ≥ 5 cm remains unclear. METHODS: This is a single-center, randomized, double-blinded, paralleled-group controlled trial. Patients scheduled to receive elective tumor resection with meningioma diameter ≥ 5 cm will be randomly assigned the high-dose TXA group, the low-dose group, and the placebo. Patients in the high-dose TXA group will be administered with a loading dose of 20 mg/kg TXA followed by continuous infusion TXA at a rate of 5 mg/kg/h. In the low-dose group, patients will receive the same loading dose of TXA followed by a continuous infusion of normal saline. In the control group, patients will receive an identical volume of normal saline. The primary outcome is the estimated intraoperative blood loss calculated using the following formula: collected blood volume in the suction canister (mL)-the volume of flushing (mL) + the volume from the gauze tampon (mL). Secondary outcomes include calculated intraoperative blood loss, intraoperative coagulation function assessed using thromboelastogram (TEG), intraoperative cell salvage use, blood product infusion, and other safety outcomes. DISCUSSION: Preclinical studies suggest that TXA could reduce intraoperative blood loss, yet the optimal dose was controversial. This study is one of the early studies to evaluate the impact of intraoperative different doses infusion of TXA on reducing blood loss in neurological meningioma patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05230381. Registered on February 8, 2022.

Risk factors for postoperative thrombosis-related complications in patients undergoing malignant brain tumor resection: a retrospective cohort study.

Introduction: Patients with malignant brain tumors frequently exhibit hypercoagulation and are at a high risk of postoperative thrombosis-related complications. However, the risk factors for postoperative thrombosis-related complications remain unclear. Methods: In this retrospective, observational study, we consecutively enrolled elective patients undergoing resection of malignant brain tumors from 26 November 2018 to 30 September 2021. The primary objective of the study was to identify risk factors for a composite of three major adverse events including postoperative lower limb deep venous thrombosis, pulmonary embolism, and cerebral ischemia. Results: A total of 456 patients were enrolled in this study, where 112 (24.6%) patients had postoperative thrombosis-related complications, 84 (18.4%) with lower limb deep venous thrombosis, 0 (0.0%) with pulmonary embolism, and 42 (9.2%) with cerebral ischemia. In a multivariate model, age more than 60 years (OR: 3.98, 95% CI: 2.30-6.88, P < 0.001), preoperative abnormal APTT (OR: 2.81, 95% CI: 1.06-7.42, P = 0.037), operation duration longer than 5 h (OR: 2.36, 95% CI: 1.34-4.16, P = 0.003), and admission to ICU (OR: 2.49, 95% CI: 1.21-5.12, P = 0.013) were independent risk factors of the postoperative deep vein thrombosis. Intraoperative plasma transfusion (OR: 6.85, 95% CI: 2.73-17.18, P < 0.001) was associated with significantly increased odds of deep vein thrombosis. Conclusion: Patients with craniocerebral malignant tumors have a high incidence of postoperative thrombosis-related complications. There is an increase in the odds of postoperative lower limb deep venous thrombosis in patients; over 60 years old, with preoperative abnormal APTT, undergoing surgeries longer than 5-h, admission to ICU, or receiving intraoperative plasma infusion. Fresh frozen plasma infusion should be used more cautiously, especially in patients with a high risk of thrombosis.

Human umbilical cord mesenchymal stem cell-derived exosomes promote murine skin wound healing by neutrophil and macrophage modulations revealed by single-cell RNA sequencing.

Introduction: Full-thickness skin wound healing remains a serious undertaking for patients. While stem cell-derived exosomes have been proposed as a potential therapeutic approach, the underlying mechanism of action has yet to be fully elucidated. The current study aimed to investigate the impact of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exosomes) on the single-cell transcriptome of neutrophils and macrophages in the context of wound healing. Methods: Utilizing single-cell RNA sequencing, the transcriptomic diversity of neutrophils and macrophages was analyzed in order to predict the cellular fate of these immune cells under the influence of hucMSC-Exosomes and to identify alterations of ligand-receptor interactions that may influence the wound microenvironment. The validity of the findings obtained from this analysis was subsequently corroborated by immunofluorescence, ELISA, and qRT-PCR. Neutrophil origins were characterized based on RNA velocity profiles. Results: The expression of RETNLG and SLC2A3 was associated with migrating neutrophils, while BCL2A1B was linked to proliferating neutrophils. The hucMSC-Exosomes group exhibited significantly higher levels of M1 macrophages (215 vs 76, p < 0.00001), M2 macrophages (1231 vs 670, p < 0.00001), and neutrophils (930 vs 157, p < 0.00001) when compared to control group. Additionally, it was observed that hucMSC-Exosomes elicit alterations in the differentiation trajectories of macrophages towards more anti-inflammatory phenotypes, concomitant with changes in ligand-receptor interactions, thereby facilitating healing. Discussion: This study has revealed the transcriptomic heterogeneity of neutrophils and macrophages in the context of skin wound repair following hucMSC-Exosomes interventions, providing a deeper understanding of cellular responses to hucMSC-Exosomes, a rising target of wound healing intervention.

The Influence of Trigeminocardiac Reflex on Postoperative Cardiac Adverse Events in Patients Undergoing Cerebellopontine Angle Tumor Resections: A Case-Control Study.

OBJECTIVE: To assess the potential impact of the trigeminocardiac reflex (TCR) on postoperative adverse cardiac events and to identify predictors of the TCR in cerebellopontine angle surgery. METHODS: Patients undergoing elective cerebellopontine angle surgery from October 1, 2015, to September 30, 2020, were recruited consecutively for this retrospective case-control study. The TCR was evaluated by reviewing electronic anesthesia records and defined as a drop in heart rate was >20%. Controls were identified from the same retrospective cohort and matched by age, sex, and similar (±5 days) surgery date in the ratio of 1:2. RESULTS: Of 2446 patients, 68 (2.78%) experienced TCR episodes. A total of 97 TCR episodes occurred among the 68 patients. In 2 TCR episodes, severe cardiac complications developed after surgery-myocardial injury in one case and cardiac arrest in the other case. The prevalence of adverse cardiovascular events was higher in the TCR group (60.3% vs. 36.0%, P = 0.001) than in the control group. The independent risk factor for the TCR in the multivariate condition logistic regression was tumor compression of the brainstem (odds ratio = 2.36, 95% confidence interval 1.40-3.95; P = 0.001). CONCLUSIONS: Intraoperative TCR episodes seemed to be associated with postoperative adverse cardiac events in patients undergoing cerebellopontine angle surgery. Moreover, tumor compression of the brainstem might be a risk factor for TCR episodes.

Dexmedetomidine administration during brain tumour resection for prevention of postoperative delirium: a randomised trial.

BACKGROUND: Delirium is common, especially after neurosurgery. Dexmedetomidine might reduce delirium by improving postoperative analgesia and sleep quality. We tested the primary hypothesis that dexmedetomidine administration during intracerebral tumour resection reduces the incidence of postoperative delirium. METHODS: This randomised, double-blind, placebo-controlled trial was conducted in two tertiary-care hospitals in Beijing. We randomised 260 qualifying patients to either dexmedetomidine (n=130) or placebo (n=130). Subjects assigned to dexmedetomidine were given a loading dose of 0.6 µg kg-1 followed by continuous infusion at 0.4 µg kg-1 h-1 until dural closure; subjects in the placebo group were given comparable volumes of normal saline. The primary outcome was the incidence of delirium, which was assessed with the Confusion Assessment Method twice daily during the initial 5 postoperative days. RESULTS: The average (standard deviation) age of participating patients was 45 (12) yr, duration of surgery was 4.2 (1.5) h, and patients assigned to dexmedetomidine were given an average of 126 (45) µg of dexmedetomidine. There was less delirium during the initial 5 postoperative days in patients assigned to dexmedetomidine (22%, 28 of 130 patients) than in those given placebo (46%, 60 of 130 patients) with a risk ratio of 0.51 (95% confidence interval: 0.36-0.74, P<0.001). Postoperative pain scores with movement, and recovery and sleep quality were improved by dexmedetomidine (P<0.001). The incidence of safety outcomes was similar in each group. CONCLUSIONS: Prophylactic intraoperative dexmedetomidine infusion reduced by half the incidence of delirium during the initial 5 postoperative days in patients recovering from elective brain tumour resection. CLINICAL TRIAL REGISTRATION: NCT04674241.

Effect of intraoperative goal-directed fluid therapy on the postoperative brain edema in patients undergoing high-grade glioma resections: a study protocol of randomized control trial.

INTRODUCTION: Brain edema is the most frequent postoperative complication after brain tumor resection, especially in patients with high-grade glioma. However, the effect of SVV-based goal-directed fluid therapy (GDFT) on postoperative brain edema and the prognosis remain unclear. METHODS AND ANALYSIS: This is a prospective, randomized, double-blinded, parallel-controlled trial aiming to observe whether stroke volume variation (SVV)-based GDFT could improve the postoperative brain edema in patients undergoing supratentorial high-grade gliomas compared with traditional fluid therapy. The patient will be given 3 ml/kg hydroxyethyl starch solution when the SVV is greater than 15% continuously for more than 5 min intraoperatively. The primary outcome will be postoperative cerebral edema volume on brain CT within 24 h. ETHICS AND DISSEMINATION: This trial has been registered at ClinicalTrials.gov (NCT03323580) and approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (reference number: KY2017-067-02). The findings will be disseminated in peer-reviewed journals and presented at national or international conferences relevant to the subject fields. TRIAL REGISTRATION: ClinicalTrials.gov NCT03323580 (First posted: October 27, 2017; Last update posted: February 11, 2022).

Safety of intravenous tranexamic acid in patients undergoing supratentorial meningiomas resection: protocol for a randomised, parallel-group, placebo control, non-inferiority trial.

INTRODUCTION: Growing evidence recommends antifibrinolytic agent tranexamic acid (TXA) to reduce blood loss and transfusions rate in various surgical settings. However, postoperative seizure, as one of the major adverse effects of TXA infusion, has been a concern that restricts its utility in neurosurgery. METHODS AND ANALYSIS: This is a randomised, placebo-controlled, non-inferiority trial. Patients with supratentorial meningiomas and deemed suitable for surgical resection will be recruited in the trial. Patients will be randomised to receive either a single administration of 20 mg/kg TXA or a placebo of the same volume with a 1:1 allocation ratio after anaesthesia induction. The primary endpoint is the cumulative incidence of early postoperative seizures within 7 days after craniotomy. Secondary outcomes include the incidence of non-seizure complications, changes of haemoglobin level from baseline, intraoperative blood loss, erythrocyte transfusion volume, Karnofsky Performance Status, all-cause mortality, and length of stay, and total hospitalisation cost. ETHICS AND DISSEMINATION: This trial is registered at ClinicalTrial.gov and approved by the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20200224). The findings will be disseminated in peer-reviewed journals and presented at national or international conferences relevant to subject fields. TRIAL REGISTRATION NUMBER: NCT04595786.

Perioperative Risk Factors Associated With Acute Kidney Injury in Patients After Brain Tumor Resection.

BACKGROUND: Acute kidney injury (AKI) is a serious complication after surgery. The aim of this study is to identify risk factors for postoperative AKI in patients undergoing brain tumor surgery. METHODS: This single-center, retrospective, matched case-control study included patients undergoing elective brain tumor surgery between January 2016 and December 2018 at Beijing Tiantan Hospital, Capital Medical University, China. Patients developing postoperative AKI were compared with controls without AKI matched by age, sex, and date of surgery in a ratio of 1:3. AKI was defined using the Kidney Disease Improving Global Outcomes criteria. RESULTS: A total of 9933 patients were identified for review, of which 115 (1.16%) developed AKI; 345 matched patients were included in the control group. AKI occurred most commonly within the first 24 hours (41/97, 42.3%) and 48 hours (33/94, 35.1%) after surgery. Preoperative administration of mannitol (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.04-2.60; P= 0.034), American Society of Anesthesiologists physical status III or higher (OR, 5.50; 95% CI, 2.23-13.59; P<0.001), preoperative blood glucose (OR, 2.53; 95% CI, 1.23-5.22; P=0.012), craniopharyngioma (OR, 8.96; 95% CI, 3.55-22.63; P<0.001), nonsteroidal anti-inflammatory drug administration (OR, 3.74; 95% CI, 1.66-8.42; P<0.001), and intraoperative hypotension (OR, 2.13; 95% CI, 1.21-3.75; P=0.009) were independent risk factors for postoperative AKI. CONCLUSION: Multiple factors, including preoperative administration of mannitol, are independently associated with the development of postoperative AKI in patients undergoing brain tumor surgery.

Autophagy-Related LC3 Accumulation Interacted Directly With LIR Containing RIPK1 and RIPK3, Stimulating Necroptosis in Hypoxic Cardiomyocytes.

The exact relationships and detailed mechanisms between autophagy and necroptosis remain obscure. Here, we demonstrated the link between accumulated autophagosome and necroptosis by intervening with autophagic flux. We first confirmed that the LC3 interacting region (LIR) domain is present in the protein sequences of RIPK1 and RIPK3. Mutual effects among LC3, RIPK1, and RIPK3 have been identified in myocardium and cardiomyocytes. Direct LC3-RIPK1 and LC3-RIPK3 interactions were confirmed by pull-down assays, and their interactions were deleted after LIR domain mutation. Moreover, after disrupting autophagic flux under normoxia with bafilomycin A1 treatment, or with LC3 or ATG5 overexpression adenovirus, RIPK1, RIPK3, p-RIPK3, and p-MLKL levels increased, suggesting necroptosis activation. Severe disruptions in autophagic flux were observed under hypoxia and bafilomycin A1 co-treated cardiomyocytes and myocardium and led to more significant activation of necroptosis. Conversely, after alleviating hypoxia-induced autophagic flux impairment with LC3 or ATG5 knockdown adenovirus, the effects of hypoxia on RIPK1 and RIPK3 levels were reduced, which resulted in decreased p-RIPK3 and p-MLKL. Furthermore, necroptosis was inhibited by siRNAs against RIPK1 and RIPK3 under hypoxia or normoxia. Based on our results, LIR domain mediated LC3-RIPK1 and LC3-RIPK3 interaction. Besides, autophagosome accumulation under hypoxia lead to necrosome formation and, in turn, necroptosis, while when autophagic flux was uninterrupted, RIPK1 and RIPK3 were cleared through an autophagy-related pathway which inhibited necroptosis. These findings provide novel insights for the role of LC3 in regulating cardiomyocyte necroptosis, indicating its therapeutic potential in the prevention and treatment of hypoxic myocardial injury and other hypoxia-related diseases.

Electric field-induced suppression of PTEN drives epithelial-to-mesenchymal transition via mTORC1 activation.

BACKGROUND: Naturally occurring electric fields (EFs) are an intrinsic property of wounds. Endogenous EFs in skin wounds play critical roles in the dynamic and well-ordered biological process of wound healing. The epithelial-to-mesenchymal transition (EMT) allows keratinocytes to transition from sedentary cells to motile cells, facilitating wound healing. However, EMT-related studies have been performed without considering endogenous EFs. Thus, the relationship between electrical signals and the EMT remain elusive. OBJECTIVE: Phosphatase and tension homolog (PTEN) and mammalian target of rapamycin complex 1 (mTORC1) are key molecules in sensing electrical cues, and they play significant roles in cellular responses to EFs. In addition, these molecules are closely related to the occurrence of the EMT in other cells. We used primary human keratinocytes to investigate the influence of EFs on the EMT as well as the roles of PTEN and mTORC1 in this process. METHODS: The effects of EFs on the EMT were investigated by analyzing the levels of specific proteins and transcription factors. The roles of mTORC1 and PTEN and their relationship with each other were studied via pharmacological inhibition or genetic knockdown. A Zeiss imaging system and scratch assays were used to study single-cell motility and monolayer cell migration. RESULTS: EFs induced a range of both biochemical changes (e.g., increased Snail, Slug, vimentin, and N-cadherin expression, decreased E-cadherin expression) and functional changes (e.g., enhanced migratory capacity) that are characteristic of the EMT. EF-stimulated cells exhibited suppressed PTEN expression, and further PTEN downregulation led to the acquisition of more mesenchymal features and the loss of epithelial characteristics, which was accompanied by increased migratory capacity. PTEN overexpression reversed the EF-induced EMT and inhibited the migratory capacity of keratinocytes. EF-induced mTORC1 activation was a required component of the causal relationship between PTEN suppression and the EMT, as mTORC1 inhibition reversed the EMT induced by PTEN downregulation. CONCLUSIONS: Our data demonstrate that the EF-induced suppression of PTEN drives the EMT via mTORC1 activation, thereby revealing a new and promising role of EFs in facilitating wound reepithelialization. These results provide a novel perspective regarding the significance of EFs in wound healing; therefore, electrical stimulation offers a new avenue of wound management for improved and accelerated wound healing.

Potent peptide agonists for human melanocortin 3 and 4 receptors derived from enzymatic cleavages of human beta-MSH(5-22) by dipeptidyl peptidase I and dipeptidyl peptidase IV.

Human beta-MSH(1-22) was first isolated from human pituitary as a 22-amino acid (aa) peptide derived from a precursor protein, pro-opiomelanocortin (POMC). However, Bertagna et al. demonstrated that a shorter human beta-MSH(5-22), (DEGPYRMEHFRWGSPPKD), is a true endogenous peptide produced in human hypothalamus. In this report, we demonstrated that in vitro enzymatic cleavage of native human beta-MSH(5-22) with two ubiquitous dipeptidyl peptidases (DPP), DPP-I and DPP-IV, generated two potent MC3/4R peptide analogues, beta-MSH(7-22) (GPYRMEHFRWGSPPKD) and beta-MSH(9-22) (YRMEHFRWGSPPKD). In fact, the MC4R binding affinity and functional potency of beta-MSH(7-22) (Ki=4.6 nM, EC50=0.6 nM) and beta-MSH(9-22) (Ki=5.7 nM, EC50=0.6 nM) are almost an order of magnitude greater than those of their parent peptide, beta-MSH(5-22) (MC4R, Ki=23 nM, EC50= 3nM). Furthermore, the DPP-I/DPP-IV cleaved peptide, beta-MSH(9-22), when administered intracerebroventricularly (ICV) at a dose of 3 nmol/rat, potently induced an acute negative energy balance in a diet-induced obese rat model, while its parent molecule, beta-MSH(5-22), administered at the same dose did not have any effect. These data suggest that DPP-I and DPP-IV may play a role in converting the endogenous beta-MSH(5-22) to more potent peptides that regulate energy homeostasis in the hypothalamus.