Interventional Effect of Donkey Bone Collagen Peptide Iron Chelate on Cyclophosphamide Induced Immunosuppressive Mice.

Immunodeficiency can disrupt normal physiological activity and function. In this study, donkey bone collagen peptide (DP) and its iron chelate (DPI) were evaluated their potential as immunomodulators in cyclophosphamide (Cytoxan®, CTX)-induced Balb/c mice. The femoral tissue, lymphocytes, and serum from groups of mice were subjected to hematoxylin and eosin (H&E) staining, methylthiazolyldiphenyl-tetrazolium bromide (MTT) cell proliferation assays, and enzyme-linked immunosorbent assay (ELISA), respectively. Furthermore, a non-targeted metabolomics analysis based on UPLC-MS/MS and a reverse transcription polymerase chain reaction (RT-qPCR) technology were used to explore the specific metabolic pathways of DPI regulating immunocompromise. The results showed that CTX was able to significantly reduce the proliferative activity of mouse splenic lymphocytes and led to abnormal cytokine expression. After DP and DPI interventions, bone marrow tissue damage was significantly improved. In particular, DPI showed the ability to regulate the levels of immune factors more effectively than Fe2+ and DP. Furthermore, metabolomic analysis in both positive and negative ion modes showed that DPI and DP jointly regulated the levels of 20 plasma differential metabolites, while DPI and Fe2+ jointly regulated 14, and all 3 jointly regulated 10. Fe2+ and DP regulated energy metabolism and pyrimidine metabolism pathways, respectively. In contrast, DPI mainly modulated the purine salvage pathway and the JAK/STAT signaling pathway, which are the key to immune function. Therefore, DPI shows more effective immune regulation than Fe2+ and DP alone, and has good application potential in improving immunosuppression.

Intraoperative hypotension is associated with decreased long-term survival in older patients after major noncardiac surgery: Secondary analysis of three randomized trials.

STUDY OBJECTIVE: To assess the association of intraoperative hypotension with long-term survivals in older patients after major noncardiac surgery mainly for cancer. DESIGN: A secondary analysis of databases from three randomized trials with long-term follow-up. SETTING: The underlying trials were conducted in 17 tertiary hospitals in China. PATIENTS: Patients aged 60 to 90 years who underwent major noncardiac thoracic or abdominal surgeries (≥ 2 h) in a single center were included in this analysis. EXPOSURES: Restricted cubic spline models were employed to determine the lowest mean arterial pressure (MAP) threshold that was potentially harmful for long-term survivals. Patients were arbitrarily divided into three groups according to the cumulative duration or area under the MAP threshold. The association between intraoperative hypotension exposure and long-term survivals were analyzed with the Cox proportional hazard regression models. MEASUREMENTS: Our primary endpoint was overall survival. Secondary endpoints included recurrence-free and event-free survivals. MAIN RESULTS: A total of 2664 patients (mean age 69.0 years, 34.9% female sex, 92.5% cancer surgery) were included in the final analysis. MAP < 60 mmHg was adopted as the threshold of intraoperative hypotension. Patients were divided into three groups according to duration under MAP < 60 mmHg (<1 min, 1-10 min, and > 10 min) or area under MAP <60 mmHg (< 1 mmHg⋅min, 1-30 mmHg⋅min, and > 30 mmHg⋅min). After adjusting confounders, duration under MAP < 60 mmHg for > 10 min was associated with a shortened overall survival when compared with the < 1 min patients (adjusted hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.09 to 1.57, P = 0.004); area under MAP < 60 mmHg for > 30 mmHg⋅min was associated with a shortened overall survival when compared with the < 1 mmHg⋅min patients (adjusted HR 1.40, 95% CI 1.16 to 1.68, P < 0.001). Similar associations exist between duration under MAP < 60 mmHg for > 10 min or area under MAP < 60 mmHg for > 30 mmHg⋅min and recurrence-free or event-free survivals. CONCLUSIONS: In older patients who underwent major noncardiac surgery mainly for cancer, intraoperative hypotension was associated with worse overall, recurrence-free, and event-free survivals.

Deciphering the molecular mechanism of long non-coding RNA HIF1A-AS1 regulating pancreatic cancer cells.

Background: HIF1A-AS1, an antisense transcript of HIF1α gene, is a 652-bp LncRNA that is globally expressed in multiple tissues of animals. Recent evidence indicated that HIF1A-AS1 was involved in tumorigenesis of several types of cancer. However, the role of lncRNA in PC has not been reported, and the molecular mechanism remains elusive. Results: In order to investigate the role of HIF1A-AS1 in PC, it was overexpressed in some PC cell lines (PANC-1, PATU8988 and SW1990), and a series of experiments including cell viability detection, flow cytometry, transwell migration, clone formation and wound healing were performed. Functionally, the results indicated that overexpression of HIF1A-AS1 could greatly inhibit proliferation and migration and promote apoptosis of PC cells. Moreover, the isobaric tags for relative and absolute quantification (iTRAQ) quantitative proteomics analysis was implemented to explore the underlying mechanism and the results indicated that OE of HIF1A-AS1 globally affected the expression levels of multiple proteins associated with metabolism of cancer. At last, the network analysis revealed that most of these differentially expressed proteins (DEPs) were integrated and severed essential roles in regulatory function. In view of this, we guessed HIF1A-AS1 overexpression induced the dysfunction of metabolism and disordered proteins' translation, which may account for its excellent tumour suppressor effect. Conclusions: HIF1A-AS1 altered the cell function of PC cell lines via affecting the expression of numerous proteins. In summary, HIF1A-AS1 may exhibit a potential therapeutic effect on PC, and our study provided useful information in this filed.

The rehabilitation efficacy of diaphragmatic breathing combined with limb coordination training for lower limb lymphedema following gynecologic cancer surgery.

Objective: To investigate the impact of diaphragmatic breathing combined with limb training on lower limb lymphedema following surgery for gynecological cancer. Methods: From January 2022 to May 2022, 60 patients with lower limb lymphedema post-gynecologic cancer surgery were chosen. They were split into a control group (n = 30) and a treatment group (n = 30). The control group underwent complex decongestive therapy (CDT) for managing lower limb lymphedema after gynecologic cancer surgery, while the treatment group received diaphragmatic breathing combined with limb coordination training alongside CDT. Both groups completed a 4-week treatment regimen. The lower limb lymphedema symptoms were evaluated using the genital, lower limb, buttock, and abdomen (GCLQ) scores; bilateral lower limb circumference measurements; and anxiety and depression scores. Results: Compared to sole CDT administration, individuals undergoing diaphragmatic breathing coupled with limb coordination training experienced notable reductions in scores for the self-perceived symptom assessment questionnaire (GCLQ), bilateral lower limb circumference, as well as anxiety and depression scores. Conclusion: The incorporation of diaphragmatic breathing combined withalongside limb coordination training can accelerate and augment the efficacy of treating lower limb lymphedema post-gynecologic cancer surgery.

Erector spinae plane block versus quadratus lumborum block for postoperative analgesia after laparoscopic nephrectomy: A randomized controlled trial.

STUDY OBJECTIVE: We compared the analgesic effects of erector spinae plane block versus quadratus lumborum block following laparoscopic nephrectomy. DESIGN: A randomized controlled trial. SETTING: A tertiary hospital in Beijing, China. PATIENTS: Patients scheduled for elective laparoscopic nephrectomy. INTERVENTIONS: A total of 110 patients were enrolled and randomized to receive either erector spinae plane block (n = 55) or quadratus lumborum block (n = 55) under ultrasound guidance. Patient-controlled sufentanil analgesia was provided after surgery. MEASUREMENTS: Our primary outcome was cumulative opioid consumption within 24 h after surgery. Secondary outcomes included postoperative pain intensity, subjective sleep quality, and quality of recovery. MAIN RESULTS: All 110 patients (mean 53 years, 57.3% female) were included in the intention-to-treat analysis. Cumulative sufentanil equivalent within 24 h was lower in patients given erector spinae plane block (median 13 µg, interquartile range 4 to 33) than in those given quadratus lumborum block (median 25 µg, interquartile range 13 to 39; median difference - 8 µg, 95% CI -15 to 0, P = 0.041). Pain intensity (0-10 range where 0 = no pain and 10 = the worst pain) at 2, 6, 12, and 24 h after surgery was lower with erector spinae plane block (at rest: median differences -1 point, all P ≤ 0.009; with movement: median differences -2 to -1 points, all P < 0.001). Subjective sleep quality on the night of surgery (the Richards-Campbell Sleep Questionnaire: 0-100 range, higher score better; median difference 12, 95% CI 2 to 23, P = 0.018) and quality of recovery at 24 h (the Quality of Recovery-15: 0-150 range, higher score better; median difference 8, 95% CI 2 to 15, P = 0.012) were better with erector spinae plane block. No procedure-related adverse events occurred. CONCLUSIONS: Compared with quadratus lumborum block, erector spinae plane block provided better analgesia as manifested by lower opioid consumption and pain intensity for up to 24 h after laparoscopic nephrectomy.

Dietary emulsifier polysorbate 80 exposure accelerates age-related cognitive decline.

Gut microbial homeostasis is crucial for the health of cognition in elderly. Previous study revealed that polysorbate 80 (P80) as a widely used emulsifier in food industries and pharmaceutical formulations could directly alter the human gut microbiota compositions. However, whether long-term exposure to P80 could accelerate age-related cognitive decline via gut-brain axis is still unknown. Accordingly, in this study, we used the senescence accelerated mouse prone 8 (SAMP8) mouse model to investigate the effects of the emulsifier P80 intake (1 % P80 in drinking water for 12 weeks) on gut microbiota and cognitive function. Our results indicated that P80 intake significantly exacerbated cognitive decline in SAMP8 mice, along with increased brain pathological proteins deposition, disruption of the blood-brain barrier and activation of microglia and neurotoxic astrocytes. Besides, P80 intake could also induce gut microbiota dysbiosis, especially the increased abundance of secondary bile acids producing bacteria, such as Ruminococcaceae, Lachnospiraceae, and Clostridium scindens. Moreover, fecal microbiota transplantation from P80 mice into 16-week-old SAMP8 mice could also exacerbated cognitive decline, microglia activation and intestinal barrier impairment. Intriguingly, the alterations of gut microbial composition significantly affected bile acid metabolism profiles after P80 exposure, with markedly elevated levels of deoxycholic acid (DCA) in serum and brain tissue. Mechanically, DCA could activate microglial and promote senescence-associated secretory phenotype production through adenosine triphosphate-binding cassette transporter A1 (ABCA1) importing lysosomal cholesterol. Altogether, the emulsifier P80 accelerated cognitive decline of aging mice by inducing gut dysbiosis, bile acid metabolism alteration, intestinal barrier and blood brain barrier disruption as well as neuroinflammation. This study provides strong evidence that dietary-induced gut microbiota dysbiosis may be a risk factor for age-related cognitive decline.

Engineered Cell Membrane-Coated Nanoparticles: New Strategies in Glioma Targeted Therapy and Immune Modulation.

Gliomas, the most prevalent primary brain tumors, pose considerable challenges due to their heterogeneity, intricate tumor microenvironment (TME), and blood-brain barrier (BBB), which restrict the effectiveness of traditional treatments like surgery and chemotherapy. This review provides an overview of engineered cell membrane technologies in glioma therapy, with a specific emphasis on targeted drug delivery and modulation of the immune microenvironment. This study investigates the progress in engineered cell membranes, encompassing physical, chemical, and genetic alterations, to improve drug delivery across the BBB and effectively target gliomas. The examination focuses on the interaction of engineered cell membrane-coated nanoparticles (ECM-NPs) with the TME in gliomas, emphasizing their potential to modulate glioma cell behavior and TME to enhance therapeutic efficacy. The review further explores the involvement of ECM-NPs in immunomodulation techniques, highlighting their impact on immune reactions. While facing obstacles related to membrane stability and manufacturing scalability, the review outlines forthcoming research directions focused on enhancing membrane performance. This review underscores the promise of ECM-NPs in surpassing conventional therapeutic constraints, proposing novel approaches for efficacious glioma treatment.

Exploring the potential of white birch sap: A natural alternative to traditional skin whitening agents with reduced side effects.

Common tyrosinase (TYR) inhibitors used in cosmetics, such as hydroquinone, kojic acid, and arbutin, can cause side effects including erythema, skin peeling, and dryness. Therefore, the development of natural whitening agents that offer excellent permeability, minimal irritation, and high safety has become a primary focus in the field of TYR inhibitors. In this study, we demonstrate that White birch sap (WBS), within a safe concentration range, effectively reduces TYR activity and melanin content in both B16F10 mouse melanoma cells and zebrafish larvae. Importantly, WBS exhibits minimal irritation to neutrophils in fluorescent zebrafish and does not affect the behavior of adult zebrafish. Furthermore, WBS downregulates the gene expression levels of microphthalmia-associated transcription factor, TYR, tyrosinase-related protein-1, and tyrosinase-related protein-2 in B16F10 cells. In conclusion, our research confirms that WBS, a naturally derived substance, offers high safety and mild effects, making it a promising candidate for a skin-whitening agent.

Experimental study of energy­absorbing and support characteristics of glass microsphere-filled steel tube columns under uniaxial compression.

An innovative energy-absorbing and bearing structure was proposed, which incorporated the coupling of glass microspheres with a metal tube. Glass microsphere-filled steel tube (GMFST) column, consisting of external steel tube and inner glass microspheres, was expected to give full play to the energy-absorbing and load-bearing capacities of the particle while restricting particle flow from collapsing, thereby enhancing the overall structural strength. Four groups of steel tubes and the GMFST specimens were designed and subjected to axial compression tests at four different loading rates to investigate the performance of the structure. These tests aimed to analyze the deformation mode, mechanical response, and energy absorption capacity of the GMFST columns under quasi-static to low-speed compression conditions. The results indicated that the deformation process and failure mode of GMFST columns were similar to those of hollow steel tubes, albeit with a different post-buckling mode. Filling the steel tubes with glass microspheres reduced the load fluctuation range, moderated load-displacement curves, and exhibited a strain rate strengthening effect. The GMFST columns demonstrated superior energy absorption capacity, with significant increases in crush force efficiency, the averaged crush force, and the total absorbed energy, particularly in terms of subsequent support capacity. The load-increasing reinforcement properties enabled GMFST columns to overcome the limitations associated with the unstable post-buckling path of energy­absorbing damping structure, exhibiting outstanding load-bearing performance and stability in the later stages. The results provided valuable guidelines for designing and engineering high-performance GMFST columns, serving as a new type of energy-absorbing and supporting structure.

Multimodal prevention of emergence cough following nasal endoscopic surgery under general anesthesia: a double-blind randomized trial.

Purpose: Cough during emergence from anesthesia is a common problem and may cause adverse events. Monotherapy faces uncertainty in preventing emergence cough due to individual differences. We aimed to evaluate the efficacy and safety of multimodal intervention for preventing emergence cough in patients following nasal endoscopic surgery. Methods: In this double-blind randomized trial, 150 adult patients undergoing nasal endoscopic surgery were randomly allocated into three groups. For the control group (n = 50), anesthesia was performed according to clinical routine, no intervention was provided. For the double intervention group (n = 50), normal saline 3 mL was sprayed endotracheally before intubation, 0.4 µg/kg dexmedetomidine was infused over 10 min after intubation, and target-controlled remifentanil infusion was maintained at an effect-site concentration of 1.5 ng/mL before extubation after surgery. For the multimodal intervention group (n = 50), 0.5% ropivacaine 3 mL was sprayed endotracheally before intubation, dexmedetomidine and remifentanil were administered as those in the double intervention group. The primary endpoint was the incidence of emergence cough, defined as single cough or more from end of surgery to 5 min after extubation. Results: The incidences of emergence cough were 98% (49/50) in the control group, 90% (45/50) in the double group, and 70% (35/50) in the multimodal group, respectively. The incidence was significantly lower in the multimodal group than those in the control (relative risk 0.71; 95% CI 0.59 to 0.86; p < 0.001) and double (relative risk 0.78; 95% CI 0.63 to 0.95; p = 0.012) groups; the difference between the double and control groups was not statistically significant (relative risk 0.92; 95% CI 0.83 to 1.02; p = 0.20). The severity of sore throat was significantly lower in the multimodal group than that in the control group (median difference-1; 95% CI -2 to 0; p = 0.016). Adverse events did not differ among the three groups. Conclusion: For adult patients undergoing endonasal surgery, multimodal intervention including ropivacaine topical anesthesia before intubation, dexmedetomidine administration after intubation, and remifentanil infusion before extubation after surgery significantly reduced emergence cough and was safe.

Microbial metabolite trimethylamine-N-oxide induces intestinal carcinogenesis through inhibiting farnesoid X receptor signaling.

PURPOSE: Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression. METHODS: Apcmin/+ mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC. RESULTS: TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/ß-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/ß-catenin pathway activation. CONCLUSION: The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.

Osteosarcoma Cells Secrete CXCL14 That Activates Integrin α11ß1 on Fibroblasts to Form a Lung Metastatic Niche.

Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell-like cluster with tumor cell-initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell-like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11ß1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFß and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11ß1 axis inhibited fibroblast TGFß production, enhanced CD8+ T cell-mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11ß1 axis is a potential strategy to inhibit osteosarcoma lung metastasis. SIGNIFICANCE: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11ß1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.

Determination of multi-mycotoxins in vegetable oil via liquid chromatography-high resolution mass spectrometry assisted by a complementary liquid-liquid extraction.

The simultaneous determination of multi-mycotoxins in food commodities are highly desirable due to their potential toxic effects and mass consumption of foods. Herein, liquid chromatography-quadrupole exactive orbitrap mass spectrometry was proposed to analyze multi-mycotoxins in commercial vegetable oils. Specifically, the method featured a successive liquid-liquid extraction process, in which the complementary solvents consisted of acetonitrile and water were optimized. Resultantly, matrix effects were reduced greatly. External calibration approach revealed good quantification property for each analyte. Under optimal conditions, the recovery ranging from 80.8% to 109.7%, relative standard deviation less than 11.7%, and good limit of quantification (0.35 to 45.4 ng/g) were achieved. The high accuracy of proposed method was also validated. The detection of 20 commercial vegetable oils revealed that aflatoxins B1 and B2, zearalenone were observed in 10 real samples. The as-developed method is simple and low-cost, which merits the wide applications for scanning mycotoxins in oil matrices.