FGF19 promotes nasopharyngeal carcinoma progression by inducing angiogenesis via inhibiting TRIM21-mediated ANXA2 ubiquitination.

PURPOSE: Nasopharyngeal carcinoma (NPC) has characteristics of high invasion and early metastasis. Most NPC patients present with locoregionally advanced illness when first diagnosed. Therefore, it is urgent to discover NPC biomarkers. Fibroblast growth Factor 19 (FGF19) plays a role in various physiological or pathological processes, including cancer. In this research, we discovered the importance of FGF19 in NPC, and clarified its role in tumour angiogenesis. METHODS: Western blotting, immunohistochemistry and ELISA were used to investigate FGF19 expression in NPC. Then we took CCK8, colony formation, Transwell and wound healing assays to identify the influence of FGF19 on NPC malignant behaviours. The proliferative and metastatic capacity of FGF19 were evaluated in nude mice and zebrafish. The role of FGF19 in angiogenesis was investigated by tube formation and Matrigel plug angiogenesis assays. We then evaluated the variation in Annexin A2(ANXA2) levels with the treatment of FGF19. Lastly, co-immunoprecipitation and ubiquitination assays were performed to identify the mechanisms involved. RESULTS: FGF19 levels were elevated in tissues and serum of NPC patients and were associated with poor clinical stages. High expression of FGF19 promoted NPC malignant behaviours. In particular, FGF19 expression was correlated with microvessel density in tissues and NPC-derived FGF19 could accelerate angiogenesis in vitro and in vivo. Mechanistically, FGF19 influenced ANXA2 expression to promote angiogenesis. Moreover, tripartite motif-containing 21(TRIM21) interacted with ANXA2 and was responsible for ANXA2 ubiquitination. CONCLUSION: FGF19 promoted NPC angiogenesis by inhibiting TRIM21-mediated ANXA2 ubiquitination. It may serve as a noninvasive biomarker for NPC and provides new insights for therapy.

Optimization of small molecule degraders and antagonists for targeting estrogen receptor based on breast cancer: current status and future.

The estrogen receptor (ER) is a classical receptor protein that plays a crucial role in mediating multiple signaling pathways in various target organs. It has been shown that ER-targeting therapies inhibit breast cancer cell proliferation, enhance neuronal protection, and promote osteoclast formation. Several drugs have been designed to specifically target ER in ER-positive (ER+) breast cancer, including selective estrogen receptor modulators (SERM) such as Tamoxifen. However, the emergence of drug resistance in ER+ breast cancer and the potential side effects on the endometrium which has high ER expression has posed significant challenges in clinical practice. Recently, novel ER-targeted drugs, namely, selective estrogen receptor degrader (SERD) and selective estrogen receptor covalent antagonist (SERCA) have shown promise in addressing these concerns. This paper provides a comprehensive review of the structural functions of ER and highlights recent advancements in SERD and SERCA-related small molecule drugs, especially focusing on their structural optimization strategies and future optimization directions. Additionally, the therapeutic potential and challenges of novel SERDs and SERCAs in breast cancer and other ER-related diseases have been discussed.

Transforming Growth Factor ß1 Ameliorates Microglial Activation in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorder (PND) is a common complication of surgery and anesthesia, especially among older patients. Microglial activation plays a crucial role in the occurrence and development of PND and transforming growth factor beta 1 (TGF-ß1) can regulate microglial homeostasis. In the present study, abdominal surgery was performed on 12-14 months-old C57BL/6 mice to establish a PND model. The expression of TGF-ß1, TGF-ß receptor 1, TGF-ß receptor 2, and phosphor-smad2/smad3 (psmad2/smad3) was assessed after anesthesia and surgery. Additionally, we examined changes in microglial activation, morphology, and polarization, as well as neuroinflammation and dendritic spine density in the hippocampus. Behavioral tests, including the Morris water maze and open field tests, were used to examine cognitive function, exploratory locomotion, and emotions. We observed decreased TGF-ß1 expression after surgery and anesthesia. Intranasally administered exogenous TGF-ß1 increased psmad2/smad3 colocalization with microglia positive for ionized calcium-binding adaptor molecule 1. TGF-ß1 treatment attenuated microglial activation, reduced microglial phagocytosis, and reduced surgery- and anesthesia-induced changes in microglial morphology. Compared with the surgery group, TGF-ß1 treatment decreased M1 microglial polarization and increased M2 microglial polarization. Additionally, surgery- and anesthesia-induced increase in interleukin 1 beta and tumor necrosis factor-alpha levels was ameliorated by TGF-ß1 treatment at postoperative day 3. TGF-ß1 also ameliorated cognitive function after surgery and anesthesia as well as rescue dendritic spine loss. In conclusion, surgery and anesthesia induced decrease in TGF-ß1 levels in older mice, which may contribute to PND development; however, TGF-ß1 ameliorated microglial activation and cognitive dysfunction in PND mice.

Impact of Spinal/Epidural Anesthesia Versus General Anesthesia on Perioperative Outcomes in Patients Undergoing Lumbar Spine Surgery: An Updated Systematic Review and Meta-analysis.

STUDY DESIGN: A systematic review and meta-analysis. OBJECTIVE: To compare impact of different anesthesia techniques on perioperative outcomes in patients undergoing lumbar spine surgery. SUMMARY OF BACKGROUND DATA: Both general anesthesia and spinal anesthesia/epidural anesthesia can be used for lumbar spine surgery. There is still much controversy that which anesthesia technique is much more suitable for lumbar spine surgery with less complications, general anesthesia or regional anesthesia. METHODS: A comprehensive search of the literature was conducted using Excerpta Medica database (EMBASE), PubMed, and Cochrane library for randomized controlled trials and independent reviewers assessed eligibility for included studies. Primary outcomes included incidences of intraoperative hypertension, hypotension, tachycardia, and bradycardia. Secondary outcomes included postoperative analgesic requirement, postoperative nausea and vomiting (PONV), headache, urinary retention, blood loss, and length of hospital stay. RESULTS: Ten randomized controlled trials consisting of 733 adult patients undergoing lumbar spine surgery were included. Spinal anesthesia/epidural anesthesia group had significant lower incidences of intraoperative hypertension [odds ratio (OR), 0.18; 95% confidence interval (CI), 0.08-0.38; P <0.00001; I2 =0.0%] and tachycardia (OR, 0.45; 95% CI, 0.26-0.79; P =0.006; I2 =0.0%), analgesic requirement in postanesthesia care unit (OR, 0.13; 95% CI, 0.08-0.22; P <0.00001; I2 =0.0%), PONV within 24 hours after surgery (OR, 0.27; 95% CI, 0.16-0.46; P <0.00001; I2 =6.0%), and shorter length of postoperative hospital stay (mean difference, -0.28; 95% CI, -0.37 to -0.18; P <0.00001; I2 =32.0%). There were no significant differences in incidences of intraoperative hypotension and bradycardia, PONV in postanesthesia care unit, analgesic requirement, urinary retention, and headache within 24 hours after surgery. CONCLUSIONS: Low to moderate quality of evidence revealed that patient undergoing lumbar spine surgery might benefit from spinal or epidural anesthesia.

Tumor-derived exosomal lincRNA ROR promotes angiogenesis in nasopharyngeal carcinoma.

Long intergenic noncoding RNAs (lincRNAs) are expressed aberrantly in several malignancies, including nasopharyngeal carcinoma (NPC), where linc-ROR expression was found to be elevated. Being a hallmark of malignant tumors, angiogenesis has prompted us to investigate the impact of linc-ROR on NPC angiogenesis. This study demonstrates that linc-ROR is substantially expressed in serum exosomes from NPC and can be taken up by HUVECs. Using qRT-PCR, the CCK8 test, the transwell migration assay, the wound healing assay, and the tube formation assay, we demonstrated that linc-ROR increases proliferation, migration, and angiogenesis in vitro. Similar to prior research, our results have shown that linc-ROR can stimulate tumor angiogenesis in the zebrafish model. Thus, the p-AKT/p-VEGFR2 pathway is the mechanism by which linc-ROR affects the aforementioned biological activities. By stimulating angiogenesis, linc-ROR appears to play a significant role in the course of NPC and could account for a therapeutic target.

Flavin catalyzed desulfurization of peptides and proteins in aqueous media.

A biomimetic method has been established for the chemo-selective desulfurization of cysteinyl peptides and proteins in aqueous media. The derivatives of biocatalytic cofactors, flavins, were found to be efficient photosensitizers in a thiyl-radical-mediated desulfurization of Cys. The reaction was conducted in an ultrafast manner with both polypeptides and proteins.

Anomalous Levels of CD47/Signal Regulatory Protein Alpha in the Hippocampus Lead to Excess Microglial Engulfment in Mouse Model of Perioperative Neurocognitive Disorders.

Background: Perioperative neurocognitive disorders (PNDs) are common complications of surgical patients, which can lead to prolonged hospitalization, increased complications, and decreased independence and quality of life. However, the underlying molecular mechanisms of PND remain largely obscure. Microglia activation and synapse loss were observed in PND. Cluster of differentiation 47 (CD47), which can bind to its receptor signal regulatory protein alpha (SIRPα) and generate "do not eat me" signal, protects synapses from excessive pruning. Therefore, we aimed to evaluate the potential role of CD47-SIRPα signaling in PND. Methods: The tibial fracture surgery was performed in aged C57BL/6 mice for PND model establishment. The expression of CD47 and SIRPα in the hippocampus was assessed. Synaptic plasticity, dendritic spine density, microglial engulfment, and hippocampal-dependent memory function were evaluated after model establishment and intervention with SIRPα overexpression. Results: CD47 and SIRPα expression in the hippocampus were both decreased after the surgery. SIRPα overexpression showed reduced engulfment within host microglia, but a total effect of excessive synapse engulfment decreased dendritic spine density and post-synaptic density protein 95 (PSD95) expression. SIRPα overexpression could not improve the synaptic dysfunction and cognitive impairment in PND. In addition, SIRPα overexpression led to increased CD47 and Iba1 expression. Conclusion: Anesthesia and surgery affect CD47-SIRPα signaling. SIRPα overexpression could not ameliorate the cognitive impairment in PND mice. One reason may be that the increased Iba1 expression leads to a total effect of excessive synapse engulfment, which results in decreased dendritic spine density and PSD95 expression.

Role of BDNF/ProBDNF Imbalance in Postoperative Cognitive Dysfunction by Modulating Synaptic Plasticity in Aged Mice.

Postoperative cognitive dysfunction (POCD) is a disturbing neurological complication in patients undergoing anesthesia and surgical procedures. Brain-derived neurotrophic factor (BDNF) and its precursor proBDNF binding to their corresponding receptors tyrosine kinase (TrkB) and p75 neurotrophin receptor (p75NTR) exert quite an opposite biological function in neuron survival and synaptic function. This study aimed to demonstrate the critical role of the BDNF/proBDNF ratio in modulating synaptic plasticity, which further leads to anesthesia-/surgery-induced POCD. It also showed that the exogenous BDNF or p75NTR inhibitor could ameliorate cognitive dysfunction. In detail, 16-month-old C57BL/6 mice were subjected to a stabilized tibial fracture surgery with isoflurane anesthesia to establish the POCD animal model. The mice were then microinjected with either p75NTR inhibitor or exogenous BDNF into the dorsal hippocampus. Behavioral experiments were performed by open field and fear conditioning tests (FCTs). Western blotting was also used to measure the expression levels of BDNF, proBDNF, TrkB, p-TrkB, p75NTR, and synapse proteins. Golgi staining and electrophysiology were applied to evaluate the neuronal synaptic plasticity. Here, we demonstrated that anesthesia/surgery induced a reduction of BDNF/proBDNF, which negatively regulates the synaptic function in hippocampus, subsequently leading to cognitive impairment in aged mice. P75NTR inhibitor and exogenous BDNF could attenuate cognitive deficits by rescuing the dendritic spine loss and long-term potentiation (LTP) via altering the BDNF/proBDNF ratio. This study unveiled that the BDNF/proBDNF ratio in the hippocampus played a key role in anesthesia-/surgery-induced POCD. Thereby, tuning the ratio of BDNF/proBDNF is supposed to be a promising therapeutic target for POCD.

Intravenous versus inhalational maintenance of anesthesia for quality of recovery in adult patients undergoing non-cardiac surgery: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Intravenous and inhalational agents are commonly used in general anesthesia. However, it is still controversial which technique is superior for the quality of postoperative recovery. This meta-analysis aimed at comparing impact of total intravenous anesthesia (TIVA) versus inhalational maintenance of anesthesia on the quality of recovery in patients undergoing non-cardiac surgery. METHODS: We systematically searched EMBASE, PubMed, and Cochrane library for randomized controlled trials (RCTs), with no language or publication status restriction. Two authors independently performed data extraction and assessed risk of bias. The outcomes were expressed as mean difference (MD) with 95% confidence interval (CI) based on a random-effect model. We performed trial sequential analysis (TSA) for total QoR-40 scores and calculated the required information size (RIS) to correct the increased type I error. RESULTS: A total of 156 records were identified, and 9 RCTs consisting of 922 patients were reviewed and included in the meta-analysis. It revealed a significant increase in total QoR-40 score on the day of surgery with TIVA (MD, 5.91 points; 95% CI, 2.14 to 9.68 points; P = 0.002; I2 = 0.0%). The main improvement was in four dimensions, including "physical comfort", "emotional status", "psychological support" and "physical independence". There was no significant difference between groups in total QoR-40 score (P = 0.120) or scores of each dimension on POD1. The TSA showed that the estimated required information size for total QoR-40 scores was not surpassed by recovered evidence in our meta-analysis. And the adjusted Z-curves did not cross the conventional boundary and the TSA monitoring boundary. CONCLUSION: Low-certainty evidence suggests that propofol-based TIVA may improve the QoR-40 score on the day of surgery. But more evidence is needed for a firm conclusion and clinical significance.

Mechanistic insights into δ-opioid-induced cardioprotection: Involvement of caveolin translocation to the mitochondria.

AIMS: The cardioprotective effects of preconditioning against ischemia-reperfusion (I/R) injury depend on the structural integrity of membrane caveolae and signaling through G protein-coupled receptors (GPCRs). However, the mechanisms underlying opioid preconditioning are not fully understood. Here, we examined whether caveolins transmitted opioid-GPCR signals to the mitochondria to mediate cardioprotection. MAIN METHODS: Mice were treated with pertussis toxin (PTX) or saline. Thirty-six hours later, mice from each group were randomly assigned to receive the δ-opioid receptor agonist SNC-121 or saline intraperitoneally 15 min before in vivo I/R. Infarct sizes in each group were compared, and immunoblot analysis was used to detect caveolin expression. The structures of caveolae and mitochondria were determined by electron microscopy (EM). The opening degree of the mitochondrial permeability transition pore (mPTP) was assessed by colorimetry, and mitochondrial respiratory function was assessed by Oxygraph-2k. KEY FINDINGS: Treatment with an opioid receptor agonist reduced the myocardial infarct size after I/R injury, increased caveolin expression, decreased mitochondrial mPTP opening, and improved mitochondrial respiratory function. EM analysis revealed that opioids induced caveolae formation in myocytes and tended to promote translocation to mitochondria. However, these protective effects were blocked by PTX. SIGNIFICANCE: Opioid-induced preconditioning depended on Gi signaling, which promoted caveolin translocation to mitochondria, supported their functional integrity, and enhanced cardiac stress adaption. Verification of this pathway will establish new targets for opioid agents in the field of cardiac protection.