ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress.

The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.

Development and Validation of a Nomogram for Prognosis Prediction in Patients with Synchronous Primary Thyroid and Breast Cancer Based on SEER Database.

This study aimed to develop prognostic prediction models for patients diagnosed with synchronous thyroid and breast cancer (TBC). Utilizing the SEER database, key predictive factors were identified, including T stage of thyroid cancer, T stage of breast cancer, M stage of breast cancer, patient age, thyroid cancer surgery type, and isotope therapy. A nomogram predicting 5-year and 10-year survival rates was constructed and validated, exhibiting strong performance (C-statistic: 0.79 in the development cohort (95% CI: 0.74-0.84), and 0.82 in the validation cohort (95% CI: 0.77-0.89)). The area under the Receiver Operator Characteristic (ROC) curve ranged from 0.798 to 0.883 for both cohorts. Calibration and decision curve analyses further affirmed the model's clinical utility. Stratifying patients into high-risk and low-risk groups using the nomogram revealed significant differences in survival rates (P < 0.0001). The successful development and validation of this nomogram for predicting 5-year and 10-year survival rates in patients with synchronous TBC hold promise for similar patient populations, contributing significantly to cancer research.

Selective optogenetic modulation of the PBN terminals in the lateral hypothalamic area and basal forebrain regulates emergence from isoflurane anesthesia in mice.

While the mechanism of general anesthesia has been extensively studied, the underlying neural circuitry has yet to be fully understood. The parabrachial nucleus (PBN) plays a crucial role in modulating wakefulness and promoting arousal from general anesthesia. However, the specific role of PBN projections in the process of general anesthesia remains unclear. In this study, we bilaterally injected AAV-associated viruses encoding excitatory or inhibitory optogenetic probes into the PBN and implanted optical fibers in the LH or BF area. After four weeks, we optogenetically activated or inhibited the PBN-LH and PBN-BF pathways under 1.5 vol% isoflurane. We calculated the time it took for anesthesia induction and emergence, simultaneously monitoring changes in the burst-suppression ratio using electroencephalogram recording. Our findings indicate that optogenetic activation of the PBN-LH and PBN-BF projections plays a significant role in promoting both cortical and behavioral emergence from isoflurane inhalation, without significantly affecting the induction time. Conversely, photoinhibition of these pathways prolonged the recovery time, with no notable difference observed during the induction phase.In summary, our results demonstrate that the PBN-LH and PBN-BF pathways are crucial for promoting arousal from isoflurane general anesthesia, but do not have a pronounced impact on the induction phase.

LncRNA PCAT19 Regulates Neuropathic Pain via Regulation of miR-182-5p/JMJD1A in a Rat Model of Chronic Constriction Injury.

INTRODUCTION: Neuropathic pain (NP) is one of the most severe chronic pain types. In recent years, more and more studies have shown that long noncoding RNA (LncRNA) plays a key role in a variety of human diseases, including NP. However, the role of LncRNA prostate cancer-associated transcript 19 (PCAT19) in NP and its specific mechanism remain unclear. METHODS: A chronic constrictive injury (CCI) rat model was established. Rat paw withdrawal threshold and paw withdrawal latency were used to evaluate the neuronal pain behavior of rats in this model. mRNA expression of PCAT19, neuroinflammatory factor, microRNA (miR)-182-5p, and Jumonji domain containing 1A (JMJD1A) were detected by quantitative real-time PCR. ELISA analysis was used to detect inflammatory factor protein expression. Dual-luciferase reporter assay was used to evaluate the targeting relationship between genes. RESULTS: PCAT19 was continuously upregulated in CCI rats. miR-182-5p was the target of PCAT19, and miR-182-5p was increased after PCAT19 knockdown. NP behaviors such as mechanical ectopic pain and thermal hyperalgesia as well as neuroinflammation can be reduced by knocking down PCAT19. However, the injection of miR-182-5p antagomir significantly reversed the level of the NP behaviors and neuroinflammation caused by PCAT19 knockdown. Besides, dual-luciferase reporter assay showed that JMJD1A was the target gene of miR-182-5p. The level of JMJD1A in CCI rats increased with time. After PCAT19 knockdown, JMJD1A was significantly decreased, but inhibition of miR-182-5p can reverse its levels. CONCLUSION: This study shows that PCAT19 plays a role in NP by targeting the miR-182-5p/JMJD1A axis, and PCAT19 can be used as a new therapeutic target for NP.

Scutellarin alleviates cerebral ischemia/reperfusion by suppressing oxidative stress and inflammatory responses via MAPK/NF-κB pathways in rats.

Neuroinflammation contributes to the progression of cerebral ischemia/reperfusion (I/R) damage. Scutellarin (SL) is a glucuronide flavonoid that has apoptotic, anti-inflammatory, and anti-tumor properties. It is anti-oxidant and anti-inflammatory mechanism as a neuroprotective against ischemic brain injury is unknown. The purpose of the study was to examine the role and mechanism of SL in preventing I/R damage in a rat model. SL (40 and 80 mg/kg) was given to the rats for 14 days before the ischemic stroke. SL administration prevented I/R mediated brain injury, and neuronal apoptosis. Malondialdehyde, superoxide dismutase, glutathione, IL-6, and IL-1ß and nitric oxide were modulated by SL. SL suppressed the p65 and p38 expressions in particular. The findings show that SL protects rats from cerebral damage caused by I/R through the nuclear factor kappa-B p65 and p38 mitogen-activated protein kinase signaling pathway. Thus, SL protected the brain of rats from ischemic injury by inhibiting the inflammatory process.

The role of chlorine atom on the binding between acrylonitrile derivatives and fat mass and obesity-associated protein.

In this work, seven acrylonitrile derivatives were selected as potential inhibitors of fat and obesity-related proteins (FTO) by the aid of fluorescence spectroscopy, ultraviolet visible spectroscopy, molecular docking, and cytotoxicity methods. Results show that the interaction between 3-amino-2-(4-chlorophenyl)-3-phenylacrylonitrile (1a) and FTO was the strongest among these derivatives. Thermodynamic analysis and molecular modeling show that the main force between 1a and FTO is hydrophobic interaction. The cytotoxicity test showed that the IC50 value of 1a was 46.64 µmol/L, which indicated 1a had the smallest IC50 value and had the best inhibitory effect on the proliferation of leukemia K562 cells among the seven derivatives. Both our previous results and this work show that chlorine atoms play important role in the binding of small molecules and FTO. This work brings new information for the study of FTO inhibitors.

Accumulation of prelamin A induces premature aging through mTOR overactivation.

Hutchinson-Gilford progeria syndrome (HGPS) arises when a truncated form of farnesylated prelamin A accumulates at the nuclear envelope, leading to misshapen nuclei. Previous studies of adult Zmpste24-deficient mice, a mouse model of progeria, have reported a metabolic response involving inhibition of the mTOR (mammalian target of rapamycin) kinase and activation of autophagy. However, exactly how mTOR or autophagy is involved in progeria remains unclear. Here, we investigate this question by crossing Zmpste24+/- mice with mice hypomorphic in mTOR (mTOR△/+ ), or mice heterozygous in autophagy-related gene 7 (Atg7+/- ). We find that accumulation of prelamin A induces premature aging through mTOR overactivation and impaired autophagy in newborn Zmpste24-/- mice. Zmpste24-/- mice with genetically reduced mTOR activity, but not heterozygosity in Atg7, show extended lifespan. Moreover, mTOR inhibition partially restores autophagy and S6K1 activity. We also show that progerin interacts with the Akt phosphatase to promote full activation of the Akt/mTOR signaling pathway. Finally, although we find that genetic reduction of mTOR postpones premature aging in Zmpste24 KO mice, frequent embryonic lethality occurs. Together, our findings show that over-activated mTOR contributes to premature aging in Zmpste24-/- mice, and suggest a potential strategy in treating HGPS patients with mTOR inhibitors.

Short-term recovery in patients suffering hypoparathyroid after thyroidectomy: a case control study.

BACKGROUND: Postoperative hypoparathyroidism is the main reason for outpatient follow-up and long-term oral calcium and calcitriol treatment. Our study investigated the influencing factors and powerful predictors of short-term postoperative parathyroid function recovery. METHODS: Logistic regression was used to compare the clinicopathological characteristics; surgical details; and serum calcium (Ca), magnesium (Mg), and phosphorus (P) concentrations of patients. A receiver operating characteristic (ROC) curve was used to analyze the predictors of normal parathyroid hormone (PTH). RESULTS: Among the 111 patients with PTH < 10 pg/mL on the first postoperative day, most patients experienced a return to normal PTH (PTH > 15 pg/mL) within 30 days postoperatively. Univariate analysis showed that Pod (postoperative day) 1 PTH, Pod3 PTH, Pod7 Ca, Pod7 Mg, and Pod7 P (P < 0.05) were associated with parathyroid function recovery to normal on the seventh postoperative day. Multivariate logistic regression analysis revealed the following independent risk factors for normal PTH levels at Pod7 after thyroidectomy: Pod3 PTH (P = 0.038), Pod1 PTH (P = 0.056), Pod7 Mg (P = 0.001), Pod7 P (P = 0.020), and the number of parathyroid glands in situ intraoperatively. The combined sensitivity of serum magnesium concentration and phosphorus concentration to predict parathyroid function recover to normal on the seventh postoperative day was 82.76%, with a sensitivity of 76.83%. CONCLUSION: Serum magnesium, phosphorus and PTH concentrations are important influencing factors and effective predictors of short-term postoperative parathyroid function recovery to normal. Serum ion is an effective auxiliary diagnostic method for hypoparathyroidism after thyroidectomy.

G-protein-coupled estrogen receptor activation upregulates interleukin-1 receptor antagonist in the hippocampus after global cerebral ischemia: implications for neuronal self-defense.

BACKGROUND: G-protein-coupled estrogen receptor (GPER/GPR30) is a novel membrane-associated estrogen receptor that can induce rapid kinase signaling in various cells. Activation of GPER can prevent hippocampal neuronal cell death following transient global cerebral ischemia (GCI), although the mechanisms remain unclear. In the current study, we sought to address whether GPER activation exerts potent anti-inflammatory effects in the rat hippocampus after GCI as a potential mechanism to limit neuronal cell death. METHODS: GCI was induced by four-vessel occlusion in ovariectomized female SD rats. Specific agonist G1 or antagonist G36 of GPER was administrated using minipump, and antisense oligonucleotide (AS) of interleukin-1ß receptor antagonist (IL1RA) was administrated using brain infusion kit. Protein expression of IL1RA, NF-κB-P65, phosphorylation of CREB (p-CREB), Bcl2, cleaved caspase 3, and microglial markers Iba1, CD11b, as well as inflammasome components NLRP3, ASC, cleaved caspase 1, and Cle-IL1ß in the hippocampal CA1 region were investigated by immunofluorescent staining and Western blot analysis. The Duolink II in situ proximity ligation assay (PLA) was performed to detect the interaction between NLRP3 and ASC. Immunofluorescent staining for NeuN and TUNEL analysis were used to analyze neuronal survival and apoptosis, respectively. We performed Barnes maze and Novel object tests to compare the cognitive function of the rats. RESULTS: The results showed that G1 attenuated GCI-induced elevation of Iba1 and CD11b in the hippocampal CA1 region at 14 days of reperfusion, and this effect was blocked by G36. G1 treatment also markedly decreased expression of the NLRP3-ASC-caspase 1 inflammasome and IL1ß activation, as well as downstream NF-κB signaling, the effects reversed by G36 administration. Intriguingly, G1 caused a robust elevation in neurons of a well-known endogenous anti-inflammatory factor IL1RA, which was reversed by G36 treatment. G1 also enhanced p-CREB level in the hippocampus, a transcription factor known to enhance expression of IL1RA. Finally, in vivo IL1RA-AS abolished the anti-inflammatory, neuroprotective, and anti-apoptotic effects of G1 after GCI and reversed the cognitive-enhancing effects of G1 at 14 days after GCI. CONCLUSIONS: Taken together, the current results suggest that GPER preserves cognitive function following GCI in part by exerting anti-inflammatory effects and enhancing the defense mechanism of neurons by upregulating IL1RA.

Hsa_circ_0011385 accelerates the progression of thyroid cancer by targeting miR-361-3p.

BACKGROUND: Thyroid cancer is an endocrine malignancy that is growing in incidence worldwide. Despite progress in diagnostics and treatment of thyroid cancer, prognosis remains poor. Emerging research has shown that circular RNAs (circRNAs) have crucial regulatory roles in cancers. However, the possible functions and mechanisms of hsa_circ_0011385 remain undetermined. MATERIALS AND METHODS: Expression levels of hsa_circ_0011385 and miR-361-3p were evaluated by qRT-PCR assay. The interaction between hsa_circ_0011385 and miR-361-3p was verified by dual-luciferase reporter assay. Effects of hsa_circ_0011385 or miR-361-3p on cell viability, proliferation, cell cycle, apoptosis, migration and invasion were confirmed by cell counting kit-8 (CCK-8), carboxyfluoresceinsuccinimidyl ester (CFSE), flow cytometry, and Transwell assays in vitro. The effect of hsa_circ_0011385 on thyroid cancer progression was also determined by in vivo tumor formation assay. Target genes of miR-361-3p were predicted by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and the expression of apoptosis- and metastasis-related proteins were assessed by Western blot assay. RESULTS: Hsa_circ_0011385 upregulated in thyroid cancer; hsa_circ_0011385 knockdown inhibited thyroid cancer cell proliferation, migration and invasion, and promoted cell cycle arrest and apoptosis. In addition, hsa_circ_0011385 could negatively regulate miR-361-3p by functioning as a sponge. Hsa_circ_0011385 promoted thyroid cancer cell proliferation, migration and invasion and suppressed cell cycle arrest and apoptosis by targeting miR-361-3p in vitro. We also found that hsa_circ_0011385 knockdown dramatically inhibited thyroid cancer growth in vivo. Furthermore, hsa_circ_0011385 regulated expression of apoptosis and metastasis-related proteins in thyroid cancer. CONCLUSIONS: Hsa_circ_0011385facilitated thyroid cancer cell proliferation, invasion and migration, and inhibited thyroid cancer cell cycle arrest and apoptosis by targeting miR-361-3p, suggesting that the hsa_circ_0011385/miR-361-3p axis might be a promising therapeutic target for thyroid cancer.

Glucagon-like peptide-1 receptor agonists and risk of bone fracture in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIMS: To evaluate the association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the risk of bone fracture in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We conducted a systematic literature search in PubMed, Embase, the Cochrane Library, and Web of Science from inception to 28 February 2018 and identified eligible randomized controlled trials. The following data were extracted from each study: first author, year of publication, sample size, patient characteristics, study design, intervention drug, control drug, follow-up time, and incident bone fracture events. A meta-analysis was conducted using Review Manager 5.3 software to calculate the odds ratio (OR) and 95% confidence intervals (CI) for dichotomous variables. RESULTS: A total of 38 studies with 39 795 patients with T2DM were included. There were 241 incident bone fracture cases (107 in the GLP-1 RAs group and 134 in the control group). Compared with patients who received placebo and other anti-diabetic drugs, those who received GLP-1 RAs treatment showed a pooled OR of 0.71 (95% CI, 0.56-0.91) for bone fracture. Subgroup analysis showed that treatments with liraglutide and lixisenatide were associated with significantly reduced risk of bone fractures (ORs, 0.56; 95% CI, 0.38-0.81 and 0.55; 95% CI, 0.31-0.97, respectively). However, other GLP-1 RAs did not show superiority to placebo or other anti-diabetic drugs. Moreover, these beneficial effects were dependent on the duration of GLP-1 RAs treatment, only a GLP-1 RAs treatment period of more than 52 weeks could significantly lower the risk of bone fracture in patients with T2DM (OR, 0.71; 95% CI, 0.56-0.91). CONCLUSIONS: Compared with placebo and other anti-diabetic drugs, liraglutide and lixisenatide were associated with a significant reduction in the risk of bone fractures, and the beneficial effects were dependent on the duration of treatment.

Predicted secreted protein analysis reveals synaptogenic function of Clstn3 during WAT browning and BAT activation in mice.

Promoting white adipose tissue (WAT) browning and enhancing brown adipose tissue (BAT) activity are attractive therapeutic strategies for obesity and its metabolic complications. Targeting sympathetic innervation in WAT and BAT represents a promising therapeutic concept. However, there are few reports on extracellular microenvironment remodeling, especially changes in nerve terminal connections. Identifying the key molecules mediating the neuro-adipose synaptic junctions is a key point. In this study, we used bioinformatics methods to identify the differentially expressed predicted secreted genes (DEPSGs) during WAT browning and BAT activation. These DEPSGs largely reflect changes of cytokines, extracellular matrix remodeling, vascularization, and adipocyte-neuronal cross-talk. We then performed functional enrichment and cellular distribution specificity analyses. The upregulated and downregulated DEPDGs during WAT browning displayed a distinctive biological pattern and cellular distribution. We listed a cluster of adipocyte-enriched DEPSGs, which might participate in the cross-talk between mature adipocytes and other cells; then identified a synaptogenic adhesion molecule, Clstn3, as the top gene expressed enriched in both mature white and brown adipocytes. Using Q-PCR and immunohistochemistry, we found significantly increased Clstn3 expression level during WAT browning and BAT activation in mice subjected to cold exposure (4 °C). We further demonstrated that treatment with isoproterenol significantly increased Clstn3 and UCP1 expression in differentiated white and beige adipocytes in vitro. In conclusion, our study demonstrates that the secretion pattern was somewhat different between WAT browning and BAT activation. We reveal that Clstn3 may be a key gene mediating the neuro-adipose junction formation or remodeling in WAT browning and BAT activation process.

[Risk factors for hypoparathyroidism after thyroidectomy].

OBJECTIVE: To investigate the risk factors for hypoparathyroidism after thyroidectomy.
 Methods: Clinical data of 492 patients, who underwent thyroidectomy from April 2015 to December 2016 from Xiangya Hospital of Central South University, were studied retrospectively. Chi-square test and multivariable logistic regression were performed to find the risk factors for postoperative hypoparathyroidism.
 Results: The incidence of postoperative hypoparathyroidism was 43.5%, and the incidence of temporary and permanent hypoparathyroidism was 43.1% and 0.4%, respectively. Univariate analysis showed that tumor pathology, thyroidectomy types, the extent of lymph node dissection, application of carbon nanoparticles, and merged Hashimoto's thyroiditis were risk factors for postoperative hypoparathyroidism (all P<0.01). Logistic regression analysis showed that: thyroidectomy types (OR=0.149, 95% CI 0.078 to 0.28), the extent lymph node dissection (OR=0.779, 95% CI 0.617 to 0.983) and application of carbon nanoparticles (OR=1.729, 95% CI 1.067 to 2.801) were independent risk factors for postoperative hypoparathyroidism (all P<0.05).
 Conclusion: Hypoparathyroidism is a common complication after thyroidectomy. The incidence of postoperative hypoparathyroidism is significantly increased in patients underwent total thyroidectomy and cervical lymph node dissection. Application of carbon nanoparticles intraoperatively can reduce the incidence of postoperative hypoparathyroidism.

Prediction of permanent hypoparathyroidism by parathyroid hormone and serum calcium 24 h after thyroidectomy.

PURPOSE: To assess the value of 24-hour intact parathyroid hormone (iPTH), serum calcium, and decreases in both were evaluated against preoperative values (iPTH and serum calcium decline) and used to determine the existence of permanent hypoparathyroidism (pHPP) after total thyroidectomy (TT). MATERIALS AND METHODS: The clinical data of patients who underwent total thyroidectomy in our hospital between September 2014 and July 2015 were retrospectively analyzed. RESULTS: There were 42 cases with normal parathyroid function, 58 cases with temporary HPP, and 10 cases with pHPP. When iPTH and serum calcium were administered at 24 h after surgery, iPTH decline and calcium decline differed significantly among the three groups above (P < .01). The accuracy and positive predictive value of 24 h iPTH for pHPP were higher than any one of the others. The sensitivity, specificity, false positive rate, and accuracy were 100%, 95%, 33.33%, and 94.45%, respectively. The AUC was 0.982 when 24-hour iPTH was equal to or <3.15 pg/mL. The use of blood calcium equal to or <2.03 mmol/L (8.12 mg/dL) pointed to a diagnosis of pHPP, with a sensitivity of 100%, specificity of 63%, false positive rate of 78.72%, and accuracy of 66.36%. CONCLUSIONS: Measurement of the postoperative 24-h intact parathyroid hormone and serum calcium concentration can predict the occurrence of permanent hypoparathyroidism and the former is more advantageous. Postoperative 24-h intact parathyroid hormone equal to or <3.15 pg/mL is a reliable index, and it is suitable for the prediction of postoperative permanent hypoparathyroidism.

Motion Synchronous Composite Decoupling with Fewer Sensors on Multichannel Hydraulic Force Control for Aircraft Structural Loading Test System.

The aircraft full-scale fatigue test is widely used in the modern aircraft industry for the safety of flight. Generally, the aircraft full-scale fatigue test is achieved by structural loading; multiple hydraulic actuators are used to apply load for force control. The fatigue loading test takes approximately several years. A key challenge is how to accelerate the loading frequency to shorten the total test time. Nevertheless, when pluralities of hydraulic actuator simultaneously increase the loading frequency, the mutual coupling force from the low rigidity of the aircraft structure will cause a large loading error, meaning that the test cannot be implemented. Although it is possible to reduce error by adding sensors, the force sensors need to connect several kilometers of cable. This paper proposed a novel motion synchronous composite decoupling control strategy with fewer sensors. The control method compensates the negative coupling effect of the channels by integrating the command signals and feedback signals of all channels. It can suppress coupling force and reduce errors at higher frequencies, thereby shortening the experiment time. Opposed to traditional decoupling control methods, advantages of this strategy are that it only needs force sensors and it does not need additional displacement or velocity and acceleration sensors to collect state variables for building the state space. Furthermore, it has been experimentally verified that the new motion synchronous composite decoupling control method can indeed guarantee sufficient control accuracy when the test frequency is increased. The method has great economic significance for shortening test duration.

Oral administration of ellagic acid mitigates perioperative neurocognitive disorders, hippocampal oxidative stress, and neuroinflammation in aged mice by restoring IGF-1 signaling.

This study investigates the potential of ellagic acid (EA), a phytochemical with antioxidant and anti-inflammatory properties, in managing perioperative neurocognitive disorders (PND). PND, which represents a spectrum of cognitive impairments often faced by elderly patients, is principally linked to surgical and anesthesia procedures, and heavily impacted by oxidative stress in the hippocampus and microglia-induced neuroinflammation. Employing an aged mice model subjected to abdominal surgery, we delve into EA's ability to counteract postoperative oxidative stress and cerebral inflammation by engaging the Insulin-like growth factor-1 (IGF-1) pathway. Our findings revealed that administering EA orally notably alleviated post-surgical cognitive decline in older mice, a fact that was manifested in improved performance during maze tests. This enhancement in the behavioral performance of the EA-treated mice corresponded with the rejuvenation of IGF-1 signaling, a decrease in oxidative stress markers in the hippocampus (like MDA and carbonylated protein), and an increase in the activity of antioxidant enzymes such as SOD and CAT. Alongside these, we observed a decrease in microglia-driven neuroinflammation in the hippocampus, thus underscoring the antioxidant and anti-inflammatory roles of EA. Interestingly, when EA was given in conjunction with an IGF1R inhibitor, these benefits were annulled, accentuating the pivotal role that the IGF-1 pathway plays in the neuroprotective potential of EA. Hence, EA could serve as a potent candidate for safeguarding against PND in older patients by curbing oxidative stress and neuroinflammation through the activation of the IGF-1 pathway.

Consistency analysis of consciousness index and bispectral index in monitoring the depth of sevoflurane anesthesia in laparoscopic surgery.

Background: The Index of Consciousness (IoC) is a new monitoring index of anesthesia depth reflecting the state of consciousness of the brain independently developed by China. The research on monitoring the depth of anesthesia mainly focuses on propofol, and bispectral index (BIS) is a sensitive and accurate objective index to evaluate the state of consciousness at home and abroad. This study mainly analyzed the effect of IoC on monitoring the depth of sevoflurane anesthesia and the consistency and accuracy with BIS when monitoring sevoflurane maintenance anesthesia. Objective: To investigate the monitoring value of the Index of Consciousness (IoC) for the depth of sevoflurane anesthesia in laparoscopic surgery. Methods: The study population consisted of 108 patients who experienced elective whole-body anesthesia procedures within the timeframe of April 2020 to June 2023 at our hospital. Throughout the anesthesia process, which encompassed induction and maintenance using inhaled sevoflurane, all patients were diligently monitored for both the Bispectral Index (BIS) and the Index of Consciousness (IoC). We conducted an analysis to assess the correlation between IoC and BIS throughout the anesthesia induction process and from the maintenance phase to the regaining of consciousness. To evaluate the predictive accuracy of IoC and BIS for the onset of unconsciousness during induction and the return of consciousness during emergence, we employed receiver operating characteristic (ROC) curve analysis. Results: The mean difference between BIS and IoC, spanning from the pre-anesthesia induction phase to the completion of propofol induction, was 1.3 (95% Limits of Agreement [-53.4 to 56.0]). Similarly, during the interval from the initiation of sevoflurane inhalation to the point of consciousness restoration, the average difference between BIS and IoC was 0.3 (95% LOA [-10.8 to 11.4]). No statistically significant disparities were observed in the data acquired from the two measurement methodologies during both the anesthesia induction process and the journey from maintenance to the regaining of consciousness (P > 0.05). The outcomes of the ROC curve analysis disclosed that the areas under the curve (AUC) for prognosticating the occurrence of loss of consciousness were 0.967 (95% CI [0.935-0.999]) for BIS and 0.959 (95% CI [0.924-0.993]) for IoC, with optimal threshold values set at 81 (sensitivity: 88.10%, specificity: 92.16%) and 77 (sensitivity: 79.55%, specificity: 95.45%) correspondingly. For the prediction of recovery of consciousness, the AUCs were 0.995 (95% CI [0.987-1.000]) for BIS and 0.963 (95% CI [0.916-1.000]) for IoC, each associated with optimal cutoff values of 76 (sensitivity: 92.86%, specificity: 100.00%) and 72 (sensitivity: 86.36%, specificity: 100.00%) respectively. Conclusion: The monitoring of sevoflurane anesthesia maintenance using IoC demonstrates a level of comparability to BIS, and its alignment with BIS during the maintenance phase of sevoflurane anesthesia is robust. IoC displays promising potential for effectively monitoring the depth of anesthesia.

Vaccarin alleviates septic cardiomyopathy by potentiating NLRP3 palmitoylation and inactivation.

BACKGROUND: Sepsis often leads to significant morbidity and mortality due to severe myocardial injury. As is known, the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome crucially contributes to septic cardiomyopathy (SCM) by facilitating the secretion of interleukin (IL)-1ß and IL-18. The removal of palmitoyl groups from NLRP3 is a crucial step in the activation of the NLRP3 inflammasome. Thus, the potential inhibitors that regulate the palmitoylation and inactivation of NLRP3 may significantly diminish sepsis-induced cardiac dysfunction. PURPOSE: The present study sought to explore the effects of the prospective flavonoid compounds targeting NLRP3 on SCM and to elucidate the associated underlying mechanisms. STUDY DESIGN: The palmitoylation and activation of NLRP3 were detected in H9c2 cells and C57BL/6 J mice. METHODS/RESULTS: Echocardiography, histological staining, western blotting, co-immunoprecipitation, qPCR, ELISA and network pharmacology were used to assess the impact of vaccarin (VAC) on SCM in mice subjected to lipopolysaccharide (LPS) injection. From the collection of 74 compounds, we identified that VAC had the strongest capability to suppress NLRP3 luciferase report gene activity in cardiomyocytes, and the anti-inflammatory characteristics of VAC were further ascertained by the network pharmacology. Exposure of LPS triggered apoptosis, inflammation, oxidative stress, mitochondrial disorder in cardiomyocytes. The detrimental alterations were significantly reversed upon VAC treatment in both septic mice and H9c2 cells exposed to LPS. In vivo experiments demonstrated that VAC treatment alleviated septic myocardial injury, indicated by enhanced cardiac function parameters, preserved cardiac structure, and reduced inflammation/oxidative response. Mechanistically, VAC induced NLRP3 palmitoylation to inactivate NLRP3 inflammasome by acting on zDHHC12. In support, the NLRP3 agonist ATP and the acylation inhibitor 2-bromopalmitate (2-BP) prevented the effects of VAC. CONCLUSION: Our findings suggest that VAC holds promise in protecting against SCM by mitigating cardiac oxidative stress and inflammation via priming NLRP3 palmitoylation and inactivation. These results lay the solid basis for further assessment of the therapeutic potential of VAC against SCM.

Patient's age with papillary thyroid cancer: Is it a key factor for cervical lymph node metastasis?

BACKGROUND: Age is one of the important prognostic indicators of papillary thyroid cancer (PTC). However, the distinct metastatic patterns and prognosis of age-related lymph node metastasis (LNM) are unclear. This study aims to investigate the impact of age on LNM. METHODS: We conducted two independent cohort studies to assess age-nodal disease association using logistic regression analysis and a restricted cubic splines model. A multivariable Cox regression model was utilized to test the impact of nodal disease on cancer-specific survival (CSS) after age stratification. RESULTS: For this study, we included 7572 and 36,793 patients with PTC in Xiangya and SEER cohorts, respectively. After adjustment, advanced age was linearly associated with decreasing risk of central LNM. Patients of age ≤18 years (OR = 4.41, P < 0.001) and 19-45 years (OR = 1.97, P = 0.002) had a higher risk of developing lateral LNM than patients of age >60 years in both cohorts. Furthermore, CSS is significantly reduced in N1b disease (P < 0.001), not N1a disease, regardless of age. The incidence of high-volume LNM (HV-LNM) was significantly higher in patients of age ≤18 years and 19-45 years than in those of age >60 years (P < 0.001), in both cohorts. In addition, CSS was compromised in patients with PTC of age 46-60 years (HR = 1.61, P = 0.022) and those of age >60 (HR = 1.40, P = 0.021) after developing HV-LNM. CONCLUSIONS: Patient age is significantly associated with LNM and HV-LNM. Patients with N1b disease or patients with HV-LNM of age >45 years have significantly shorter CSS. Age can, thus, be a useful guide for determining treatment strategies in PTC.

Effects of oral ß-caryophyllene (BCP) treatment on perioperative neurocognitive disorders: Attenuation of neuroinflammation associated with microglial activation and reinforcement of autophagy activity in aged mice.

Perioperative neurocognitive disorders (PND) are a constellation of cognitive impairments that arise following surgical procedures and anesthesia, with a higher incidence in elderly patients. PND is deeply entwined with microglia-mediated neuroinflammation and disrupted autophagy. ß-caryophyllene (BCP) is a natural terpene that occurs widely in dietary plants, and possesses robust anti-inflammatory properties by selectively activating CB2 receptors (CB2R). Accordingly, the present study endeavors to investigate the potential of BCP in ameliorating PND in aged mice, by mitigating hippocampal neuroinflammation and improving autophagy. In this study, an abdominal surgery was utilized to induce perioperative neurocognitive disorders (PND) in aged mice. BCP was administered orally at a dosage of 200 mg/kg for seven consecutive days prior to the scheduled surgery. In order to explore the relationship between BCP and CB2 receptors (CB2R), a co-administration of intraperitoneal injections of the CB2R antagonist AM630 was implemented, 30 min preceding the oral gavage of BCP. Postoperative cognitive functions were assessed using Morris water maze (MWM) tests. The extent of hippocampal inflammation was examined by measuring the microglial marker Iba-1 protein levels, Iba-1 and GFAP immunoactivity, as well as IL-1ß and IL-6 concentrations. Evaluation of autophagy activity was conducted based on the ratio of LC3B2/LC3B1 and protein levels of Beclin-1, p62, and phospho-mTOR (p-mTOR). After being orally administered BCP, the compromised behavioral performance of abdominal surgical interventions on aged mice was alleviated. This was evident by the extended escape latency, reduced time spent in the target quadrant, and fewer platform crossings observed through MWM testing. While hippocampal CB2R mRNA or protein expression remained unaffected by the abdominal surgical procedure, their levels were significantly upregulated in mice that were administered BCP. Moreover, the oral administration of BCP was able to reduce neuroinflammation in response to microglia activation, as evidenced by the decreased levels of Iba-1 protein and immunoactivity, as well as the reduction of IL-1ß and IL-6 concentrations. Additionally, BCP intensified autophagic activity, as detected by increased LC3B2/LC3B1 ratio and Beclin-1 protein levels, coupled with decreased levels of p62 and p-mTOR in the hippocampus of aged mice. Conversely, the treatment of AM630 ameliorated the suppressive effect of BCP triggered by the neuroinflammation caused by microglial activation post-surgery in aged mice (increased Iba-1 protein levels and immunoactivity, accompanied by higher IL-1ß and IL-6 concentrations). Furthermore, the pro-autophagy effect of BCP on aged mice following surgery was partially blocked by AM630, culminating in decreased LC3B2/LC3B1 ratio and Beclin-1 protein levels. However, the levels of p62 and p-mTOR remained unchanged by AM630. Our investigation unveils the remarkable therapeutic benefits of oral BCP administration for managing PND in aged mice through the attenuation of neuroinflammation associated with microglial activation and the fortification of autophagy activity. Hence, BCP holds great promise as a formidable candidate englobing various potential physiological mechanisms that would mitigate cognitive decline associated with aging.