Interleukin-18 in chronic pain: Focus on pathogenic mechanisms and potential therapeutic targets.

Chronic pain has been proven to be an independent disease, other than an accompanying symptom of certain diseases. Interleukin-18 (IL-18), a pro-inflammatory cytokine with pleiotropic biological effects, participates in immune modulation, inflammatory response, tumor growth, as well as the process of chronic pain. Compelling evidence suggests that IL-18 is upregulated in the occurrence of chronic pain. Antagonism or inhibition of IL-18 expression can alleviate the occurrence and development of chronic pain. And IL-18 is located in microglia, while IL-18R is mostly located in astrocytes in the spinal cord. This indicates that the interaction between microglia and astrocytes mediated by the IL-18/IL-18R axis is involved in the occurrence of chronic pain. In this review, we described the role and mechanism of IL-18 in different types of chronic pain. This review provides strong evidence that IL-18 is a potential therapeutic target in pain management.

Toll-like Receptor 2-Melatonin Feedback Loop Regulates the Activation of Spinal NLRP3 Inflammasome in Morphine-Tolerant Rats.

BACKGROUND AND PURPOSE: Morphine is amongst the most effective analgesics available for the management of severe pain. However, prolonged morphine treatment leads to analgesic tolerance which limits its clinical usage. Previous studies have demonstrated that melatonin ameliorates morphine tolerance by reducing neuroinflammation. However, little is known about the relationship between Toll like receptor 2 (TLR2) and neuroinflammation in morphine tolerance. The aim of this study was to explore the role of TLR2 in morphine tolerance and its connections with melatonin and Nod-like receptor protein 3 (NLRP3) inflammasome. METHODS: Sprague-Dawley rats were treated with morphine for 7 days and tail-flick latency test was performed to identify the induction of analgesic tolerance. The roles of TLR2 in microglia activation and morphine tolerance were assessed pharmacologically, and the possible interactions between melatonin, TLR2 and NLRP3 inflammasome were investigated. KEY RESULTS: Morphine tolerance was accompanied by increased TLR2 expression and NLRP3 inflammasome activation in spinal cord. whereas melatonin level was down-regulated. Chronic melatonin administration resulted in a reduced TLR2 expression and NLRP3 inflammasome activation. Moreover, the analgesic effect of morphine was partially restored. Inhibition of TLR2 suppressed the microglia and NLRP3 inflammasome activation, as well as restored the spinal melatonin level while attenuated the development of morphine tolerance. Furthermore, the inhibition of microglia activation ameliorated morphine tolerance via inhibiting TLR2-NLRP3 inflammasome signaling in spinal cord. CONCLUSION: In this study, we directly demonstrate a TLR2-melatonin negative feedback loop regulating microglia and NLRP3 inflammasome activation during the development of morphine tolerance.

Activation of spinal PDGFRß in microglia promotes neuronal autophagy via p38 MAPK pathway in morphine-tolerant rats.

The adverse side effects of opioids, especially antinociceptive tolerance, limit their clinical application. A recent study reported that platelet-derived growth factor receptor ß (PDGFRß) blockage selectively inhibited morphine tolerance. Autophagy has been reported to contribute to the cellular and behavioral responses to morphine. However, little is known about the relationship between PDGFRß and autophagy in the mechanisms of morphine tolerance. In this study, rats were intrathecally administered with morphine twice daily for 7 days to induce antinociceptive tolerance, which was evaluated using a tail-flick latency test. By administration autophagy inhibitor 3-Methyladenine, PDGFRß inhibitor imatinib, p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 hydrochloride and minocycline hydrochloride, western blot, immunofluorescence, and transmission electron microscopy techniques were used to elucidate the roles of PDGFRß, autophagy, and related signaling pathways in morphine tolerance. This study demonstrated for the first time that spinal PDGFRß in microglia promotes autophagy in gamma-aminobutyric acid (GABA) interneurons through activating p38 MAPK pathway during the development of morphine tolerance, which suggest a potential strategy for preventing the development of morphine tolerance clinically, thereby improving the use of opioids in pain management.

NADPH-Oxidase 2 Promotes Autophagy in Spinal Neurons During the Development of Morphine Tolerance.

Repeated morphine administration results in analgesic tolerance. However, the underlying mechanism of morphine analgesic tolerance remains unclear. NADPH-oxidase 2 (NOX2) is the first discovered NADPH oxidase, which mainly functions to produce reactive oxygen species. Its specific role in morphine tolerance has not been fully investigated. In this work, we found that chronic morphine administration significantly increased the expression of NOX2 in spinal cord. Pretreatment of NOX2 inhibitor blocked the upregulation of NOX2 and autophagy markers, including LC3B and P62, and consequently the development of morphine tolerance. NOX2 and LC3B were both colocalized with NeuN in spinal dorsal horn in morphine-tolerant rats. Our results suggest that the increased autophagy activity in spinal neurons promoted by NOX2 activation contributes to the development of morphine tolerance. NOX2 may be considered as a new therapeutic target for morphine tolerance.

Association between tea drinking and plasma folate concentration among women aged 18-30 years in China.

OBJECTIVE: Association was found between tea and neural tube defects. However, few studies investigated the relationship between tea consumption and blood folate levels. We aimed to investigate the association between tea consumption and plasma folate concentrations among women aged 18-30 years in different ethnicities of China. DESIGN: Data were obtained from a national cross-sectional study conducted from 2005 to 2006 of women aged 18-30 years in China. Socio-demographic characteristics and lifestyle were obtained from a questionnaire. Dietary folate intake was determined by 24-h dietary recall. Plasma folate concentrations were measured by a microbiological assay. Multiple linear regression model was used to calculate partial regression coefficients after adjusting for confounding factors. SETTING: Nine provinces or autonomous regions in China. PARTICIPANTS: A total of 2932 women aged 18-30 years in China. RESULTS: After stratifying by ethnicity and tea type, tea consumption was significantly positively associated with plasma folate levels in Han women who drank unfermented tea weekly (ß = 0·067, and P = 0·037) or daily (ß = 0·119, and P = 0·031) and in Uighur women who drank fermented tea weekly (ß = 0·325, and P = 0·028). For women who drank unfermented tea in Han ethnicity, weekly and daily tea drinkers had 6·77 % (95 % CI: 6·36 %, 7·21 %) and 7·13 % (95 % CI: 6·40 %, 7·96 %) increase in plasma folate concentration compared with no tea drinkers. CONCLUSIONS: There is a suggestion of possible positive association between unfermented tea drinking in Han ethnicity and plasma folate concentrations, for Chinese women aged 18-30 years. The relationship between tea drinking in other ethnic groups and plasma folate still needs to be further explored.

Evaluation of the lignite biotransformation capacity of Fusarium sp. NF01 cultured on different growth substrates.

The screening and studying the lignite solubilization/degradation capacities of indigenous microorganisms are key to exploring the in-situ biotransformation of lignite. Herein, a fungus was isolated from in-situ lignite samples and identified as Fusarium sp. NF01. This isolate was then cultured on four different carbon sources to evaluate its lignite-transformation capacity. When cultured on a solid agar medium containing sodium gluconate or sodium glutamate, Fusarium sp. NF01 completely liquefied 0.5 g of lignite within 6 days, and when cultured in a liquid medium containing sodium gluconate, the weight of lignite decreased by 28.4% within 7 days. Elemental analysis showed that the rate of lignite biodegradation was inversely proportional to the C:O ratio of the residual lignite samples. Additionally, a 5.9% biodesulfurization rate was achieved when Fusarium sp. NF01 was cultured in the presence of sodium gluconate. Finally, Fourier-transform infrared analysis of the residual lignite samples revealed relatively weak signal intensities of the signature peaks representing the following: aromatic ring side chains; ether, ester, and alcohol bonds; aromatic ring carbon-carbon double bonds; and aliphatic methyl and methylene. The results show that Fusarium sp. NF01 degrades lignite in a carbon-dependent manner and could be thus used for the bioconversion of subsurface coalbeds.

Environmental complex exposure and the risk of influenza-like illness among housewives: A case study in Shanxi Province, China.

The association between environmental pollution and risk of influenza-like illness (ILI) among general population has been reported. However, the relationships between the individual pollutants and ILI risk are still under discussion. Our study aimed to explore the associations of the typical environmental polycyclic aromatic hydrocarbons (PAHs) and metal(loid)s with ILI risk among women population. We carried out a cross-sectional study and included a total of 396 housewives in Shanxi Province, China. The information on their general characteristics and ILI frequency was collected by questionnaire. We collected their hair samples and analyzed the concentrations of PAHs and various metal(loid)s. The results indicated that only acenaphthylene concentration of the nine detected PAH congeners in the hair was significantly associated with ILI risk with adjusted odds ratio (AOR) and 95% confidence interval (95% CI) of 0.58 (0.38 - 0.91). Among the concerned 4 toxic metal(loid)s and 15 rare earth elements, only the hair concentration of arsenic had a positive dose-response relationship with ILI risk. In addition, we found that there were negative dose-response associations of the three essential trace elements (i.e. chromium, cobalt, and nickel), and four essential alkaline earth elements (i.e. magnesium, calcium, strontium, barium) with ILI risk. It was concluded that the environmental exposure to certain compounds of housewives may contribute to their ILI development.

Inhibition of spinal BRD4 alleviates pyroptosis and M1 microglia polarization via STING-IRF3 pathway in morphine-tolerant rats.

BACKGROUND: Morphine tolerance has been a challenging medical issue. Neuroinflammation is considered as a critical mechanism for the development of morphine tolerance. Bromodomain-containing protein 4 (BRD4), a key regulator in cell damage and inflammation, participates in the development of chronic pain. However, whether BRD4 is involved in morphine tolerance and the underlying mechanisms remain unknown. METHODS: The morphine-tolerant rat model was established by intrathecal administration of morphine twice daily for 7 days. Behavior test was assessed by a tail-flick latency test. The roles of BRD4, pyroptosis, microglia polarization and related signaling pathways in morphine tolerance were elucidated by Western blot, real-time quantitative polymerase chain reaction, and immunofluorescence. RESULTS: Repeated morphine administration upregulated BRD4 level, induced pyroptosis, and promoted microglia M1-polarization in spinal cord, accompanied by the release of proinflammatory cytokines, such as TNF-α and IL-1ß. JQ-1, a BRD4 antagonist, alleviated the development of morphine tolerance, diminished pyroptosis and induced the switch of microglia from M1 to M2 phenotype. Mechanistically, stimulator of interferon gene (STING)- interferon regulatory factor 3 (IRF3) pathway was activated and the protective effect of JQ-1 against morphine tolerance was at least partially mediated by inhibition of STING-IRF3 pathway. CONCLUSION: This study demonstrated for the first time that spinal BRD4 contributes to pyroptosis and switch of microglia polarization via STING-IRF3 signaling pathway during the development of morphine tolerance, which extend the understanding of the neuroinflammation mechanism of morphine tolerance and provide an alternative strategy for the precaution against of this medical condition.

Exposure biomarker profiles of polycyclic aromatic hydrocarbons based on a rat model using a versatile analytical framework.

Polycyclic aromatic hydrocarbons (PAHs) are an important group of organic toxic pollutants. Parent PAHs (pPAHs) are mainly metabolized into mono-hydroxylated PAHs (OH-PAHs) after entering the human body. Until now, it is still an urgent need to select appropriate exposure biomarkers for PAHs and analyze them at the trace level. Based on gas chromatography coupled with triple-quadrupole tandem mass spectrometry, we have developed a versatile analytical method for the systemic analysis of pPAHs and OH-PAHs in routinely collected biological samples. This method was further applied to analyze plasma, hair and urine samples from 24 rats exposed to 13 pPAH congeners at four levels. The detection rate for pPAHs in three types of samples was 100%, except for dibenz(a,h)anthracene (DahA) in plasma, while the detection rate for OH-PAHs ranged from 25% to 100%. A significant linear relationship was observed between pPAH exposure levels and their corresponding OH-PAH levels in three different types of samples. It was found that each unit increase in pPAH exposure level was associated with an increase in OH-PAHs ranging from 0.03% (0.01-0.05%) to 5.27% (1.74-8.81%). Furthermore, significant positive correlations were found between any two types of samples for most OH-PAHs, but not observed for most pPAHs. The correlation patterns of 1-hydroxypyrene (1-OH-PYR) across three types of samples differed from other congeners. Strong correlations were identified between five types of hydroxyphenanthrene (OH-PHE) and pPAH exposure levels. In conclusion, OH-PAHs were more sensitive exposure biomarkers than pPAHs, particularly in hair and urine samples.

Improving image quality consistency and diagnostic accuracy in lower extremity CT angiography using a split-bolus contrast injection protocol.

OBJECTIVES: To evaluate the clinical value of using a split-bolus contrast injection protocol in improving image quality consistency and diagnostic accuracy in lower extremity CT angiography (CTA). METHODS: Fifty (mean age, 66 ± 12 years) and 39 (mean age, 66 ± 11 years) patients underwent CTA in the lower extremity arteries using split-bolus and fixed-bolus injection schemes, respectively. The objective and subjective image quality of the 2 groups were compared and the diagnostic efficacy for the degree of vessel stenosis was compared using digital subtraction angiography as the gold standard. A P < .05 was considered statistically significant. RESULTS: In comparison with the fixed-bolus scheme, the split-bolus scheme greatly improved the consistency of image quality of the low extremities by significantly increasing the arterial enhancement (337.87 ± 64.67HU vs. 254.74 ± 71.58HU, P < .001), signal-to-noise ratio (22.58 ± 11.64 vs. 7.14 ± 1.98, P < .001), and contrast-to-noise ratio (37.21 ± 10.46 vs. 31.10 ± 15.40, P = .041) in the infrapopliteal segment. The subjective image quality was better (P < .001) and the diagnostic accuracy was higher in the split-bolus group than in the fixed-bolus group (96.00% vs. 91.67%, P < .05, for diagnosing >50% stenosis, and 97.00% vs. 89.10%, P < .05, for diagnosing occlusion) for the infrapopliteal segment arteries. CONCLUSIONS: Compared with the fixed-bolus injection scheme, the split-bolus injection scheme improves the image quality consistency and diagnostic accuracy especially for the infrapopliteal segment arteries in lower extremity CTA. ADVANCES IN KNOWLEDGE: (1) The split-bolus injection scheme of CTA of the lower extremity arteries improves the overall image quality, uniformity of contrast enhancement. (2) Compared with the fixed-bolus injection scheme, the split-bolus injection scheme especially improves the infrapopliteal segment arteries image quality and diagnostic efficacy.

Co-exposure to phthalates and polycyclic aromatic hydrocarbons and the risk of gestational hypertension in Chinese women.

Phthalates (PAEs) and polycyclic aromatic hydrocarbons (PAHs) are frequently detected in females of reproductive age. Many studies have found that environmental PAE and PAH levels are independent risk factors for gestational hypertension. However, exposure to both components is a more realistic scenario. To better assess the health effects of PAEs and PAHs in pregnant women, we explored the associations of exposure to both individual and combined PAEs and PAHs with gestational hypertension. This nested case-control study was a component of a prospective cohort study conducted in Beijing, China. We included 206 women with gestational hypertension and 214 pregnant controls. We used gas chromatography/tandem mass spectrometry (GC-MS/MS) to detect 8 PAEs and 13 PAHs in > 80 % of all collected hair samples. Multiple linear regression models were employed to test the individual associations between each component and gestational hypertension. A quantile-based g-computation (qgcomp) model and a weighted quantile sum (WQS) regression model were used to estimate whether exposure to both PAEs and PAHs increased the risk of gestational hypertension. The individual exposure analyses revealed that diethyl phthalate (DEP), diisobutyl phthalate (DIBP) (both PAEs), benzo(k)fluoranthene (BKF), anthracene, (ANT), and benzo(a)pyrene (BAP) (all PAHs) were positively associated with increased risk of gestational hypertension. In mixed-effect analyses, the qgcomp model indicated that co-exposure to PAEs and PAHs increased the risk of gestational hypertension (odds ratio = 2.01; 95 % confidence interval: 1.02, 3.94); this finding was verified by the WQS regression model. Our findings support earlier evidence that both PAEs and PAHs increase the risk of gestational hypertension, both individually and in combination. This suggests that reductions in exposure to endocrine system-disrupting chemicals such as PAEs and PAHs might reduce the risk of gestational hypertension.

Sympathetic hyperinnervation drives abdominal aortic aneurysm development by promoting vascular smooth muscle cell phenotypic switching.

INTRODUCTION: Sympathetic hyperinnervation plays an important role in modulating the vascular smooth muscle cell (VSMC) phenotype and vascular diseases, but its role in abdominal aortic aneurysm (AAA) is still unknown. OBJECTIVES: This study aimed to investigate the role of sympathetic hyperinnervation in promoting AAA development and the underlying mechanism involved. METHODS: Western blotting and immunochemical staining were used to detect sympathetic hyperinnervation. We performed sympathetic denervation through coeliac ganglionectomy (CGX) and 6-OHDA administration to understand the role of sympathetic hyperinnervation in AAA and investigated the underlying mechanisms through transcriptome and functional studies. Sema4D knockout (Sema4D-/-) mice were utilized to determine the involvement of Sema4D in inducing sympathetic hyperinnervation and AAA development. RESULTS: We observed sympathetic hyperinnervation, the most important form of sympathetic neural remodeling, in both mouse AAA models and AAA patients. Elimination of sympathetic hyperinnervation by CGX or 6-OHDA significantly inhibited AAA development and progression. We further revealed that sympathetic hyperinnervation promoted VSMC phenotypic switching in AAA by releasing extracellular ATP (eATP) and activating eATP-P2rx4-p38 signaling. Moreover, single-cell RNA sequencing revealed that Sema4D secreted by osteoclast-like cells induces sympathetic nerve diffusion and hyperinnervation through binding to Plxnb1. We consistently observed that AAA progression was significantly ameliorated in Sema4D-deficient mice. CONCLUSIONS: Sympathetic hyperinnervation driven by osteoclast-like cell-derived Sema4D promotes VSMC phenotypic switching and accelerates pathological aneurysm progression by activating the eATP/P2rx4/p38 pathway. Inhibition of sympathetic hyperinnervation emerges as a potential novel therapeutic strategy for preventing and treating AAA.

Development and validation of a fully automated system using deep learning for opportunistic osteoporosis screening using low-dose computed tomography scans.

Background: Bone density measurement is an important examination for the diagnosis and screening of osteoporosis. The aim of this study was to develop a deep learning (DL) system for automatic measurement of bone mineral density (BMD) for osteoporosis screening using low-dose computed tomography (LDCT) images. Methods: This retrospective study included 500 individuals who underwent LDCT scanning from April 2018 to July 2021. All images were manually annotated by a radiologist for the cancellous bone of target vertebrae and post-processed using quantitative computed tomography (QCT) software to identify osteoporosis. Patients were divided into the training, validation, and testing sets in a ratio of 6:2:2 using a 4-fold cross validation method. A localization model using faster region-based convolutional neural network (R-CNN) was trained to identify and locate the target vertebrae (T12-L2), then a 3-dimensional (3D) AnatomyNet was trained to finely segment the cancellous bone of target vertebrae in the localized image. A 3D DenseNet was applied for calculating BMD. The Dice coefficient was used to evaluate segmentation performance. Linear regression and Bland-Altman (BA) analyses were performed to compare the calculated BMD values using the proposed system with QCT. The diagnostic performance of the system for osteoporosis and osteopenia was evaluated with receiver operating characteristic (ROC) curve analysis. Results: Our segmentation model achieved a mean Dice coefficient of 0.95, with Dice coefficients greater than 0.9 accounting for 96.6%. The correlation coefficient (R2) and mean errors between the proposed system and QCT in the testing set were 0.967 and 2.21 mg/cm3, respectively. The area under the curve (AUC) of the ROC was 0.984 for detecting osteoporosis and 0.993 for distinguishing abnormal BMD (osteopenia and osteoporosis). Conclusions: The fully automated DL-based system is able to perform automatic BMD calculation for opportunistic osteoporosis screening with high accuracy using LDCT scans.

The value of using a deep learning image reconstruction algorithm of thinner slice thickness to balance the image noise and spatial resolution in low-dose abdominal CT.

Background: Traditional reconstruction techniques have certain limitations in balancing image quality and reducing radiation dose. The deep learning image reconstruction (DLIR) algorithm opens the door to a new era of medical image reconstruction. The purpose of the study was to evaluate the DLIR images at 1.25 mm thickness in balancing image noise and spatial resolution in low-dose abdominal computed tomography (CT) in comparison with the conventional adaptive statistical iterative reconstruction-V at 40% strength (ASIR-V40%) at 5 and 1.25 mm. Methods: This retrospective study included 89 patients who underwent low-dose abdominal CT. Five sets of images were generated using ASIR-V40% at a 5 mm slice thickness and 1.25 mm (high-resolution) with DLIR at 1.25 mm using 3 strengths: low (DLIR-L), medium (DLIR-M), and high (DLIR-H). Qualitative evaluation was performed for image noise, artifacts, and visualization of small structures, while quantitative evaluation was performed for standard deviation (SD), signal-to-noise ratio (SNR), and spatial resolution (defined as the edge rising slope). Results: At 1.25 mm, DLIR-M and DLIR-H images had significantly lower noise (SD in fat: 14.29±3.37 and 9.65±3.44 HU, respectively), higher SNR for liver (3.70±0.78 and 5.64±1.20, respectively), and higher overall image quality (4.30±0.44 and 4.67±0.40, respectively) than did the respective values in ASIR-V40% images (20.60±4.04 HU, 2.60±0.63, and 3.77±0.43; all P values <0.05). Compared with the 5 mm ASIR-V40% images, the 1.25 mm DLIR-H images had lower noise (SD: 9.65±3.44 vs. 13.63±10.03 HU), higher SNR (5.64±1.20 vs. 4.69±1.28), and higher overall image quality scores (4.67±0.40 vs. 3.94±0.46) (all P values <0.001). In addition, DLIR-L, DLIR-M, and DLIR-H images had a significantly higher spatial resolution in terms of edge rising slope (59.66±21.46, 58.52±17.48, and 59.26±13.33, respectively, vs. 33.79±9.23) and significantly higher image quality scores in the visualization of fine structures (4.43±0.50, 4.41±0.49, and 4.38±0.49, respectively vs. 2.62±0.49) than did the 5 mm ASIR-V40 images. Conclusions: The 1.25 mm DLIR-M and DLIR-H images had significantly reduced image noise and improved SNR and overall image quality compared to the 1.25 mm ASIR-V40% images, and they had significantly improved the spatial resolution and visualization of fine structures compared to the 5 mm ASIR-V40% images. DLIR-H images had further reduced image noise compared with the 5 mm ASIR-V40% images, and DLIR-H was the most effective technique at balancing the image noise and spatial resolution in low-dose abdominal CT.

Extracellular vesicle-derived CircWhsc1 promotes cardiomyocyte proliferation and heart repair by activating TRIM59/STAT3/Cyclin B2 pathway.

INTRODUCTION: Extracellular vesicles (EVs)-mediated cell-to-cell communication is crucial for hypoxia-induced cell proliferation and tissue repair, but its function in endogenous cardiac regeneration is still unknown. OBJECTIVES: Herein, we aimed to determine whether hypoxia-inducible circWhsc1 in endothelial EVs promoted cardiomyocyte (CM) proliferation and cardiac regeneration. METHODS: RNA-sequence data was used to identify EV circRNAs that were involved into endogenous cardiac regeneration. Quantitative polymerase chain reactions were conducted to determine circRNA expression in tissue, cells and EVs. Gain- and loss-of-function assays were performed to explore the function of EV-derived circWhsc1 during cardiac regeneration. Western blotting and RNA pulldown assays were used to investigate its underlying mechanism. RESULTS: We found that circWhsc1 was enriched in neonatal mouse hearts, particularly in cardiac ECs, and was further upregulated both in ECs and EC-derived EVs under hypoxic conditions. When cocultured with hypoxia-preconditioned neonatal ECs or their secreted EVs, both neonatal and adult CMs exhibited an increased proliferation rate and G2/M ratio, which could be attenuated by knockdown of circWhsc1 in ECs. In vivo, EC-restricted overexpression of circWhsc1 and EV-mediated delivery of circWhsc1 induced CM proliferation, alleviated cardiac fibrosis and restored cardiac function following myocardial infarction in adult mice. Mechanistic studies revealed that EV-derived circWhsc1 activated TRIM59 by enhancing its phosphorylation, thereby reinforcing the binding of TRIM59 to STAT3, phosphorylating STAT3 and inducing CM proliferation. CONCLUSION: The current study demonstrated that hypoxia-inducible circWhsc1 in EC-derived EVs induces CM proliferation and heart regeneration. EC-CM communication mediated by EV-derived circWhsc1 might represent a prospective therapeutic target for inducing cardiac repair post-myocardial infarction.

Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms.

Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by various pathophysiological processes, including chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Stress-induced premature senescence (SIPS) has been implicated in regulating these pathophysiological processes, but whether SIPS contributes to AAA formation remains unknown. Here, we detected SIPS in AAA from patients and young mice. The senolytic agent ABT263 prevented AAA development by inhibiting SIPS. Additionally, SIPS promoted the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, whereas inhibition of SIPS by the senolytic drug ABT263 suppressed VSMC phenotypic switching. RNA sequencing and single-cell RNA sequencing analysis revealed that fibroblast growth factor 9 (FGF9), secreted by stress-induced premature senescent VSMCs, was a key regulator of VSMC phenotypic switching and that FGF9 knockdown abolished this effect. We further showed that the FGF9 level was critical for the activation of PDGFRß/ERK1/2 signaling, facilitating VSMC phenotypic change. Taken together, our findings demonstrated that SIPS is critical for VSMC phenotypic switching through the activation of FGF9/PDGFRß/ERK1/2 signaling, promoting AAA development and progression. Thus, targeting SIPS with the senolytic agent ABT263 may be a valuable therapeutic strategy for the prevention or treatment of AAA.

A Response Surface Analysis of the Combination of Dexmedetomidine and Sufentanil for Attenuating the Haemodynamic Response to Endotracheal Intubation.

Purpose: Dexmedetomidine combined with opioids has been extensively used to blunt cardiovascular responses to endotracheal intubation. To determine their interaction, we aimed to develop a response surface model between dexmedetomidine and sufentanil. Methods: One hundred and twenty patients undergoing scheduled gynaecological surgery were recruited. According to a simulation of slice design, patients received different dose pairs of dexmedetomidine (0 to 1.1 µg/kg) and sufentanil (.1 to .5 µg/kg). The mean arterial blood pressure and heart rate of patients were recorded just before endotracheal intubation, immediately after intubation, and during the first 3 min after intubation. The primary outcomes were haemodynamic changes. The full dose-response relationship between dexmedetomidine and sufentanil was analysed using a logit model. Results: This response surface model revealed that the interaction between dexmedetomidine and sufentanil was additive. The dose pairs that could effectively attenuate the haemodynamic response to endotracheal intubation primarily ranged from .3 to .4 µg/kg and .5 to 1.1 µg/kg for sufentanil and dexmedetomidine, respectively. Conclusion: When used propofol as the main hypnotic drug during anaesthesia induction, dexmedetomidine could effectively reduce the requirement of sufentanil in an additive manner. However, it is not an effective drug for ablating the cardiovascular response to endotracheal intubation when used alone. The clinical trial registry. The trial registry name: Chinese Clinical Trial Registry. Registration number: ChiCTR1800015273. URL:http://www.chictr.org.cn.

Passive Smoking Is Associated with Multiple Heavy Metal Concentrations among Housewives in Shanxi Province, China.

BACKGROUND: Passive smoking may increase the content of heavy metals in housewives. However, this association remains a subject of debate. Female passive smoking is widespread, particularly in Chinese rural areas. OBJECTIVE: This study aimed to assess the association between heavy metal accumulation and passive smoking status among rural housewives. METHODS: 405 women were recruited in Shanxi Province of Northern China, and 384 (94.8%, 384/405) participants were included in the final study, of whom 117 women were exposed to passive smoking. The information on their basic characteristics was collected via a structured questionnaire. We used inductively coupled plasma mass spectrometry (ICP-MS) to analyze the concentrations of nine heavy metals, including cadmium (Cd), germanium (Ge), arsenic (As), lead (Pb), titanium (Ti), copper (Cu), iron (Fe), cobalt (Co), and chromium (Cr), in hair samples. RESULTS: The results indicated that higher As, Ge, Ti, and Fe concentrations were significantly associated with passive smoking. After adjusting for potential confounders, the adjusted odds ratios and the 95% confidence intervals of As, Ge, Ti, and Fe were (1.80 (1.13-2.90), p = 0.028), (1.78 (1.14-2.80), p = 0.007), (1.70 (1.09-2.67), p = 0.019), and (1.67 (1.07-2.63), p = 0.035), respectively. The statistically significant linear trend of the adjusted odds ratios at different levels further supported their association. CONCLUSION: Our research concluded that exposure to environmental tobacco smoke might contribute to As, Ge, Ti, and Fe accumulation among housewives.

Chemokine CXCL10 regulates pain behaviors via PI3K-AKT signaling pathway in mice.

The analgesic efficacy of morphine can be affected by a variety of factors. Our previous studies demonstrated that chemokine (CXC motif) ligand 10 (CXCL10) could induce algesia directly and attenuate the analgesic effect produced by a single dose of morphine. However, the underlying mechanism remains unclear. In the present study, we aimed to further investigate the mechanism of CXCL10-mediated inhibition on morphine analgesic effect. According to our findings, recombinant CXCL10 protein (rmCXCL10) could increase the phosphorylation of serine-threonine kinase AKT reduced by morphine in spinal cord. Blocking AKT activation by phosphoinositide 3-kinase (PI3K) inhibitor could effectively attenuate CXCL10-induced algesia, and reverse the decrease of paw withdrawal thresholds caused by the co-administration of morphine and rmCXCL10. Furthermore, rmCXCL10 could enhance the spinal expression of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1ß, which could be blocked by PI3K inhibitor. In summary, these findings suggest that PI3K-AKT signaling pathway mediates the effect of CXCL10 on the regulation of morphine analgesia and the release of cytokines in spinal cord. Our study provides a new insight into the mechanism of chemokine-relative pain regulation.

Passive Smoking and Risk of Gestational Diabetes Mellitus among Nonsmoking Women: A Prospective Cohort Study in China.

Background: Increasing evidence has shown that active smoking can increase the risk of gestational diabetes mellitus (GDM), but the effect of passive smoking is still unknown. Women in pregnancy are vulnerable to secondhand smoke. This study explored the association of passive smoking with GDM in China. Method: A total of 3083 nonsmoking pregnant women living in Beijing were recruited into a prospective cohort study. Sociodemographic and passive smoking data were collected with structured questionnaires during face-to-face interviews. Glucose levels were measured by physicians according to standard protocols. Multivariate logistic regression was performed for the association estimation after accounting for potential confounders. Result: In total, 562 of the 3083 participants developed GDM (18.23%); 779 participants (25.27%) reported exposure to passive smoking. After adjusting for age, BMI, ethnicity, education, occupation, and parity, passive smoking conferred an approximately 1.4-fold risk increase in GDM (adjusted odds ratio (OR) = 1.37, 95% confidence interval (CI): (1.11, 1.70)). The adjusted ORs with 95% CIs for passive smoking levels of <1, 1−6, and ≥7 times per week were 1.21 (0.94, 1.55), 1.81 (1.22, 2.69), and 1.70 (1.02, 2.84), respectively. An obvious passive-smoking−GDM association was observed among only nulliparous women (adjusted OR = 1.45, 95% CI: (1.14, 1.85)). Conclusion: Frequent exposure to secondhand smoke could increase the risk of GDM among nonsmoking pregnant women. Parity status might modify their association. Public policies should be advocated to prevent passive smoking among this population.