High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage.

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.

Phospholipid Removal for Enhanced Chemical Exposomics in Human Plasma.

The challenge of chemical exposomics in human plasma is the 1000-fold concentration gap between endogenous substances and environmental pollutants. Phospholipids are the major endogenous small molecules in plasma, thus we validated a chemical exposomics protocol with an optimized phospholipid-removal step prior to targeted and non-targeted liquid chromatography high-resolution mass spectrometry. Increased injection volume with negligible matrix effect permitted sensitive multiclass targeted analysis of 77 priority analytes; median MLOQ = 0.05 ng/mL for 200 µL plasma. In non-targeted acquisition, mean total signal intensities of non-phospholipids were enhanced 6-fold in positive (max 28-fold) and 4-fold in negative mode (max 58-fold) compared to a control method without phospholipid removal. Moreover, 109 and 28% more non-phospholipid molecular features were detected by exposomics in positive and negative mode, respectively, allowing new substances to be annotated that were non-detectable without phospholipid removal. In individual adult plasma (100 µL, n = 34), 28 analytes were detected and quantified among 10 chemical classes, and quantitation of per- and polyfluoroalkyl substances (PFAS) was externally validated by independent targeted analysis. Retrospective discovery and semi-quantification of PFAS-precursors was demonstrated, and widespread fenuron exposure is reported in plasma for the first time. The new exposomics method is complementary to metabolomics protocols, relies on open science resources, and can be scaled to support large studies of the exposome.

Diagnostic accuracy of extended HPV DNA genotyping and its application for risk-based cervical cancer screening strategy.

OBJECTIVES: To evaluate the consistency of 14 high-risk HPVs (hr-HPVs) detection between extended HPV DNA genotyping and a well-validated partial HPV genotyping kit, and to explore the diagnostic accuracy of risk stratification strategy based on extended HPV genotyping for cervical cancer (CC) screening. METHODS: Baseline data from a clinical trial of recombinant HPV 9-valent vaccine in China was analyzed. All enrolled women aged 20-45 years received cervical cytology, HPV detection by extended and partial HPV genotyping kits. Those who met the indications would further receive colposcopy. The primary endpoints were cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+). RESULTS: A total of 8,000 women were enrolled between April 2020 and July 2020 and 83/33 cases were diagnosed as CIN2+/CIN3+. The overall agreement between the extended and partial HPV genotyping was 92.66 %. And the agreement further increased with the progression of lesions, which lead to similarly high sensitivity and negative predictive value of these kits. A stratified triage strategy of CC screening was constructed based on the immediate CIN2+/CIN3+ risk of specific HPV. Compared with the conventional HPV primary CC screening strategy, the risk-based strategy had higher specificity for CIN (CIN2+: 94.84 vs. 92.46 %, CIN3+: 96.05 vs. 91.92 %), and needed fewer colposcopies for detecting one cervical disease. CONCLUSIONS: Extended HPV genotyping had good agreement with a well-validated partial HPV genotyping CC primary screening kit in hr-HPV detection. Extended HPV genotyping could facilitate risk-based stratified management strategy and improve the diagnostic accuracy of primary CC screening.

Rho-Kinase Inhibition Improves the Outcome of Focal Subcortical White Matter Lesions.

BACKGROUND: Subcortical white matter lesions are exceedingly common in cerebral small vessel disease and lead to significant cumulative disability without an available treatment. Here, we tested a rho-kinase inhibitor on functional recovery after focal white matter injury. METHODS: A focal corpus callosum lesion was induced by stereotactic injection of N5-(1-iminoethyl)-L-ornithine in mice. Fasudil (10 mg/kg) or vehicle was administered daily for 2 weeks, starting one day after lesion induction. Resting-state functional connectivity and grid walk performance were studied longitudinally, and lesion volumes were determined at one month. RESULTS: Resting-state interhemispheric functional connectivity significantly recovered between days 1 and 14 in the fasudil group (P<0.001), despite worse initial connectivity loss than vehicle before treatment onset. Grid walk test revealed an increased number of foot faults in the vehicle group compared with baseline, which persisted for at least 4 weeks. In contrast, the fasudil arm did not show an increase in foot faults and had smaller lesions at 4 weeks. Immunohistochemical examination of reactive astrocytosis, synaptic density, and mature oligodendrocytes did not reveal a significant difference between treatment arms. CONCLUSIONS: These data show that delayed fasudil posttreatment improves functional outcomes after a focal subcortical white matter lesion in mice. Future work will aim to elucidate the mechanisms.

Intermittent theta-burst stimulation improves motor function by inhibiting neuronal pyroptosis and regulating microglial polarization via TLR4/NFκB/NLRP3 signaling pathway in cerebral ischemic mice.

BACKGROUND: Neuronal pyroptosis and neuroinflammation with excess microglial activation are widely involved in the early pathological process of ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive neuromodulatory technique, has recently been reported to be anti-inflammatory and regulate microglial function. However, few studies have elucidated the role and mechanism of rTMS underlying regulating neuronal pyroptosis and microglial polarization. METHODS: We evaluated the motor function in middle cerebral artery occlusion/reperfusion (MCAO/r) injury mice after 1-week intermittent theta-burst rTMS (iTBS) treatment in the early phase with or without depletion of microglia by colony-stimulating factor 1 receptor (CSF1R) inhibitor treatment, respectively. We further explored the morphological and molecular biological alterations associated with neuronal pyroptosis and microglial polarization via Nissl, EdU, TTC, TUNEL staining, electron microscopy, multiplex cytokine bioassays, western blot assays, immunofluorescence staining and RNA sequencing. RESULTS: ITBS significantly protected against cerebral ischemia/reperfusion (I/R) injury-induced locomotor deficits and neuronal damage, which probably relied on the regulation of innate immune and inflammatory responses, as evidenced by RNA sequencing analysis. The peak of pyroptosis was confirmed to be later than that of apoptosis during the early phase of stroke, and pyroptosis was mainly located and more severe in the peri-infarcted area compared with apoptosis. Multiplex cytokine bioassays showed that iTBS significantly ameliorated the high levels of IL-1ß, IL-17A, TNF-α, IFN-γ in MCAO/r group and elevated the level of IL-10. ITBS inhibited the expression of neuronal pyroptosis-associated proteins (i.e., Caspase1, IL-1ß, IL-18, ASC, GSDMD, NLRP1) in the peri-infarcted area rather than at the border of infarcted core. KEGG enrichment analysis and further studies demonstrated that iTBS significantly shifted the microglial M1/M2 phenotype balance by curbing proinflammatory M1 activation (Iba1+/CD86+) and enhancing the anti-inflammatory M2 activation (Iba1+/CD206+) in peri-infarcted area via inhibiting TLR4/NFκB/NLRP3 signaling pathway. Depletion of microglia using CSF1R inhibitor (PLX3397) eliminated the motor functional improvements after iTBS treatment. CONCLUSIONS: rTMS could alleviate cerebral I/R injury induced locomotor deficits and neuronal pyroptosis by modulating the microglial polarization. It is expected that these data will provide novel insights into the mechanisms of rTMS protecting against cerebral I/R injury and potential targets underlying neuronal pyroptosis in the early phase of stroke.

Focal Subcortical White Matter Lesions Disrupt Resting State Cortical Interhemispheric Functional Connectivity in Mice.

The corpus callosum is the largest white matter tract and critical for interhemispheric connectivity. Unfortunately, neurocognitive deficits after experimental white matter lesions are subtle and variable, limiting their translational utility. We examined resting state functional connectivity (RSFC) as a surrogate after a focal lesion in the lateral corpus callosum induced by stereotaxic injection of L-NIO in mice. RSFC was performed via optical intrinsic signal imaging through intact skull before and on days 1 and 14 after injection, using interhemispheric homotopic and seed-based temporal correlation maps. We measured the lesion volumes at 1 month in the same cohort. L-NIO induced focal lesions in the corpus callosum. Interhemispheric homotopic connectivity decreased by up to 50% 24 h after L-NIO, partially sparing the visual cortex. All seeds showed loss of connectivity to the contralateral hemisphere. Moreover, ipsilesional motor and visual cortices lost connectivity within the same hemisphere. Sham-operated mice did not show any lesion or connectivity changes. RSFC imaging reliably detects acute disruption of long interhemispheric and intrahemispheric connectivity after a corpus callosum lesion in mice. This noninvasive method can be a functional surrogate to complement neurocognitive testing in both therapeutic and recovery studies after white matter injury.

High-Intensity Interval Training Improves Physical Function, Prevents Muscle Loss, and Modulates Macrophage-Mediated Inflammation in Skeletal Muscle of Cerebral Ischemic Mice.

Although skeletal muscle is the main effector organ largely accounting for disability after stroke, considerably less attention is paid to the secondary abnormalities of stroke-related skeletal muscle loss. It is necessary to explore the mechanism of muscle atrophy after stroke and further develop effective rehabilitation strategy. Here, we evaluated the effects of high-intensity interval (HIIT) versus moderate-intensity aerobic training (MOD) on physical function, muscle mass, and stroke-related gene expression profile of skeletal muscle. After the model of middle cerebral artery occlusion (MCAO) was successfully made, the blood lactate threshold corresponding speed (S LT) and maximum speed (S max) were measured. Different intensity training protocols (MOD < S LT; S LT < HIIT < S max) were carried out for 3 weeks beginning at 7 days after MCAO in the MOD and HIIT groups, respectively. We found that both HIIT and MOD prevented stroke-related gastrocnemius muscle mass loss in MCAO mice. HIIT was more beneficial than MOD for improvements in muscle strength, motor coordination, walking competency, and cardiorespiratory fitness. Furthermore, HIIT was superior to MOD in terms of reducing lipid accumulation, levels of IL-1ß and IL-6 in paretic gastrocnemius, and improving peripheral blood CD4+/CD8+ T cell ratio, level of IL-10. Additionally, RNA-seq analysis revealed that the differentially expressed genes among HIIT, MOD, and MCAO groups were highly associated with signaling pathways involved in inflammatory response, more specifically the I-kappaB kinase/NF-kappaB signaling. Following the outcome, we further investigated the infiltrating immune cells abundant in paretic muscles. The results showed that HIIT modulated macrophage activation by downregulating CD86+ (M1 type) macrophages and upregulating CD163+ (M2 type) macrophages via inhibiting the TLR4/MyD88/NFκB signaling pathway and exerting an anti-inflammatory effect in paretic skeletal muscle. It is expected that these data will provide novel insights into the mechanisms and potential targets underlying muscle wasting in stroke.

An Enriched Environment Enhances Angiogenesis Surrounding the Cingulum in Ischaemic Stroke Rats.

An enriched environment (EE) has been demonstrated to improve functional recovery in animal models of ischaemic stroke through enhancing vascular endothelial growth factor- (VEGF-) mediated neuroprotection accompanied by angiogenesis in the ischaemic hemisphere. Whether EEs also promote VEGF-mediated neuroprotection and angiogenesis in the contralateral hemisphere remains unclear. Here, we explored the effect of EEs on VEGF expression and angiogenesis within the contralateral cerebral cortex in a rat middle cerebral artery occlusion/reperfusion (MCAO/r) model. We assessed the expression levels of platelet endothelial cell adhesion molecule-1 (CD31), VEGF, and endothelial nitric oxide synthase (eNOS) in the whole contralateral cerebral cortex using Western blotting assay but did not find an increase in the expression of CD31, VEGF, or eNOS in MCAO/r rats housed in EEs, which suggested that EEs did not enhance the overall expression of VEGF and eNOS or angiogenesis in the entire contralateral cortex. We further analysed the local effect of EEs by immunohistochemistry and found that in and around the bilateral cingulum in MCAO/r rats housed in EEs, haematopoietic progenitor cell antigen- (CD34-) positive endothelial progenitor cells were significantly increased compared with those of rats housed in standard cages (SCs). Further experiments showed that EEs increased neuronal VEGF expression surrounding the cingulum in MCAO/r rats and robustly upregulated eNOS expression. These results revealed that EEs enhanced angiogenesis, VEGF expression, and activation of the VEGF-eNOS pathway in and/or around the cingulum in MCAO/r rats, which were involved in the functional recovery of MCAO/r rats.

The malignant role of exosomes in the communication among colorectal cancer cell, macrophage and microbiome.

Colorectal cancer (CRC) is a complex and heterogeneous malignant cancer characterized by its high prevalence and poor prognosis. Among different etiologies, impairment of immune surveillance and dysbiosis are important events to mediate the invasion and metastasis of CRC. Although aberrant distribution of macrophages and microbiota exhibits distinct properties to modulate the malignant behaviors of CRC, the crosstalk among macrophages, microbiomes and tumor cells remains unclear. Exosomes are intercellular messengers carrying different cargo to regulate the biological and pathologic changes of recipient cells. CRC-derived exosomes can educate macrophages and facilitate the angiogenesis and establishment of premetastatic niche. Meanwhile, exosomes from macrophages and microbiome can regulate the tumor microenvironment for tumor progression and dissemination. The aim of this review is to highlight the innovative role of exosomes in the pathogenesis of CRC. Theoretical elaboration of the underlying mechanism provides valuable treating targets of CRC.

Integrative prognostic subtype discovery in high-grade serous ovarian cancer.

OBJECTIVE: We sought to identify novel molecular subtypes of high-grade serous ovarian cancer (HGSC) by the integration of gene expression and proteomics data and to find the underlying biological characteristics of ovarian cancer to improve the clinical outcome. METHODS: The iCluster method was utilized to analysis 131 common HGSC samples between TCGA and Clinical Proteomic Tumor Analysis Consortium databases. Kaplan-Meier survival curves were used to estimate the overall survival of patients, and the differences in survival curves were assessed using the log-rank test. RESULTS: Two novel ovarian cancer subtypes with different overall survival (P = .00114) and different platinum status (P = .0061) were identified. Eighteen messenger RNAs and 38 proteins were selected as differential molecules between subtypes. Pathway analysis demonstrated arrhythmogenic right ventricular cardiomyopathy pathway played a critical role in the discrimination of these two subtypes and desmosomal cadherin DSG2, DSP, JUP, and PKP2 in this pathway were overexpression in subtype I compared with subtype II. CONCLUSION: Our study extended the underlying prognosis-related biological characteristics of high-grade serous ovarian cancer. Enrichment of desmosomal cadherin increased the risk for HGSC prognosis among platinum-sensitive patients, the results guided the revision of the treatment options for platinum-sensitive ovarian cancer patients to improve outcomes.

An immunophenotyping of renal clear cell carcinoma with characteristics and a potential therapeutic target for patients insensitive to immune checkpoint blockade.

Renal clear cell carcinoma (RCC) patients who do not achieve optimal control of progression with immune checkpoint blockade (ICB) should be further studied. Unsupervised consensus clustering was used to group 525 RCC patients based on two typical ICB pathways, CTLA-4 and pogrammed death 1 (PD-1)/programmed death-ligand 1 (PD-L1), as well as two new discovered regulators, CMTM6 and CMTM4. Three immune molecular subtypes (IMMSs) with different clinical and immunological characteristics were identified (type I, II, and III), among which there were more stage I and low-grade tumors in type I RCC than in type II and III. The proportion of males was highest in type II RCC. Overall survival of type II and III was similar (5.2 and 6 years) and statistically shorter than that of type I (7.6 years) before and after adjusting for age and gender. When conducting stratified analysis, our IMMSs were able to identify high-risk patients among middle-aged patients, males, and stage IV patients. Among the differentially expressed genes, approximately 84% were highly expressed in type II and III RCC. Genes related to ICB (CTLA-4, CD274, and PDCD1LG2) and cytotoxic lymphocytes (CD8A, GZMA, and PRF1) were all highly expressed in type II and III RCC. These results documented that patients with type II and III cancer may be more sensitive to anti-CTLA-4 therapy, anti-PD-1/PD-L1 therapy, and a combination of immunotherapies. High expression of CMTM4 in type I RCC (69%) and a statistically significant interaction of CD274 and CMTM6 indicated that CMTM4/6 might be new therapy targets for type I, who are resistant to ICB.

Selection of small plasma peptides for the auxiliary diagnosis and prognosis of epithelial ovarian cancer by using UPLC/MS-based nontargeted and targeted analyses.

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer-related death due to its nonspecific characteristics compared to benign cases and poor prognosis after conventional therapies. Small peptides (SPs) demonstrated to have potential for diagnosis and prognosis were focused on in our study for the discovery of biomarkers that address these issues. Metabolic profiles of 15 SPs, including nine dipeptides and six tripeptides were acquired from plasma samples of 140 EOC and 158 benign ovarian tumor (BOT) patients. Partial least square discriminant analysis showed separations between EOC and BOT subjects of different age brackets. Hyp-Leu, Glu-Trp and Phe-Phe were selected as promising predictive SP-biomarkers for better EOC diagnosis compared to conventional biomarkers. Combined Hyp-Leu, Glu-Trp and CA125 presented an area under the curve (AUC) of 0.904, with a sensitivity and specificity of 0.804 and 0.944, respectively. This finding suggested that the combination of these biomarkers performed much better than CA125 alone. Hyp-Leu and Gly-Phe-Trp showed significantly improved performances in the log-rank tests and Kaplan-Meier curves demonstrating their prognostic potential. All SP-biomarkers proved to have excellent stabilities at room temperature. Correlation network analysis implied latent conversions among amino acids, dipeptides and tripeptides during EOC. In conclusion, the selected SPs in combination with CA125 show profound promise for discriminating EOCs from BOTs and for predicting the progression after surgery, which provides invaluable information for clinicians in the precision diagnosis and treatment of EOC.

Pro-endometriotic niche in endometriosis.

Endometriosis is a complex and heterogeneous disorder of unknown aetiology. This benign disease possesses special biological behaviours that mimic those of malignant tumours. A pro-endometriotic niche established by an existing lesion is a supportive micro-environment for the progression of endometriosis. After the accumulation of cells by an existing lesion, these components display distinct characteristics that impair immune surveillance. Subsequent retrograde menstruation of endometrial stromal cells into the pro-endometriotic niche facilitates endometriotic progression from early initiation to an advanced lesion. This study aimed to highlight the innovative role of the pro-endometriotic niche in endometriosis, and to provide valuable treatment targets for endometriosis.

Predicting ovarian cancer recurrence by plasma metabolic profiles before and after surgery.

BACKGROUND: Previous metabolomic studies have revealed that plasma metabolic signatures may predict epithelial ovarian cancer (EOC) recurrence. However, few studies have performed metabolic profiling of pre- and post-operative specimens to investigate EOC prognostic biomarkers. OBJECTIVE: The aims of our study were to compare the predictive performance of pre- and post-operative specimens and to create a better model for recurrence by combining biomarkers from both metabolic signatures. METHODS: Thirty-five paired plasma samples were collected from 35 EOC patients before and after surgery. The patients were followed-up until December, 2016 to obtain recurrence information. Metabolomics using rapid resolution liquid chromatography-mass spectrometry was performed to identify metabolic signatures related to EOC recurrence. The support vector machine model was employed to predict EOC recurrence using identified biomarkers. RESULTS: Global metabolomic profiles distinguished recurrent from non-recurrent EOC using both pre- and post-operative plasma. Ten common significant biomarkers, hydroxyphenyllactic acid, uric acid, creatinine, lysine, 3-(3,5-diiodo-4-hydroxyphenyl) lactate, phosphohydroxypyruvic acid, carnitine, coproporphyrinogen, L-beta-aspartyl-L-glutamic acid and 24,25-hydroxyvitamin D3, were identified as predictive biomarkers for EOC recurrence. The area under the receiver operating characteristic (AUC) values in pre- and post-operative plasma were 0.815 and 0.909, respectively; the AUC value after combining the two sets reached 0.964. CONCLUSION: Plasma metabolomic analysis could be used to predict EOC recurrence. While post-operative biomarkers have a predictive advantage over pre-operative biomarkers, combining pre- and post-operative biomarkers showed the best predictive performance and has great potential for predicting recurrent EOC.

Villainous role of estrogen in macrophage-nerve interaction in endometriosis.

Endometriosis is a complex and heterogeneous disorder with unknown etiology. Dysregulation of macrophages and innervation are important factors influencing the pathogenesis of endometriosis-associated pain. It is known to be an estrogen-dependent disease, estrogen can promote secretion of chemokines from peripheral nerves, enhancing the recruitment and polarization of macrophages in endometriotic tissue. Macrophages have a role in the expression of multiple nerve growth factors (NGF), which mediates the imbalance of neurogenesis in an estrogen-dependent manner. Under the influence of estrogen, co-existence of macrophages and nerves induces an innovative neuro-immune communication. Persistent stimulation by inflammatory cytokines from macrophages on nociceptors of peripheral nerves aggravates neuroinflammation through the release of inflammatory neurotransmitters. This neuro-immune interaction regulated by estrogen sensitizes peripheral nerves, leading to neuropathic pain in endometriosis. The aim of this review is to highlight the significance of estrogen in the interaction between macrophages and nerve fibers, and to suggest a potentially valuable therapeutic target for endometriosis-associated pain.

Effects of constraint-induced movement therapy on brain glucose metabolism in a rat model of cerebral ischemia: a micro PET/CT study.

PURPOSE: Constraint-induced movement therapy (CIMT) can improve motor functions in stroke patients and ischemic rats. This study examined the effect of CIMT in ischemic rats using positron emission tomography (PET). METHODS: We used middle cerebral artery occlusion (MCAO) procedure to induce cerebral ischemia in rats. Male rats were divided into a negative control group (Normal, n = 4), a sham-operated group (Sham, n = 6), an ischemic group (Control, n = 6) and an ischemic CIMT-treated group (CIMT, n = 6). CIMT started at postoperative day 8 (d8) and lasted for 2 weeks. We utilized 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) micro PET/CT imaging to evaluate glucose metabolism in different brain regions at baseline, before, and after treatment, respectively. RESULTS: CIMT improved behavioral performance in the ischemic CIMT group. At the end of treatment, the CIMT group showed lower standardized uptake values (SUVs) in the ipsilateral cingulate, motor and somatosensory cortex, respectively; as well as the anterodorsal hippocampus compared to the Control group (1.80% ± 0.10% vs. 1.92% ± 0.08%, 1.32% ± 0.14% vs. 1.48% ± 0.09%, 1.18% ± 0.14% vs. 1.42% ± 0.15%, 1.68% ± 0.09% vs. 1.79% ± 0.06%, P < 0.05). We also observed higher SUVs in the acbcore shell and cortex insular of the contralateral hemisphere compared to the Control group (2.07% group in the acbcore shell and cortex insular of contralateral P < 0.05). CONCLUSION: CIMT improved behavioral outcomes in cerebral ischemic rats and this effect can be attributed to increased glucose utilization in the contralateral hemisphere.

Macrophage and nerve interaction in endometriosis.

Dysregulation of the immune system in endometriotic milieus has been considered to play a pivotal role in the pathogenesis of endometriosis. Macrophage recruitment and nerve fiber infiltration are the two major characteristics of this aberrant immune environment. First, the recruitment of macrophages and their polarization phenotype within the endometriotic lesion have been demonstrated to facilitate the development and maintenance of endometriosis. M1 phenotype of macrophages has the capacity to secrete multiple cytokines for inflammatory response, while M2 macrophage possesses an opposite property that can mediate the process of immunosuppression and neuroangiogenesis. Upon secretion of multiple abnormal signal molecules by the endometriotic lesion, macrophages could alter their location and phenotype. These changes facilitate the accommodation of the aberrant microenvironment and the exacerbation of disease progression. Second, the infiltration of nerve fibers and their abnormal distribution are proved to be involved in the generation of endometriosis-associated pain and inflammatory response. An imbalance in sensory and sympathetic innervation and the abnormal secretion of different cytokines could mediate neurogenesis and subsequent peripheral neuroinflammation in endometriosis. Although endometriosis creates an inflammatory milieu promoting macrophage infiltration and an imbalanced innervation, interaction between macrophages and nerve fibers in this process remains unknown. The aim of this review is to highlight the role of macrophage and nerve interaction in endometriosis, where macrophage recruitment and neurogenesis can be the underlying mechanism of neuroinflammation and pathogenesis of endometriosis.

Enriched Environment Enhances Poststroke Neurological Function Recovery on Rat: Involvement of p-ERK1/2.

BACKGROUND: Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia or reperfusion injury is neuroprotective in animal models, including that EE enhances functional recovery after ischemic stroke. However, the mechanism underlying this effect remains unclear. To clarify this critical issue, the current study investigated the effects of EE on the role of extracellular signal-regulated kinase (ERK) after cerebral ischemia or reperfusion injury of rat. METHODS: Adult rats were subjected to ischemia induced by middle cerebral artery occlusion (MCAO) followed by reperfusion. Ladder walking task and limb-use asymmetry task were used to test the recovery of rat behavior on postoperative days 1, 3, 5, 7, 14 and days 3, 7, 14, respectively. On the eighth day after MCAO, infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining. Expressions of phosphorylated ERK1/2 (p-ERK1/2) and total ERK1/2 were examined by western blot, and electron microscopy was used to evaluate the astrocytes morphology surround in the perivascular 14 days after MCAO. RESULTS: EE improves the recovery of coordination and integration of motor movements on rats after cerebral ischemia or reperfusion injury. EE downregulates the level of p-ERK1/2 in the rat cortex after cerebral ischemia or reperfusion injury. Furthermore, EE reduces astrocytic swelling and injury. CONCLUSIONS: These findings suggest that EE could promote rehabilitation after ischemia via regulation of p-ERK1/2 expression, which may provide a therapeutic approach for cerebral ischemia or reperfusion injury. The suppression of postischemic astrocytic swelling in the brain of the ischemic rats through the intervention of EE would be one of the underlying mechanisms in the protective effect of cerebral ischemia.

Prognostic significance of heart rate turbulence parameters in patients with chronic heart failure.

BACKGROUND: This study is aimed to evaluate the clinical significance of heart rate turbulence (HRT) parameters in predicting the prognosis in patients with chronic heart failure (CHF). METHODS: From June 2011 to December 2012, a total of 104 CHF patients and 30 healthy controls were enrolled in this study. We obtained a 24-hour Holter ECG recording to assess the HRT parameters, included turbulence onset (TO), turbulence slope (TS), standard deviation of N-N intervals (SDNN), and resting heart rate (RHR). The relationships between HRT parameters and the prognosis of CHF patients were determined. RESULTS: The assessment follow-up period lasted until January 31, 2013. The overall mortality of CHF patients was 9.6% (10/104). Our results revealed that CHF patients had higher levels of TO than those of healthy subjects, but the TS levels of CHF patients were lower than that of the control group. CHF patients with NYHA grade IV had higher HRT1/2 rate than those with NYHA grade II/III. There were statistical differences in TS, LVEF, SDNN and RHR between the non-deteriorating group and the non-survivor group. Significant differences in TS among the three groups were also found. Furthermore, CHF patients in the non-survivor group had lower levels of TS than those in the deteriorating group. Correlation analyses indicated that TO negatively correlate with SDNN, while TS positively correlated with SDNN and left ventricular ejection fraction (LVEF). We also observed negative correlations between TS and left ventricular end-diastolic cavity dimension (LVEDD), RHR, homocysteine (Hcy) and C-reactive protein (CRP). Multivariate Cox regression analysis further confirmed that LVEF (≤30%), HRT2, SDNN and RHR were independent risk factors which can indicate poor prognosis in CHF patients. CONCLUSIONS: Our findings indicate that HRT may have good clinical predictive value in patients with CHF. Thus, quantifying HRT parameters could be a useful tool for predicting mortality in CHF patients.

Rules of acupoint selection in treatment of cancer-related insomnia with acupuncture and moxibustion based on data mining technology. / åŸºäºŽæ•°æ®æŒ–æŽ˜æŠ€æœ¯æŽ¢æžé’ˆç¸æ²»ç–—è‚¿ç˜¤ç›¸å ³æ€§å¤±çœ çš„é€‰ç©´è§„å¾‹.

OBJECTIVES: To analyze the rules of acupoint selection in treatment of cancer-related insomnia with acupuncture and moxibustion by data mining technology. METHODS: The articles of cancer-related insomnia treated with acupuncture and moxibustion were searched from CNKI, Wanfang, VIP, SinoMed, PubMed, WOS, Cochrane, and Embase databases, from the inception of each database to January 5, 2024. The prescription database of acupuncture and moxibustion for cancer-related insomnia was established. The descriptive analysis was conducted on the use frequency, meridian tropism and distribution of acupoints. Using SPSS Modeler 18.0 Apriori algorithm, the association rules of acupoint prescriptions were analyzed. With Cytoscape3.9.1 software used, the complex network diagram was plotted, and the cluster analysis of high-frequency acupoints was performed by SPSS26.0 software. RESULTS: Forty-one articles were included, and 67 prescriptions were extracted with 89 acupoints involved, and the total use frequency was 447 times. The top 4 acupoints of the high use frequency were Baihui (GV20), Sanyinjiao (SP6), Shenmen (HT7) and Shenting (GV24). The included meridians were the governor vessel, the spleen meridian, the bladder meridian, the conception vessel, the heart meridian and the stomach meridian. The selected acupoints were mostly distributed on the head, the neck and and the upper and lower limbs. The special acupoints of the high use frequency included the five-Shu points, the crossing points and yuan-primordial points. Regarding acupoint combination, GV24, SP6, HT7, and GV20 were highly correlated. The three effective clusters were categorized among the top 12 acupoints of the high use frequency. CONCLUSIONS: In treatment of cancer-related insomnia with acupuncture and moxibustion, the principle focuses on supporting the healthy qi, eliminating pathogens, regulating yin and yang, promoting the circulation of the governor vessel for regulating the spirit, and tranquilizing the mind. The core acupoint prescription may includes GV24, SP6, HT7 and GV20；combined with Zusanli (ST36) and Yintang (GV4+) to enhance the therapeutic effect.