LC-MS/MS untargeted lipidomics uncovers placenta lipid signatures from intrahepatic cholestasis of pregnancy.

Aims: Intrahepatic cholestasis of pregnancy (ICP) stands as the predominant liver disorder affecting pregnant women, with a prevalence ranging from 0.2% to 15.6%. While ICP is known to heighten the chances of perinatal mortality and morbidity, its pathogenesis remains elusive, and therapeutic options are limited. The objective of this study was to explore the characteristic lipid signature in placentas collected from normal pregnancies and those with mild and severe intrahepatic cholestasis of pregnancy. This research aims to clarify the pathogenesis and identify lipid biomarker for ICP through LC-MS/MS based lipidomic analysis. Methods and materials: Placenta samples were collected from 30 normal pregnancy women and 30 mild and severe ICP women respectively. Women with normal pregnancy and ICP were recruit from April 2021 to July 2022 in Chengdu, China. And LC-MS/MS based lipidomic analysis was used to explore the characteristic placental lipids in mild and severe ICP. Results: Fourty-four lipids were differentially expressed both in mild and severe ICP placenta. The pathway analysis revealed these lipids are mainly enriched in glycerophospholipid metabolism and autophagy pathway. Weighted correlation network analysis (WGCNA) identified the correlation network module of lipids highly related to ICP. Using multiple logistic regression analysis, we identified three and four combined metabolites that had an area under receiver operating characteristic curves (AUC) ≥ 0.90. Conclusion: Our results systematically revealed the lipid signature in mild and severe ICP placenta. The results may provide new insight into the treatment and early prediction of ICP.

Intrahepatic cholestasis of pregnancy: insights into pathogenesis and advances in omics studies.

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease. It is characterized by pruritus, abnormal liver function and elevated total bile acid (TBA) levels, increasing the risk of maternal and fetal adverse outcomes. Its etiology remains poorly elucidated. Over the years, various omics techniques, including metabolomics, microbiome, genomics, etc., have emerged with the advancement of bioinformatics, providing a new direction for exploring the pathogenesis, diagnosis and treatment of ICP. In this review, we first summarize the role of bile acids and related components in the pathogenesis of ICP and then further illustrate the results of omics studies.

Are immune checkpoint inhibitors ineffective in treating patients with head and neck squamous cell carcinoma aged 75 years or Older? A Meta-Analysis.

OBJECTIVES: The efficacy of immune checkpoint inhibitors (ICIs) is unclear in patients aged ≥ 75 years with head and neck squamous cell carcinoma (HNSCC). We conducted a systematic review and meta-analysis of randomized trials that compared ICIs with standard-of-care (SOC) therapy for recurrent/metastatic HNSCC. MATERIALS AND METHODS: PubMed, EMBASE, Web of Science, and ClinicalTrials.gov were searched for eligible trials. We evaluated the overall survival (OS) benefit of ICIs versus SOC according to patient age (<75 versus ≥ 75 years). The OS benefit was evaluated and compared between the age subgroups using hazard ratios (HRs). Data were pooled using a random-effects model. RESULTS: Five phase 3 trials involving 3437 patients were included. In patients aged ≥ 75 years (n = 207), ICIs did not improve OS compared to SOC (HR = 1.30, 95 % confidence interval [CI]: 0.93-1.81, P = 0.127). However, an improvement in OS was observed in patients aged < 75 years (n = 3230, HR = 0.90, 95 % CI: 0.83-0.99, P = 0.025). There is a significant difference in OS benefit between patients aged < 75 and ≥ 75 years (ratio of HR = 0.69, 95 % CI: 0.49-0.98, P = 0.036). Subgroup, meta-regression, and sensitivity analyses supported the reliability of the results. CONCLUSIONS: Given the small sample size, our findings showing no improvement in OS suggest a lack of evidence to support the use of ICIs in patients with recurrent/metastatic HNSCC aged ≥ 75 years. Therefore, prospective studies are needed to clarify their efficacy among this age group.

The role of noncoding RNA and its diagnostic potential in intrahepatic cholestasis of pregnancy: a research update.

Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder that generally occurs during the second or third trimester of pregnancy. It rarely causes any harm to the mother; however, it can result in short- and long-term complications in the offspring. Therefore, it is crucial to diagnose and treat this condition to avoid poor pregnancy outcomes. The identification of novel markers with potential diagnostic, prognostic, and therapeutic utility in ICP has gained attention. Noncoding RNAs (ncRNAs), including microRNA, long noncoding RNA, and circular RNA, are a type of transcripts that are not translated into proteins. They possess vital biological functions, including transcriptional and translational regulation and DNA, RNA, and protein interactions. The pathogenesis of ICP is related to the aberrant expression of several circulating or placenta-related ncRNAs. In this review, we summarized all recent findings on ncRNAs and ICP and outlined the concepts that form the basis for the early diagnosis and targeted treatment of ICP.

LncRNA-encoded peptides: unveiling their significance in cardiovascular physiology and pathology-current research insights.

Long non-coding RNAs (lncRNAs), which are RNA transcripts exceeding 200 nucleotides were believed to lack any protein-coding capacity. But advancements in -omics technology have revealed that some lncRNAs have small open reading frames (sORFs) that can be translated by ribosomes to encode peptides, some of which have important biological functions. These encoded peptides subserve important biological functions by interacting with their targets to modulate transcriptional or signalling axes, thereby enhancing or suppressing cardiovascular disease (CVD) occurrence and progression. In this review, we summarize what is known about the research strategy of lncRNA-encoded peptides, mainly comprising predictive websites/tools and experimental methods that have been widely used for prediction, identification, and validation. More importantly, we have compiled a list of lncRNA- encoded peptides, with a focus on those that play significant roles in cardiovascular physiology and pathology, including ENSRNOT (RNO)-sORF6/RNO-sORF7/RNO-sORF8, dwarf open reading frame (DOWRF), myoregulin (NLN), etc. Additionally, we have outlined the functions and mechanisms of these peptides in cardiovascular physiology and pathology, such as cardiomyocyte hypertrophy, myocardial contraction, myocardial infarction, and vascular remodelling. Finally, an overview of the existing challenges and potential future developments in the realm of lncRNA-encoded peptides was provided, with consideration given to prospective avenues for further research. Given that many lncRNA-encoded peptides have not been functionally annotated yet, their application in CVD diagnosis and treatment still requires further research.

Predictive value of albumin for intravenous immunoglobulin resistance in a large cohort of Kawasaki disease patients.

BACKGROUND: Intravenous immunoglobulin (IVIG) has been the mainstay of treatment for Kawasaki disease (KD) over the past decades. However, 10-20% of KD patients are resistant to IVIG treatment which puts those patients at high risk of coronary artery lesions (CALs). Therefore, it is important to predict whether patients will be resistant to IVIG before the treatment. This study aimed to investigate the risk factors for IVIG non-responsive patients with KD. METHODS: This study enrolled patients diagnosed with KD and divided them into two groups, IVIG responders and IVIG non-responders. We compared the differences in demographics and clinical data between the two groups. Differences among the groups were analyzed by ANOVA and Chi-square analysis. Predictors of IVIG resistance were determined by multiple logistic regression analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: In total, 907 KD patients were reviewed, with 841 IVIG responders and 66 IVIG non-responders. Patients in IVIG responders were younger than IVIG non-responders. The length of hospitalization of the IVIG non-responders was significantly longer than IVIG responders. The neutrophils%, C-reaction protein (CRP), and CRP/albumin ratio in IVIG responders were significantly lower than in IVIG non-responders (P < 0.05). The lymphocyte% and Albumin in IVIG responders were significantly higher than in IVIG non-responders. Multivariable logistic regression analysis demonstrated that albumin (OR = 0.881, 95% CI, 0.781 to 0.994, p-value = 0.039) was an independent risk factor for predicting IVIG resistance. The area under the ROC curve was 0.644, with a cut-off of ≤ 33.4 g/L determined by Youden's index. The sensitivity and specificity in predicting IVIG resistance were 40.91% and 83.47%, respectively. CONCLUSION: Albumin can serve as a potential predicting marker for IVIG resistance in KD. A lower albumin level may be useful for identifying KD patients with a high risk of IVIG resistance to guide further therapy strategies.

Excessive salt intake accelerates the progression of cerebral small vessel disease in older adults.

BACKGROUND: It is unclear whether excessive salt intake accelerates the progression of cerebral small vessel disease (CSVD). The major objective of this study was to investigate the harmful effect of excessive salt intake on the progression of CSVD in older individuals. METHODS: Between May 2007 and November 2010, 423 community-dwelling individuals aged 60 years and older were recruited from the Shandong area, China. Salt intake was estimated using 24-hour urine collection for 7 consecutive days at baseline. Participants were classified into low, mild, moderate and high groups according to the salt intake estimation. CSVD including white matter hyperintensities (WMHs), lacunes, microbleeds and an enlarged perivascular space (EPVS) were determined using brain magnetic resonance imaging. RESULTS: During an average of five years of follow-up, the WMH volume and WMH-to-intracranial ratio were increased in the four groups. However, the increasing trends in the WMH volume and WMH-to-intracranial ratio were significantly faster in the higher salt intake groups compared with the lower salt intake groups (Padjusted < 0.001). The cumulative hazard ratios of new-incident WMHs (defined as those with Fazekas scale scores ≥ 2), new-incident lacunes, microbleeds or an EPVS, as well as composites of CSVD, were respectively 2.47, 2.50, 3.33, 2.70 and 2.89 for the mild group; 3.72, 3.74, 4.66, 4.01 and 4.49 for the moderate group; and 7.39, 5.82, 7.00, 6.40 and 6.61 for the high group, compared with the low group after adjustment for confounders (Padjusted < 0.001). The risk of new-incident WMHs, lacunes, microbleeds or an EPVS, and composites of CSVD was significantly increased with each 1-standard-deviation increment in salt intake (Padjusted < 0.001). CONCLUSION: Our data indicates that excessive salt intake is an important and independent contributor to the progression of CVSD in older adults.

Association of intraoperative hypotension and severe postoperative complications during non-cardiac surgery in adult patients: A systematic review and meta-analysis.

Background: Intraoperative hypotension (IOH) is a common side effect of non-cardiac surgery that might induce poor postoperative outcomes. The relationship between the IOH and severe postoperative complications is still unclear. Thus, we summarized the existing literature to evaluate whether IOH contributes to developing severe postoperative complications during non-cardiac surgery. Methods: We conducted a comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, and the CBM from inception to 15 September 2022. The primary outcomes were 30-day mortality, acute kidney injury (AKI), major adverse cardiac events (myocardial injury or myocardial infarction), postoperative cognitive dysfunction (POCD), and postoperative delirium (POD). Secondary outcomes included surgical-site infection (SSI), stroke, and 1-year mortality. Results: 72 studies (3 randomized; 69 non-randomized) were included in this study. Low-quality evidence showed IOH resulted in an increased risk of 30-day mortality (OR, 1.85; 95% CI, 1.30-2.64; P < .001), AKI (OR, 2.69; 95% CI, 2.15-3.37; P < .001), and stroke (OR, 1.33; 95% CI, 1.21-1.46; P < .001) after non-cardiac surgery than non-IOH. Very low-quality evidence showed IOH was associated with a higher risk of myocardial injury (OR, 2.00; 95% CI, 1.17-3.43; P = .01), myocardial infarction (OR, 2.11; 95% CI, 1.41-3.16; P < .001), and POD (OR, 2.27; 95% CI, 1.53-3.38; P < .001). Very low-quality evidence showed IOH have a similar incidence of POCD (OR, 2.82; 95% CI, 0.83-9.50; P = .10) and 1-year-mortality (OR, 1.66; 95% CI, 0.65-4.20; P = .29) compared with non-IOH in non-cardiac surgery. Conclusion: Our results suggest IOH was associated with an increased risk of severe postoperative complications after non-cardiac surgery than non-IOH. IOH is a potentially avoidable hazard that should be closely monitored during non-cardiac surgery.

Placental mesenchymal stem cells ameliorate NLRP3 inflammasome-induced ovarian insufficiency by modulating macrophage M2 polarization.

BACKGROUND: Premature ovarian insufficiency (POI) is a common clinical problem, however, there are currently no effective therapies. Pyroptosis induced by the NLRP3 inflammasome is considered a possible mechanism of POI. Placental mesenchymal stem cells (PMSCs) have excellent immunomodulatory potential and offer a promising method for treating POI. METHODS: Female Sprague-Dawley rats were randomly divided into four treatment groups: control (no POI), POI with no PMSCs, POI with PMSCs transplant, and POI with hormones (estrogen + progesterone) as positive control. POI was induced by exposure to 4-vinylcyclohexene diepoxide (VCD) for 15 days. After four weeks, all animals were euthanized and examined for pathology. Hormone levels were measured and ovarian function was evaluated in relation to the estrous cycle. Levels of NLRP3 inflammasome pathway proteins were determined by immunohistochemistry and western blot. RESULTS: VCD significantly damaged rat follicles at different estrous stages. Injection of human PMSCs improved ovarian function and reproductive ability of POI rats compared to the sham and hormone groups. Our data also showed that PMSCs markedly suppress cell pyroptosis via downregulation of the NLRP3 inflammasome, caspase-1, IL-1ß and IL-18 compared to the other two groups. The human PMSCs increased the expression of IL-4 and IL-10 and decreased pro-inflammatory factors by phenotypic changes in macrophages. CONCLUSIONS: Our findings revealed a novel mechanism of follicular dysfunction and ovarian fibrosis via activation of the NLRP3 inflammasome followed by secretion of pro-inflammatory factors. Transplantation of PMSCs into POI rats suppressed pro-inflammatory factor production, NLRP3 inflammasome formation and pyroptosis, and improved ovarian function.

The role of red blood cell distribution width in predicting coronary artery lesions in pediatric patients with kawasaki disease.

Background: Recent studies have shown that red blood cell distribution width (RDW) has emerged as a novel predictor of cardiovascular diseases. We aim to investigate the association between RDW and the risk of coronary artery lesions (CALs) in pediatric patients with Kawasaki disease (KD). Methods: KD patients were classified as the CALs group (patients with CALs) and non-CALs group (patients without CALs). Differences among the groups were analyzed by Mann-Whitney U-test and Chi-square analysis. The independent risk factors of CALs were identified by multivariate logistic regression analysis, followed by receiver operating characteristic (ROC) curve analysis to calculate the optimal cut-off value. Results: The red blood cell distribution width (RDW) and C-reactive protein were significantly higher in the CALs group than those in the non-CALs group (p < 0.01). Multivariate logistic regression analysis revealed that RDW (OR = 5.2, 95% CI, 4.064 to 6.654) was independent risk factors of CALs in KD patients (p < 0.01). The subgroup analysis also confirmed that the high level of RDW was an independent risk factor for the development of CALs in patients with complete and incomplete KD. The ROC analysis showed the optimal cut-off value of RDW for predicting CALs was >13.86%, with a sensitivity of 75.79% and specificity of 92.81% (AUC = 0.869, 95% CI = 0.844-0.892; p < 0.0001). Conclusions: RDW is an independent predictor with high sensitivity and specificity to predict CALs in KD patients. The elevation in RDW level (>13.86%) may be used as novel biomarkers for early predicting CALs in KD patients during the acute phase.

Vascular lipidomics analysis reveales increased levels of phosphocholine and lysophosphocholine in atherosclerotic mice.

OBJECTIVE: Atherosclerosis (AS) is the major cause of cardiovascular disease, and dyslipidemia is a principal determinant of the initiation and progression of AS. Numerous works have analyzed the lipid signature of blood, but scarce information on the lipidome of vascular tissue is available. This study investigated the lipid profile in the aorta of ApoE-/- mice. METHOD: ApoE-/- mice were randomly divided into two groups: (1) the normal diet (ND) group and (2) the high-fat diet (HFD) group. After feeding for 8 weeks, the plasma low-density lipoprotein (LDL), total cholesterol (TC), and triglyceride (TGs) levels were measured. UHPLC-Q Exactive plus MS was used to assess the lipid profile using both positive and negative ionization modes. RESULTS: LDL and TC levels were significantly increased in HFD mice, and lipid deposition, plaque area and collagen fiber levels were increased in HFD group. In addition, a total of 131 differential lipids were characterized, including 57 lipids with levels that were increased in the HFD group and 74 with levels that were decreased. Further analysis revealed that the levels of several differentially expressed phosphocholines (PCs) and lysophosphocholines (LPCs) were significantly increased. These PCs included PC (38:3), PC (36:4), PC (36:3), PC (36:2), PC (36:1), PC (34:1e), PC (34:1), PC (32:1), PC (18:0/18:1), and PC (38:5), and the LPCs included LPC (18:1), LPC (18:0) and LPC (16:0). CONCLUSION: Our findings indicate the presence of a comprehensive lipid profile in the vascular tissue of atherosclerotic mice, particularly involving PC and LPC, which exhibited significantly increased levels in AS.

Excessive Dietary Salt Intake Exacerbates Cognitive Impairment Progression and Increases Dementia Risk in Older Adults.

OBJECTIVES: To investigate excessive dietary salt intake as an independent risk factor of cognitive impairment and dementia in older adults. DESIGN: Prospective, population-based cohort study. SETTINGS AND PARTICIPANTS: Two thousand forty-one community residents aged ≥60 years were recruited between April 2007 and August 2009 from the Shandong area of China. MEASUREMENTS: Participants were classified into low, mild, moderate, and high salt intake groups according to urinary sodium measurements for 7 consecutive days. Global cognitive function was assessed at baseline and biennially thereafter using the Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Dementia Rating Scale (DRS), and Informant Questionnaire on Cognitive Decline in the Elderly. Demographics and apolipoprotein E (APOE) genotype were also obtained for each participant. Participants were monitored for 11.4 ± 2.0 years. RESULTS: During follow-up, MMSE, MoCA, and DRS scores decreased progressively faster with increasing salt intake (Padjustment < 0.05 among all intake groups). In total, 319 participants (13.74 per 1000 person-years) developed cognitive impairment. Compared with the low salt intake group, cognitive impairment risk was increased by 75% in the mild group (Padjustment = 0.027), 180% in the moderate group (Padjustment < 0.001), and 330% in the high group (Padjustment < 0.001) after adjustment for age, education, mean, and variability in visit-to-visit systolic and diastolic blood pressure, and APOE genotype. The hazard ratio for cognitive impairment increased by 1.59 (95% CI 1.40-1.79) with each 1-SD increment in salt intake after confounder adjustment (Padjustment < 0.001). CONCLUSIONS AND IMPLICATIONS: Excessive dietary salt impairs cognitive function and increases cognitive impairment risk in older adults independently of known risk factors, including hypertension and APOE genotype.

Clinical research on RSV prevention in children and pregnant women: progress and perspectives.

Respiratory syncytial virus (RSV) is a significant causative agent of bronchitis and pneumonia in infants and children. The identification and structural analysis of the surface fusion glycoprotein of RSV represents a pivotal advancement in the development of RSV prevention. This review provides a comprehensive summary of RSV monoclonal antibody (mAb) and vaccine clinical trials registered on ClinicalTrials.gov, emphasizing on the classification, name, target, phase, clinical outcomes, and safety data of RSV vaccination in newborns, infants and children. We also discuss the characteristics of the types of RSV vaccines for maternal immunity and summarize the current clinical research progress of RSV vaccination in pregnant women and their protective efficacy in infants. This review will provide new ideas for the development of RSV prevention for children in the future.

The progress of peptide vaccine clinical trials in gynecologic oncology.

Peptide vaccine are a type of immunotherapy that are synthesized according to the amino acid sequence of known or predicted tumor antigen epitopes. They are safe and well tolerated and have shown exciting results in gynecologic oncology. However, no peptide vaccine has yet been licensed in this field. This review examines peptide vaccine clinical trials in gynecology registered on ClinicalTrials.gov through January 1, 2022, analyzes the global progress and current achievements of peptide vaccines in gynecology, and explores the efforts focused on devising new methods to boost immunotherapeutic outcomes, including the use of adjuvants, multi-epitope vaccines, combinations of helper T cell epitopes, personalized peptide vaccines, synthetic long peptides, new peptide delivery, and combination therapy.

Advancements in lead therapeutic phytochemicals polycystic ovary syndrome: A review.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women of reproductive age and features complex pathological symptoms and mechanisms. Existing medical treatments have, to some extent, alleviated the deterioration of PCOS. However, these strategies only temporarily control symptoms, with a few side effects and no preventive effect. Phytochemicals extracted from medicinal herbs and plants are vital for discovering novel drugs. In recent years, many kinds of research have proven that phytochemicals isolated from traditional Chinese medicine (TCM) and medicinal plants show significant potential in preventing, alleviating, and treating PCOS. Nevertheless, compared to the abundance of experimental literature and minimal specific-topic reviews related to PCOS, there is a lack of systematic reviews to summarize these advancements in this promising field. Under this background, we systematically document the progress of bioactive phytochemicals from TCM and medicinal plants in treating PCOS, including flavonoids, polyphenols, and alkaloids. According to the literature, these valuable phytochemicals demonstrated therapeutic effects on PCOS supported by in vivo and in vitro experiments, mainly depending on anti-inflammatory, antioxidation, improvement of hormone disorder and insulin resistance (IR), and alleviation of hyperinsulinemia. Based on the current progress, future research directions should emphasize 1) exploring bioactive phytochemicals that potentially mediate bone metabolism for the treatment of PCOS; 2) improving unsatisfactory bioavailability by using advanced drug delivery systems such as nanoparticles and antibody-conjugated drugs, as well as a chemical modification; 3) conducting in-depth research on the pathogenesis of PCOS to potentially impact the gut microbiota and its metabolites in the evolution of PCOS; 4) revealing the pharmacological effects of these bioactive phytochemicals on PCOS at the genetic level; and 5) exploring the hypothetical and unprecedented functions in regulating PCOS by serving as proteolysis-targeting chimeras and molecular glues compared with traditional small molecule drugs. In brief, this review aims to provide detailed mechanisms of these bioactive phytochemicals and hopefully practical and reliable insight into clinical applications concerning PCOS.

Efficacy and safety of acupoint injection therapy for allergic rhinitis: A protocol for systematic review and meta-analysis.

BACKGROUND: Allergic rhinitis (AR), characterized by nasal itching, sneezing, and congestion, is a common disorder of nose. In the United States, AR affects 10% to 20% of adults. The negative impact of the high prevalence of AR has caused a great economic burdens worldwide. Modern Western Medicine mainly treats AR with antihistamine drugs, glucocorticoids, allergic immunotherapy (AIT), but it seriously affects patients compliance because of its long course of treatment, high medical costs and side effect. And now, as an important mean of treating AR, acupoint injection has been widely used in clinics, and has achieved significant efficacy. METHODS AND ANALYSIS: The following databases will be searched for relevant information before July 2020: PubMed, Embase, Cochrane Library, Web of Science, and CNKI. MAJOR RESULTS: scores of Rhinitis Quality of Life (RQLQ), Rhinitis Total Symptom Scores (RTSS). Secondary results: levels of antigen-specific serum immunoglobulin E (IgE), total effective rate, adverse event. Data will be collected independently by 2 researchers, and the risk of bias in meta-analysis will be evaluated according to "Cochrane Handbook for Systematic Reviews of Interventions". All data analysis will be conducted using Review Manager V.5.3. and Stata V.12.0. RESULTS: The curative effect and safety of acupoint injection treatment for AR patients will be evaluated systematically. CONCLUSION: The systematic review of this study will summarize the currently published evidence of acupoint injection treatment for AR to further guide its promotion and application. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.Open Science Framework (OSF) registration number: https://osf.io/fa9dq.

Salidroside Decreases Atherosclerosis Plaque Formation via Inhibiting Endothelial Cell Pyroptosis.

Pyroptosis, a new pro-inflammatory programmed cell death, is linked to atherosclerosis (AS). Our previous studies suggested that salidroside (SAL) can alleviate AS and exert anti-oxidative and anti-inflammatory properties. However, the effect of SAL on atherosclerosis-related pyroptosis has not been studied. Here, we investigated the effect of SAL on pyroptosis to explain the underlying mechanisms of SAL on atherosclerosis-related inflammation. We established an atherosclerosis mouse model via western diet (HFD) to explore the protective effect of SAL. According to our results, administration of SAL for 12 weeks markedly reduced the atherosclerotic plaque in aorta. Meanwhile, SAL also alleviated the pyroptosis, as evidenced by inhibiting caspase-1 activation, interleukin-1ß (IL-1ß) release, and TUNEL-positive staining, and decreasing the expression of Gasdermin D (GSDMD). Furthermore, SAL also decreased the activation of caspase-1 and inhibited the release of IL-1ß induced by lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in human umbilical vein endothelial cell (HUVECs). Our data indicate that SAL inhibit NLRP3-related pyroptosis, which might be the underlying mechanism of SAL anti-inflammatory in atherosclerosis.

NLRP3/IL1ß inflammasome associated with the aging bladder triggers bladder dysfunction in female rats.

Bladder dysfunction is associated with fibrosis­-mediated aging, but the corresponding mechanism remains to be elucidated. Activation of the NACHT, LRR and PYD domains­containing protein 3 (NLRP3) inflammasome is related to chronic diseases associated with aging, including organ fibrosis. The present study aimed to explore the role of NLRP3/interleukin 1ß in aging­associated bladder dysfunction. Female Sprague­Dawley rats were divided into the following two groups (n=10 rats/group): 2­month­old group (young group) and 24­month­old group (old group). Urodynamics were performed to assess the bladder function of the rats. The histological alterations were identified using Masson's trichrome staining. The protein expression of the NLRP3 inflammasome and NAD­dependent protein deacetylase sirtuin­3, mitochondrial (SIRT3) were detected by western blot analysis, and immunohistochemistry was used to examine a senescence marker (p21) and the NLRP3 inflammasome in the bladder. The localization of the key molecule Caspase1 was determined using immunofluorescence. The voiding time was longer in the old group compared with the young group. The expression levels of SIRT3 were reduced in the bladders of the old group, while those of the NLRP3 inflammasome and the senescence marker were significantly higher in the bladders of the old group compared with the young group. Increased collagen deposition leads to chronic bladder fibrosis with increased NLRP3. In the histological examination, the bladders of the old group displayed increased collagen deposition, urothelial thinning and detrusor shrinkage compared with the young group. Tissue fibrosis and urothelial alterations are the principal causes of bladder dysfunction during aging. Downregulated SIRT3 and upregulated expression of the NLRP3 inflammasome are involved in the degradation of aging bladders. Inflamm­aging is a novel mechanism underlying bladder dysfunction.

Metabonomic study of the protective effect of Fukeqianjin formula on multi-pathogen induced pelvic inflammatory disease in rats.

BACKGROUND: Fukeqianjin formula has been effectively used in the treatment of pelvic inflammatory disease (PID) and the related complications in clinic. Although there have been some studies about the underlying mechanism that focus on its anti-inflammatory and immunoregulatory activities. But the mechanism is still not fully understood. The aim of this study was to investigate the alteration of plasma metabolic profiles in PID rats and the regulatory effect of Fukeqianjin formula on potential biomarkers. METHODS: Pelvic inflammatory model was established by intrauterine inoculation of multiple pathogens combined with mechanical injury of endometrium. Rats were randomly divided into normal group, model group, azithromycin group, high-and low-dose of Fukeqianjin formula treatment group (FF-H, and FF-L, respectively). After 14 days of intragastric administration, the plasm levels of interleukin-1ß (IL-1ß) and nitric oxide (NO) were measured. To further recognize and identify potential biomarkers and metabolic pathways, an ultra-performance liquid chromatography-quadrupole-Exactive Orbitrap-mass spectrometry (UPLC-Q-Exactive Orbitrap-MS) metabonomic method combined with multivariate analyses including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA), was employed to analyze the metabolic profiling. RESULTS: Compared with normal group, the plasma levels of IL-1ß and NO were significantly increased in the PID model group (P < 0. 05), and obviously decreased after high-dose intervention of Fukeqianjin formula (P < 0. 01). The PCA, PLS-DA and OPLS-DA analysis showed that PID rats were clearly separated from normal rats. Compared with the PID model group, the metabolite profiles of Fukeqianjin formula treatment group was gradually restored to normal. Meanwhile, 14 potential metabolite biomarkers, which were mainly related to the metabolic pathways of intervening glycerophospholipid metabolism, linoleic acid metabolism/alpha-linolenic acid metabolism, amino acid metabolism, arachidonic acid metabolism, and unsaturated fatty acids biosynthesis, have been identified. Fukeqianjin formula exerts good regulatory effect on the abnormal metabolism of PID rats. CONCLUSIONS: Intrauterine inoculation of multiple pathogens combined with mechanical injury of endometrium could significantly disturb the plasma metabolic profiles of rats. Fukeqianjin formula has potential therapeutic effect on multi-pathogen-induced PID by ameliorating metabolism disorders and alleviating the inflammatory response.

Salidroside Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease via AMPK-Dependent TXNIP/NLRP3 Pathway.

Our previous studies suggested that salidroside could alleviate hepatic steatosis in type 2 diabetic C57BLKS/Leprdb (db/db) mice. The aim of the present study was to evaluate the therapeutic effect of salidroside on high-fat diet- (HFD-) induced nonalcoholic fatty liver disease (NAFLD) by investigating underlying mechanisms. Mice were fed with HFD or regular diet, randomly divided into two groups, and treated with salidroside or vehicle for 8 weeks. Then, biochemical analyses and histopathological examinations were conducted in vivo and in vitro. Salidroside administration attenuated HFD-induced obesity, blood glucose variability, and hepatic lipid deposition, markedly increasing insulin sensitivity in HFD mice. In addition, salidroside suppressed oxidative stress, thioredoxin-interacting protein (TXNIP) expression, and NLRP3 inflammasome activation in the liver. In cultured hepatocytes, salidroside dose dependently regulated lipid accumulation, reactive oxygen species (ROS) generation, and NLRP3 inflammasome activation as well as improved AMP-activated protein kinase (AMPK) activity and insulin sensitivity. The inhibition of AMPK activation by inhibitor or short interfering RNA (siRNA) resulted in the suppression of the beneficial effects of salidroside in hepatocytes. Our findings demonstrated that salidroside protects against NAFLD by improving hepatic lipid metabolism and NLRP3 inflammasome activation, and these actions are related to the regulation of the oxidative stress and AMPK-dependent TXNIP/NLRP3 pathways.