Comparing Sonazoid contrast-enhanced ultrasound to contrast-enhanced CT and MRI for differentially diagnosing renal lesions: a prospective multicenter study.

PURPOSE: To evaluate the diagnostic performance of contrast-enhanced (CE) ultrasound using Sonazoid (SNZ-CEUS) by comparing with contrast-enhanced computed tomography (CE-CT) and contrast-enhanced magnetic resonance imaging (CE-MRI) for differentiating benign and malignant renal masses. MATERIALS AND METHODS: 306 consecutive patients (from 7 centers) with renal masses (40 benign tumors, 266 malignant tumors) diagnosed by both SNZ-CEUS, CE-CT or CE-MRI were enrolled between September 2020 and February 2021. The examinations were performed within 7 days, but the sequence was not fixed. Histologic results were available for 301 of 306 (98.37%) lesions and 5 lesions were considered benign after at least 2 year follow-up without change in size and image characteristics. The diagnostic performances were evaluated by sensitivity, specificity, positive predictive value, negative predictive value, and compared by McNemar's test. RESULTS: In the head-to-head comparison, SNZ-CEUS and CE-MRI had comparable sensitivity (95.60 vs. 94.51%, P = 0.997), specificity (65.22 vs. 73.91%, P = 0.752), positive predictive value (91.58 vs. 93.48%) and negative predictive value (78.95 vs. 77.27%); SNZ-CEUS and CE-CT showed similar sensitivity (97.31 vs. 96.24%, P = 0.724); however, SNZ-CEUS had relatively lower than specificity than CE-CT (59.09 vs. 68.18%, P = 0.683). For nodules > 4 cm, CE-MRI demonstrated higher specificity than SNZ-CEUS (90.91 vs. 72.73%, P = 0.617) without compromise the sensitivity. CONCLUSIONS: SNZ-CEUS, CE-CT, and CE-MRI demonstrate desirable and comparable sensitivity for the differentiation of renal mass. However, the specificity of all three imaging modalities is not satisfactory. SNZ-CEUS may be a suitable alternative modality for patients with renal dysfunction and those allergic to gadolinium or iodine-based agents.

[Essentials for high-quality development of fangjiomics].

The development of modern omics technology has facilitated in-depth research on many disciplines in the field of medicine. For instance, the introduction of omics-related technology has facilitated research on the mechanism of formula's action and led to the innovative development of sophisticated pharmacological analysis methods. However, in general, the previous ideas are only limited to the application level, failing to integrate with the discipline connotation of formulaology. Furthermore, they are unable to fulfill their potential role in the future evolution of formulaology and steer comprehensive research on the clinical efficacy and safety of formulas. We should not forget our origins, which are compatible with other countries, and embrace the future. Therefore, this paper proposes the three essentials of "holism, macro, and practice" to investigate the future direction of high-quality development in fangjiomics.

RAAS in diabetic retinopathy: mechanisms and therapies.

Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.

Wunderlich syndrome in a patient with pyelonephritis.

An elderly female patient with left pyelonephritis developed worsening left flank pain, hypotension and a drop in haemoglobin (Hb) from 97 g/L to 67g/L on the third day of her admission. There was no recent trauma, history of coagulopathy or risk factors for renal malignancy or vascular disease.A contrasted CT scan of the kidneys revealed a 3.8 cm left renal subcapsular haematoma with no active contrast extravasation. Her atraumatic subcapsular haematoma fulfils two out of three clinical features of Lenk's triad (acute flank pain, hypovolaemic shock), suggestive of Wunderlich syndrome. Urine and blood cultures grew Klebsiella pneumoniae and she was managed conservatively with culture-directed antibiotics, fluids and blood products.Wunderlich syndrome is a rare complication of pyelonephritis and should be considered in patients with pyelonephritis who develop acute severe flank pain, Hb drop and haemodynamic instability. Appropriate medical and surgical therapies need to be instituted early to ensure good outcomes.

Mechanistic insights into Qiteng Xiaozhuo Granules' regulation of autophagy for chronic glomerulonephritis treatment: Serum pharmacochemistry, network pharmacology, and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Qiteng Xiaozhuo Granules (QTXZG), a traditional Chinese medicine prescription, is widely acknowledged for its therapeutic efficacy and lack of discernible toxicity in clinical practice, substantiating its potential in the treatment of chronic glomerulonephritis (CGN). Nevertheless, the specific effectiveness and underlying mechanisms of QTXZG remain insufficiently explored. AIM OF THE STUDY: The purpose of this study was to explore the mechanism of the QTXZG in the treatment of CGN via targeting autophagy based on serum pharmacochemistry, network pharmacology, and experimental validation. METHODS: Serum samples from SD rats orally administered QTXZG were analyzed using UPLC-QE/MS to identify contained compounds. Network and functional enrichment analyses elucidated QTXZG's targets and biological mechanisms. Reliability was ensured through molecular docking, in vivo and in vitro experiments. RESULTS: After oral administration of QTXZG, 39 enriched compounds in serum samples collected 1 h later were identified as potential active agents, with 508 potential targets recognized as QTXZG-specific targets. Through integration of various databases, intersection analysis of QTXZG targets, CGN-related genes, and autophagy-related targets identified 10 core autophagy-related targets for QTXZG in CGN. GO and KEGG analyses emphasized their roles in autophagy, inflammation, and immune processes, particularly emphasizing the enrichment of the AMPK/mTOR signaling pathway. Molecular docking results demonstrated strong binding affinities between QTXZG's key compounds and the predicted core targets. In animal experiments, QTXZG was found to ameliorate renal tissue damage in CGN model mice, significantly reducing serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Importantly, both animal and cell experiments revealed QTXZG's ability to decrease excessive ROS and inflammatory factor release in mesangial cells. Furthermore, in vitro and in vivo experiments confirmed QTXZG's capacity to upregulate Beclin1 and LC3II/I expression, decrease p62 expression, and induce CGN autophagy through modulation of the AMPK/mTOR pathway. CONCLUSIONS: This study indicated that QTXZG can induce autophagy in CGN by affecting the AMPK/mTOR pathway, and induction of autophagy may be one of the possible mechanisms of QTXZG's anti-CGN.

Insulin resistance is associated with the presence and severity of retinopathy in patients with type 2 diabetes.

BACKGROUND: To assess the relationship between novel insulin resistance (IR) indices and the presence and severity of diabetic retinopathy (DR) in patients with type 2 diabetes. METHODS: This is a cross-sectional study involving 2211 patients. The study outcomes were DR events. The study exposures were IR indices including estimated glucose disposal rate (eGDR), natural logarithm of glucose disposal rate (lnGDR), metabolic insulin resistance score (METS-IR), triglyceride glucose index-body mass index (TyG-BMI), triglyceride glucose index-waist-to-hip ratio (TyG-WHR), and triglyceride/high-density lipoprotein cholesterol(TG/HDL-c ratio). We used binary and multivariate ordered logistic regression models to estimate the association between different IR indices and the presence and severity of DR. Subject work characteristic curves were used to assess the predictive power of different IR indices for DR. RESULTS: DR was present in 25.4% of participants. After adjusting for all covariates, per standard deviation (SD) increases in eGDR (ratio [OR] 0.38 [95% CI 0.32-0.44]), lnGDR (0.34 [0.27-0.42]) were negatively associated with the presence of DR. In contrast, per SD increases in METS-IR (1.97 [1.70-2.28]), TyG-BMI (1.94 [1.68-2.25]), TyG-WHR (2.34 [2.01-2.72]) and TG/HDL-c ratio (1.21 [1.08-1.36]) were positively associated with the presence of DR. eGDR was strongly associated with severity of DR. Of all variables, eGDR had the strongest diagnostic value for DR (AUC = 0.757). CONCLUSIONS: Of the six IR indices, eGDR was significantly associated with the presence and severity of DR in patients with type 2 diabetes. eGDR has a good predictive value for DR. Thus, eGDR maybe a stronger marker of DR.

Parathyroid carcinoma: Three case reports.

BACKGROUND: Parathyroid carcinoma (PC) is a rare, slow-growing malignant tumor and a rare cause of primary hyperfunctioning of the parathyroid, with a highly variable clinical course, depending on the aggressiveness of the individual tumor and the degree of hypercalcemia. CASE SUMMARY: The aim of this report is to summarize the diagnosis and treatment of three cases of PC and to review and conclude aspects regarding the three collected cases with reference to other relevant cases to explore the value of ultrasound in the diagnosis of PC. All three patients had hypercalcemia, consisting of a high serum calcium level and a high level of parathyroid hormone that was > 2-fold (even > 30-fold) of the normal upper limit. The ultrasonographic findings of the parathyroid gland showed that the glands were all > 30 mm, and the internal echo was uneven. All patients underwent surgery. PC in three cases was confirmed by routine histopathology and immunohistochemistry. CONCLUSION: As clinical signs and laboratory results are nonspecific, it is difficult to diagnose PC preoperatively, so imaging examinations are often needed.

Identification of Hub Genes and Typing of Tuberculosis Infections Based on Autophagy-Related Genes.

Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the leading causes of morbidity and death in humans worldwide. Some autophagy genes associated with TB and some miRNAs regulating TB have been found, but the identification of autophagy-related genes in M. tuberculosis remains to be explored. Forty-seven autophagy-related genes differentially expressed in TB were identified in this study by analysis of TB-related datasets in the Gene Expression Omnibus (GEO) and autophagy-related genes in the Human Autophagy Database. The potential crucial genes affecting TB were found through the protein-protein interaction (PPI) network, and the possible pathways affected by these genes were verified. Analysis of the PPI network of miRNAs associated with M. tuberculosis infection and their target genes revealed that hsa-let-7, hsa-mir-155, hsa-mir-206, hsa-mir-26a, hsa-mir-30a, and hsa-mir-32 may regulate the expression of multiple autophagy-related genes (MAPK8, UVRAG, UKL2, and GABARAPL1) alone or in combination. Subsequently, Cytoscape was utilized to screen the differentially expressed genes related to autophagy. The hub genes (GABARAPL1 and ULK2) affecting TB were identified. Combined with Gene Set Enrichment Analysis (GSEA), the signaling pathways affected by the hub genes were verified. Finally, we divided TB patients into two subgroups based on autophagy-related genes, and the immune microenvironment of patients in different subgroups was significantly different. Our study found two autophagy-related hub genes that could affect TB and divide TB samples into two subgroups. This finding is of great significance for TB treatment and provides new ideas for exploring the pathogenesis of M. tuberculosis.

Uric acid index is a risk for mild cognitive impairment in type 2 diabetes.

BACKGROUND: A new uric acid (UA) index has recently been proposed, while serum uric acid (SUA), fasting triglyceride, and fasting blood glucose levels in the index are shown to affect cognitive function. This study aims to investigate the clinical value of the UA index for assessing mild cognitive impairment (MCI) in type 2 diabetes (T2D) patients. METHODS: This was an observational cross-sectional study with 616 participants. A generalized additive model was used to determine a linear or curvilinear relationship between cognitive performance and the UA index. Logistic regression and random forest models were both developed. A receiver operating characteristic curve (ROC) was delineated and the area under the curve (AUC) was calculated. RESULTS: MCI was diagnosed in 313 participants (50.81%). Compared with the T2D-normal cognitive function group, MCI subjects had higher UA indexes, lower cognitive scores, and lower education levels (p < 0.001). Generalized additive models showed the UA index and the Montreal Cognitive Assessment (MoCA) score to be decreased linearly (p < 0.001). The UA index AUC was 0.751 (95% CI = 0.713-0.789, p < 0.001). The optimal cut-off point for the identification of MCI based on the UA index was 11.26 (sensitivity: 62.3%, specificity: 75.9%). Results for females in the cohort yielded an AUC change of + 2.5%, the less-educated population (AUC change of + 4.7%), and the hypertensive population (AUC change of + 1.1%). The AUCs were 0.791 (95% CI = 0.720-0.863) for the random forest model and 0.804 (95% CI = 0.770-0.837) for the logistic regression model, and no statistical significance was found (p = 0.758). CONCLUSION: This study showed that the increased UA index was independently associated with MCI in patients with T2D, especially among female, less-educated, and hypertensive patients. It could be a potential indicator of MCI in T2D patients.

Effects of perioperative use of esketamine on postpartum depression risk in patients undergoing cesarean section: A randomized controlled trial.

BACKGROUND: Postpartum depression (PPD) is a prevalent public health issue. Although ketamine has prophylactic effects on PPD in women undergoing cesarean section, the effects of esketamine on PPD remain unclear. This trial aimed to evaluate the efficacy of perioperative esketamine infusion on PPD risk by assessing Edinburgh Postnatal Depression Scale (EPDS) scores and blood biomarkers. METHODS: A total of 150 participants undergoing elective cesarean section were randomly allocated to receive either esketamine or normal saline. Since 27 participants were excluded due to consent withdrawal or loss to follow-up, 123 patients were included. The primary outcome was the prevalence of PPD risk. Secondary outcomes included the prevalence of postpartum anxiety (PPA) risk, levels of biomarkers, postoperative pain intensity, and cumulative sufentanil consumption. RESULTS: The prevalence of PPD and PPA risk at 3 days, 42 days, 3 months, and 6 months postpartum did not differ between the two groups. Furthermore, EPDS scores, pain intensity at rest, and during coughing on postoperative days (POD) 1 and 2 did not differ between the two groups. Sufentanil consumption during 0-12 h, 12-24 h, 0-24 h, and 0-48 h postoperatively were significantly lower in the esketamine group compared to the control group. Blood biomarkers did not differ between the two groups on POD 3. LIMITATIONS: The sample size was small. PPD risk was simply screened, not diagnosed. CONCLUSIONS: Perioperative administration of esketamine did not decrease the incidence of PPD risk in women after elective cesarean section. However, esketamine reduced opioid consumption.

[Three oral Chinese patent medicines for children with tic disorder: a rapid health technology assessment].

This study aims to comprehensively evaluate the clinical value of Shaoma Zhijing Granules(SZG), Changma Xifeng Tablets(CXT), and Jiuwei Xifeng Granules(JXG) in the treatment of children with tic disorder with the method of rapid health technology assessment(RHTA), which is expected to serve as a reference for medical and health decision-making and clinical rational use of drugs in children. To be specific, relevant articles were retrieved from eight databases and three clinical trial registry platforms. After the quality evaluation, rapid assessment was carried out from the dimensions of disease burden and unmet needs, technical characteristics, safety, efficacy and economy, and the results were analyzed and presented descriptively. A total of 22 articles(1 in English, 21 in Chinese) were screened out: 18 randomized controlled trials(RCTs) and 4 clinical controlled trials(CCTs). Among them, 5 were about the SZG(all RCTs) and 9 were on CXT(6 RCTs and 3 CCTs). The rest 8 focused on JXG(7 RCTs and 1 CCT). Moreover, the overall risk of bias for 94.40% RCTs was evaluated as "some concerns" and only one(5.60%) had high risk of bias. In terms of quality, the 4 CCTs scored 5-6 points(<7 points), suggesting low quality. SZG alone or in combination with tiapride has obvious advantages in improving traditional Chinese medicine syndromes and tic symptoms compared with tiapride alone, with the average daily cost of CNY 79.44-119.16. Compared with conventional western medicine or placebo, CXT alone or in combination with conventional western medicine can improve the total effective rate and alleviate tic symptoms, and the average daily cost is CNY 22.50-67.50. JXG alone or in combination with conventional western medicine can effectively relieve tic symptoms compared with conventio-nal western medicine or placebo, with the average daily cost of CNY 82.42-164.85. The adverse events related to the three Chinese patent medicines mainly occurred in the digestive, respiratory, and nervous systems, all of which were mild. In general, SZG, CXT, and JXG are effective for children with tic disorder. They have been approved to be used in this field, of which SZG was approved in 2019, with the most up-to-date research evidence and high-quality RCT in Q1 journals. However, the comparative analysis of the three was affected by many factors, which should be further clarified. Based on the large sample data available in multiple dimensions, a comprehensive comparative evaluation of the three Chinese patent medicines should be carried out, thereby highlighting the advantages and disadvantages of them and serving a reference for rational clinical use and drug supervision.

[Determination of 13 halobenzoquinone disinfection by-products in drinking water using solid phase extraction-ultra performance liquid chromatography-triple quadrupole mass spectrometry].

Disinfection of drinking water is critical to prevent waterborne diseases. An unexpected consequence of water disinfection is the formation of disinfection by-products by the interaction of disinfectants with organic matter (natural or anthropogenic) and halides, which present significant toxicological effects and carcinogenic risks. As an emerging disinfection by-product, halobenzoquinones (HBQs) have attracted increasing attention owing to their severe toxicity and high detection rates. The credible determination of HBQs is essential for further studies on their occurrence, toxicity, and control measures; however, HBQs are usually detected in drinking water at trace levels. Therefore, accurate and efficient analytical techniques are critical for HBQ determination and quantitation. In this study, a method based on solid phase extraction (SPE) combined with ultra performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MS/MS) was developed to determine 13 HBQs, including six chlorobenzoquinones, six bromobenzoquinones, and one iodobenzoquinone, in drinking water. One-liter water samples were added with 2.5 mL of formic acid, and 500 mL of each sample was collected for further enrichment. Pretreatment optimization mainly focused on the SPE column, washing solvent, and nitrogen blowing temperature. After extraction using Plexa SPE columns (200 mg/6 mL), the samples were washed with ultrapure water containing 0.25% formic acid combined with 30% methanol aqueous solution containing 0.25% formic acid, eluted with 6 mL of methanol containing 0.25% formic acid, and then nitrogen blown at 30 ℃. The UPLC-MS/MS parameters were optimized by comparing the results of two reversed-phase columns (BEH C18 and HSS T3) and various concentrations of formic acid in the mobile phase, as well as by establishing the best instrumental conditions. The separation of 13 HBQs was performed using an HSS T3 column (100 mm×2.1 mm, 1.8 µm) via gradient elution with a mixture of 0.1% formic acid aqueous solution and methanol as the mobile phase for 16 min. The 13 HBQs were detected using a triple quadrupole mass spectrometer equipped with a negative electrospray ionization source (ESI-) in multiple reaction monitoring (MRM) mode. Matrix-matched calibration curves were used to quantify the HBQs owing to intense matrix inhibitory effects. The results reflected the good linear relationships of the 13 HBQs and yielded correlation coefficients (r) greater than 0.999. The method detection limits (MDLs, S/N=3) were 0.2-10.0 ng/L, while the method quantification limits (MQLs, S/N=10) were 0.6-33.0 ng/L. The recoveries of the 13 HBQs were 56%-88% at three spiked levels (10, 20, 50 ng/L), and the relative standard deviations (RSDs, n=6) were less than or equal to 9.2%. The optimization method was applied to analyze HBQs in five drinking water samples. Four HBQs, namely, 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), 2,5-dibromo-1,4-benzoquinone (2,5-DBBQ), 2,6-dibromo-1,4-benzoquinone (2,6-DBBQ), and 2,6-dibromo-3,5-dimethyl-1,4-benzoquinone (2,6-DBDMBQ), were detected in the samples with detection rates of 100%, 20%, 80%, and 20%, respectively. The most frequently detected HBQ, 2,6-DCBQ, also exhibited the highest content (15.0-56.2 ng/L). The method showed high sensitivity, stability, accuracy, and efficiency, rendering it suitable for the analysis of 13 HBQs in drinking water. Compared with previous methods that mainly focused on 2,6-DCBQ and 2,6-DBBQ, the developed method achieved higher throughput and enabled the simultaneous analysis of 13 HBQs. The method presented in this study provides an opportunity to explore different types and concentrations of HBQs in drinking water, offers a deeper understanding of the occurrence of HBQs, and facilitates further studies on the health risks and control measures of these compounds.

[A cohort study of vincristine-induced peripheral neuropathy in children]. / é•¿æ˜¥æ–°ç¢±è¯±å¯¼çš„å‘¨å›´ç¥žç»ç— å˜çš„å„¿ç«¥é˜Ÿåˆ—ç ”ç©¶.

OBJECTIVES: To study the characteristics of vincristine-induced peripheral neuropathy (VIPN) in children with acute lymphoblastic leukemia (ALL) and the factors influencing the development of VIPN. METHODS: The children with ALL, aged 1-18 years, who were treated with CCCG-ALL2015 or CCCG-ALL2020 regimen in the Affiliated Hospital of Guizhou Medical University from January 2018 to February 2022 were enrolled as subjects. According to the influence of age on risk, the children were divided into 1-10 years group with 91 children and >10 years group with 29 children. VIPN was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (5th edition), and the incidence rate, severity, and type of VIPN were compared between different groups. RESULTS: A total of 120 children were enrolled in this study, among whom 56 (46.7%) developed VIPN. The >10 years group had a significantly higher incidence rate of VIPN than the 1-10 years group (69% vs 40%, P<0.05). Among the 56 children with VIPN, 12 (21%) had grade 3 VIPN or above, and 44 (79%) had grade 2 VIPN. There were 77 cases of autonomic nerve symptoms (59.7%), 42 cases of peripheral nerve injury (32.5%), and 10 cases of cranial nerve injury (7.8%). There were no significant differences in the severity and type of VIPN between the groups with different ages, sexes, degrees of risk, or treatment regimens (P>0.05). The results of binary logistic regression analysis showed that age is the influencing factor for the occurrence of VIPN (P>0.05). CONCLUSIONS: There is a relatively high incidence rate of VIPN in children with ALL, with the highest incidence rate of autonomic nervous symptoms. The incidence of VIP in children over 10 years old is relatively high.

The Pathological Mechanism of Neuronal Autophagy-Lysosome Dysfunction After Ischemic Stroke.

The abnormal initiation of autophagy flux in neurons after ischemic stroke caused dysfunction of autophagy-lysosome, which not only led to autophagy flux blockage, but also resulted in autophagic death of neurons. However, the pathological mechanism of neuronal autophagy-lysosome dysfunction did not form a unified viewpoint until now. In this review, taking the autophagy lysosomal dysfunction of neurons as a starting point, we summarized the molecular mechanisms that led to neuronal autophagy lysosomal dysfunction after ischemic stroke, which would provide theoretical basis for the clinical treatment of ischemic stroke.

Identification of the passion fruit (Passiflora edulis Sims) MYB family in fruit development and abiotic stress, and functional analysis of PeMYB87 in abiotic stresses.

Environmental stresses are ubiquitous in agricultural cultivation, and they affect the healthy growth and development of edible tissues in passion fruit. The study of resistance mechanisms is important in understanding the adaptation and resistance of plants to environmental stresses. In this work, two differently resistant passion fruit varieties were selected, using the expression characteristics of the transcription factor MYB, to explore the resistance mechanism of the MYB gene under various environmental stresses. A total of 174 MYB family members were identified using high-quality passion fruit genomes: 98 2R-MYB, 5 3R-MYB, and 71 1R-MYB (MYB-relate). Their family information was systematically analyzed, including subcellular localization, physicochemical properties, phylogeny at the genomic level, promoter function, encoded proteins, and reciprocal regulation. In this study, bioinformatics and transcriptome sequencing were used to identify members of the PeMYB genes in passion fruit whole-genome data, and biological techniques, such as qPCR, gene clone, and transient transformation of yeast, were used to determine the function of the passion fruit MYB genes in abiotic stress tolerance. Transcriptomic data were obtained for differential expression characteristics of two resistant and susceptible varieties, three expression patterns during pulp development, and four induced expression patterns under abiotic stress conditions. We further focused on the resistance mechanism of PeMYB87 in environmental stress, and we selected 10 representative PeMYB genes for quantitative expression verification. Most of the genes were differentially induced by four abiotic stresses, among which PeMYB87 responded significantly to high-temperature-induced expression and overexpression of the PeMYB87 gene in the yeast system. The transgenic PeMYB87 in yeast showed different degrees of stress resistance under exposure to cold, high temperatures, drought, and salt stresses. These findings lay the foundation for further analysis of the biological functions of PeMYBs involved in stress resistance in passion fruit.

[Effect of Erjing Pills on alleviating neuroinflammation of AD rats based on TLR4/NF-κB/NLRP3 pathway and its mechanism].

This paper aimed to study the effect of Erjing Pills on the improvement of neuroinflammation of rats with Alzheimer's di-sease(AD) induced by the combination of D-galactose and Aß_(25-35) and its mechanism. SD rats were randomly divided into a sham group, a model control group, a positive drug group(donepezil, 1 mg·kg~(-1)), an Erjing Pills high-dose group(9.0 g·kg~(-1)), and an Erjing Pills low-dose group(4.5 g·kg~(-1)), with 14 rats each group. To establish the rat model of AD, Erjing Pills were intragastrically administrated to rats for 5 weeks after 2 weeks of D-galactose injection. D-galactose was intraperitoneally injected into rats for 3 weeks, and then Aß_(25-35) was injected into the bilateral hippocampus. The new object recognition test was used to evaluate the learning and memory ability of rats after 4 weeks of intragastric administration. Tissues were acquired 24 h after the last administration. The immunofluorescence method was used to detect the activation of microglia in the brain tissue of rats. The positive expressions of Aß_(1-42) and phosphory protein Tau~(404)(p-Tau~(404)) in the CA1 area of the hippocampus were detected by immunohistochemistry. The levels of inflammatory factors interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α), and interleukin-6(IL-6) in the brain tissue were determined by enzyme-linked immunosorbent assay(ELISA). Toll-like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)/nucleotide-binding oligomerization domain-like receptors 3(NLRP3) pathway-associated proteins in the brain tissue were determined by Western blot. The results showed that as compared with the sham group, the new object recognition index of rats in the model control group decreased significantly, the deposition of Aß_(1-42) and p-Tau~(404) positive protein in the hippocampus increased significantly, and the levels of microglia activation increased significantly in the dentate gyrus. The levels of IL-1ß, TNF-α, and IL-6 in the hippocampus of the model control group increased significantly, and the expression levels of TLR4, p-NF-κB p65/NF-κB p65, p-IκBα/IκBα, and NLRP3 proteins in the hippocampus increased significantly. Compared with the model control group, the Erjing Pill groups enhanced the new object recognition index of rats, decreased the deposition of Aß_(1-42) and the expression of p-Tau~(404) positive protein in the hippocampus, inhibited the activation of microglia in the dentate gyrus, reduced the levels of inflammatory factors IL-1ß, TNF-α, and IL-6 in the hippocampus, and down-regulated the expression levels of TLR4, p-NF-κB P65/NF-κB P65, p-IκBα/IκBα, and NLRP3 proteins in the hippocampus. In conclusion, Erjing Pills can improve the learning and memory ability of the rat model of AD presumably by improving the activation of microglia, reducing the expression levels of neuroinflammatory factors IL-1ß, TNF-α, and IL-6, inhibiting the TLR4/NF-κB/NLRP3 neuroinflammation pathway, and decreasing hippocampal deposition of Aß and expression of p-Tau, thereby restoring the hippocampal morphological structure.

Mechanism of human chorionic gonadotropin in endometrial receptivity via the miR-126-3p/PI3K/Akt/eNOS axis.

Human chorionic gonadotropin (hCG) might affect endometrial receptivity, exerting integral roles in embryo implantation. This study explored the action of hCG in endometrial receptivity via the miR-126-3p/PIK3R2/PI3K/Akt/eNOS axis. The embryo implantation dysfunction (EID) mouse models were established by administrating mifepristone and human endometrial epithelial cells (EECs) were used for in vivo experiments, both followed by hCG treatment. Expression level of CD105 and protein levels of cadherin CD144 and CD146 in mice were determined by immunohistochemistry and Western blot. The levels of miR-126-3p and PIK3R2 mRNA and PIK3R2, p-PI3K p85 α, PI3K p110 α, p-Akt, Akt, p-eNOS, and eNOS protein levels were measured. Cell proliferation was evaluated by CCK-8 and EdU assays. The binding sites of miR-126-3p and PIK3R2 were predicted and verified. hCG-treated EECs were further transfected with miR-126-inhibitor for functional rescue experiments. hCG ameliorated endometrial receptivity in EID mice. Moreover, hCG promoted miR-126-3p and suppressed PIK3R2 in EID mice and EECs. miR-126-3p targeted PIK3R2. EEC proliferation was enhanced after hCG treatment but inhibited by miR-126-3p downregulation. Both in vivo and in vitro experiments validated that hCG activated the PI3K/Akt/eNOS pathway through the miR-126-3p/PIK3R2 axis. Collectively, hCG improves endometrial receptivity by activating the PI3K/Akt/eNOS pathway via regulating miR-126-3p/PIK3R2.

MKRN2 knockout causes male infertility through decreasing STAT1, SIX4, and TNC expression.

Makorin-2 (Mkrn2) is an evolutionarily conserved gene whose biological functions are not fully known. Although recent studies have shed insights on the potential causes of male infertility, its underlining mechanisms still remain to be elucidated. We developed a Mrkn2 knockout mice model to study this gene and found that deletion of Mkrn2 in mice led to male infertility. Interestingly, the expression level of signal transducer and activator of the transcription (STAT)1 was significantly decreased in MKRN2 knockout testis and MEF cells. Co-IP assay showed an interaction between MKRN2 and STAT1. Moreover, our results further indicated that MKRN2 regulated the expression level of SIX4 and tenascin C (TNC) via the EBF transcription factor 2 (EBF2) in mice. The results of our study will provide insights into a new mechanism of male infertility.