Biogated mesoporous silica nanoagents for inhibition of cell migration and combined cancer therapy.

Migration is an initial step in tumor expansion and metastasis; suppressing cellular migration is beneficial to cancer therapy. Herein, we designed a novel biogated nanoagents that integrated the migration inhibitory factor into the mesoporous silica nanoparticle (MSN) drug delivery nanosystem to realize cell migratory inhibition and synergistic treatment. Antisense oligonucleotides (Anti) of microRNA-330-3p, which is positively related with cancer cell proliferation, migration, invasion, and angiogenesis, not only acted as the locker for blocking drugs but also acted as the inhibitory factor for suppressing migration via gene therapy. Synergistic with gene therapy, the biogated nanoagents (termed as MSNs-Gef-Anti) could achieve on-demand drug release based on the intracellular stimulus-recognition and effectively kill tumor cells. Experimental results synchronously demonstrated that the migration suppression ability of MSNs-Gef-Anti nanoagents (nearly 30%) significantly contributed to cancer therapy, and the lethality rate of the non-small-cell lung cancer was up to 70%. This strategy opens avenues for realizing efficacious cancer therapy and should provide an innovative way for pursuing the rational design of advanced nano-therapeutic platforms with the combination of cancer cell migratory inhibition.

Genome-wide screen reveals cellular functions that counteract rifampicin lethality in Escherichia coli.

IMPORTANCE: Rifamycins are a group of antibiotics with a wide antibacterial spectrum. Although the binding target of rifamycin has been well characterized, the mechanisms underlying the discrepant killing efficacy between gram-negative and gram-positive bacteria remain poorly understood. Using a high-throughput screen combined with targeted gene knockouts in the gram-negative model organism Escherichia coli, we established that rifampicin efficacy is strongly dependent on several cellular pathways, including iron acquisition, DNA repair, aerobic respiration, and carbon metabolism. In addition, we provide evidence that these pathways modulate rifampicin efficacy in a manner distinct from redox-related killing. Our findings provide insights into the mechanism of rifamycin efficacy and may aid in the development of new antimicrobial adjuvants.

Treatment of polycystic ovary syndrome and its associated psychiatric symptoms with the Mongolian medicine Nuangong Qiwei Pill and macelignan.

ETHNOPHARMACOLOGICAL RELEVANCE: The Mongolian medicine Nuangong Qiwei Pill (NGQW) is a folk prescription with a long history of use by the Mongolian people. NGQW comprises seven Mongolian medicines, which have the effects of regulating and nourishing blood, warming the uterus, dispelling cold and relieving pain. For a long time, it has been used as a good remedy for gynecological diseases, with remarkable curative effects, favored by the majority of patients and recommended by doctors. Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder that can lead to menstrual disorders or infertility. In the gynecological classification of Mongolian medicine, polycystic ovary syndrome has not been distinguished in detail, and the mechanism of NGQW in the treatment of polycystic ovary syndrome has not been scientifically studied and standardized. AIM OF THE STUDY: The aim of this study was to clarify the mechanism of action of NGQW and macelignan in the treatment of PCOS and to provide a reference for the clinical application of these drugs. MATERIALS AND METHODS: The effect of intragastric administration of NGQW and macelignan on PCOS model mice was observed. The mental status of mice was examined behaviorally, and serum hormone levels and oxidative stress parameters were measured by ELISA. Giemsa staining was used to detect the reproductive cycle, and HE staining was used to observe the ovarian status. Immunofluorescence staining was performed to observe the proliferation and apoptosis of ovarian granulosa cells. qRT‒PCR was conducted to measure the expression of IL-6, BAX, BCL-2, and estrogen synthesis-related genes in ovarian tissue and particle cells. RESULTS: In the dehydroepiandrosterone (DHEA)-induced PCOS model mice, both NGQW and macelignan improved the estrous cycle; increased the estradiol (E2) content; lowered testosterone (T), progesterone (P) and luteinizing hormone (LH) levels; reduced the number of polycystic follicles; promoted granulosa cell proliferation; reduced granulosa cell apoptosis; and alleviated depression and anxiety. In addition, Nuangong Qiwei Pill and macelignan reduced the mRNA levels of the ovarian inflammatory factor IL-6; improved the disordered levels of the antioxidant indicators GSH, MDA, and SOD; and activated the TGF-ß3 signaling pathway to increase the transcription of Cyp19a1, which increases estrogen secretion. CONCLUSION: NGQW and macelignan can treat PCOS through the TGF-ß3/Smad/Cyp19a1 signaling pathway to regulate the secretion ability of ovarian granulosa cells. Our research justifies the traditional use of NGQW to treat PCOS and enriches the scope of action of macelignan.

Systematic review and meta-analysis on microRNAs in amyotrophic lateral sclerosis.

MicroRNAs (miRNAs) exhibit a crucial role in the pathogenesis and progress of neurodegenerative disorders. Recent studies have shown abnormal levels of miRNA expression in patients with amyotrophic lateral sclerosis (ALS). Clinical data also confirmed that miRNAs in these patients are inconsistent across studies. A comprehensive systematic review and meta-analysis of current studies can help recognize the important roles of miRNAs during ALS development. Therefore, we initially aimed to perform a systematic literature review on the muscle or serum miRNAs in patients with ALS and healthy individuals. Subsequently, we quantitatively summarized the clinical data of muscle or serum miRNA of patients with ALS and healthy individuals using a meta-analytical technique. 11 studies comprising 281 patients with ALS and 244 healthy control (HC) controls were identified from PubMed and Web of Science for meta-analysis. A systematic review revealed that miRNA levels are closely associated with the occurrence of ALS disease. The expression levels of the most relevant miRNAs were either increased or decreased. The random-effects meta-analysis indicated that the levels of miR-206, miR-133b, and miR-338-3p were significantly elevated in patients with ALS than in HC subjects. By contrast, there was no significant differences in the miR-133a levels between patients with ALS and HC subjects. Collectively, our outcomes demonstrated that serum miR-206, miR-133b, and miR-338-3p were significantly increased in patients with ALS. We speculated that the increased expression levels of miR-206, miR-133b and miR-338-3p are potential promising biomarkers for ALS.

Effects of brain-derived neurotrophic factor (BDNF) on the Schizophrenia model of animals.

BACKGROUND: Schizophrenia（SCZ）is a common clinically chronic psychiatric disease, and there have no effective specific therapeutic drugs in clinical practice currently. Studies have shown that the expression level of brain-derived neurotrophic factor (BDNF) in schizophrenics has decreased, so the expression level of BDNF has always been one of the evaluation indicators of SCZ. The neurotrophic factor hypothesis believes that increase or decrease of the expression level of BDNF may be one of the pathophysiological basis of SCZ. METHODS: In this study, schizophrenic mice model with MK-801-induced glutamate dysfunction was established, and two doses of BDNF were administered to schizophrenic mice by intranasal administration. The four groups of mice: Control group, Model group, BDNF-20, BDNF-100 performed a series of behavioral tests to explore the effects of BDNF on sensory motor gating, anxiety, depression, social interaction, spontaneous activity, and memory in schizophrenic mice. Transcriptome sequencing of the BDNF high group and Model group in prefrontal cortex and hippocampus, using Metascape for gene function annotation and enrichment pathway analysis, to obtain BDNF transcription regulation information, understand the molecular mechanism of BDNF in SCZ further. Subsequently，immunofluorescence detected the effects of BDNF on neurons and glial cells in the prefrontal cortex and hippocampus. CONCLUSION: The results show that BDNF can improve the behavior of SCZ by regulating the construction of the nervous system, affecting the growth and distribution of neurons and glial cells, and changing inflammation and apoptosis in the brain.

The antifibrotic effects of the novel compound gorse isoflavone alkaloid on chemical liver injury in rats.

OBJECTIVE: Liver fibrosis is a frequently occurring liver injury which lacks of effective treatment clinically. Here, we investigated the protective effects of a novel compound Gorse isoflavone alkaloid (GIA) against liver fibrosis. METHODS: Totally forty rats were randomly divided into four groups. Then we established a model of liver fibrosis induced by the intragastric administration of carbon tetrachloride (CCl4). This treated group was followed by the intragastric administration of GIA and colchicine. Then the liver index and spleen index, and liver function indexes were detected by kit. Western blotting assay was performed to estimate the expression of Transforming Growth Factor-ß1 (TGF-ß1) and related proteins. Tissue fibrosis was observed by Masson staining. RESULTS: Our results suggested that GIA reduced the deposition of collagen fibres and the fibrosis index hydroxyproline (Hyp) of liver tissue. Furthermore, we found that GIA significantly decreased the expression of Transforming Growth Factor-ß1 (TGF-ß1) and the ratio of p-smad2/3 to smad2/3, enhanced the level of superoxide dismutase (SOD), and decreased the concentration of malonic dialdehyde (MDA) in the liver. CONCLUSIONS: Our findings revealed that GIA has a beneficial effect to resist the liver fibrosis, and could be ideal for potential use in antifibrotic drugs for the liver.

Selenylation Chemistry Suitable for On-Plate Parallel and On-DNA Library Synthesis Enabling High-Throughput Medicinal Chemistry.

Click chemistry is a concept wherein modular synthesis is used for rapid functional discovery. To this end, continuous discovery of clickable chemical transformations is the pillar to support the development of this field. This report details the development of a clickable C3-H selenylation of indole that is suitable for on-plate parallel and DNA-encoded library (SeDEL) synthesis via bioinspired LUMO activation strategy. This reaction is modular, robust and highly site-selective, and it features a simple and mild reaction system (catalyzed by nonmetallic B(C6 F5 )3 at room temperature), high yields and excellent functional group compatibility. Using this method, a library of 1350 indole-selenides was parallel synthesized in an efficient and practical manner, enabling the rapid identification of 3 ai as a promising compound with nanomolar antiproliferative activity in cancer cells via in situ phenotypic screening. These results indicate the great potential of this new clickable selenylation reaction in high-throughput medicinal chemistry and chemical biology.

Angioleiomyoma of the Epiglottis Mimicking Epiglottic Hemangioma: Clinical Experience and Literature Review.

We describe a case of laryngeal angioleiomyoma, discuss its characteristic features and management, and provide a review of the literature, to improve clinical diagnosis and treatment. We report the oldest patient with a laryngeal angioleiomyoma to date and analyze the clinicopathological features reported in the literature. To the best of our knowledge, a total of 36 cases have been described in the English and Chinese medical literature (including our case). The male-to-female ratio was 5:1 and the mean age was 53.89 years. The most common laryngeal site was the supraglottic region (23 cases; 63.89%), followed by the subglottic region (8 cases; 22.22%), and glottis (5 cases; 13.89%). The most common and serious intra- and postoperative complication was massive bleeding. Angioleiomyoma is a benign tumor that rarely occurs in the larynx. Biopsy of this lesion should not be performed; complete surgical resection is the best treatment. Recurrence and malignant transformation are extremely rare.

Oxidative stress marker aberrations in children with autism spectrum disorder: a systematic review and meta-analysis of 87 studies (N = 9109).

There is increasing awareness that oxidative stress may be implicated in the pathophysiology of autism spectrum disorder (ASD). Here we aimed to investigate blood oxidative stress marker profile in ASD children by a meta-analysis. Two independent investigators systematically searched Web of Science, PubMed, and Cochrane Library and extracted data from 87 studies with 4928 ASD children and 4181 healthy control (HC) children. The meta-analysis showed that blood concentrations of oxidative glutathione (GSSG), malondialdehyde, homocysteine, S-adenosylhomocysteine, nitric oxide, and copper were higher in children with ASD than that of HC children. In contrast, blood reduced glutathione (GSH), total glutathione (tGSH), GSH/GSSG, tGSH/GSSG, methionine, cysteine, vitamin B9, vitamin D, vitamin B12, vitamin E, S-adenosylmethionine/S-adenosylhomocysteine, and calcium concentrations were significantly reduced in children with ASD relative to HC children. However, there were no significance differences between ASD children and HC children for the other 17 potential markers. Heterogeneities among studies were found for most markers, and meta-regressions indicated that age and publication year may influence the meta-analysis results. These results therefore clarified blood oxidative stress profile in children with ASD, strengthening clinical evidence of increased oxidative stress implicating in pathogenesis of ASD. Additionally, given the consistent and large effective size, glutathione metabolism biomarkers have the potential to inform early diagnosis of ASD.

Peripheral blood neurotrophic factor levels in children with autism spectrum disorder: a meta-analysis.

Increasing evidence suggests that abnormal regulation of neurotrophic factors is involved in the etiology and pathogenesis of Autism Spectrum Disorder (ASD). However, clinical data on neurotrophic factor levels in children with ASD were inconsistent. Therefore, we performed a systematic review of peripheral blood neurotrophic factors levels in children with ASD, and quantitatively summarized the clinical data of peripheral blood neurotrophic factors in ASD children and healthy controls. A systematic search of PubMed and Web of Science identified 31 studies with 2627 ASD children and 4418 healthy controls to be included in the meta-analysis. The results of random effect meta-analysis showed that the peripheral blood levels of brain-derived neurotrophic factor (Hedges' g = 0.302; 95% CI = 0.014 to 0.591; P = 0.040) , nerve growth factor (Hedges' g = 0.395; 95% CI = 0.104 to 0.686; P = 0.008) and vascular endothelial growth factor (VEGF) (Hedges' g = 0.097; 95% CI = 0.018 to 0.175; P = 0.016) in children with ASD were significantly higher than that of healthy controls, whereas blood neurotrophin-3 (Hedges' g = - 0.795; 95% CI = - 1.723 to 0.134; P = 0.093) and neurotrophin-4 (Hedges' g = 0.182; 95% CI = - 0.285 to 0.650; P = 0.445) levels did not show significant differences between cases and controls. Taken together, these results clarified circulating neurotrophic factor profile in children with ASD, strengthening clinical evidence of neurotrophic factor aberrations in children with ASD.

Blood Oxidative Stress Marker Aberrations in Patients with Huntington's Disease: A Meta-Analysis Study.

Huntington's disease (HD) is a hereditary autosomal dominant neurodegenerative disease. Although studies have shown that blood oxidative stress markers are dysregulated in HD patients, clinical data on the blood oxidative stress markers of HD patients is inconsistent. To better understand the pathogenesis of HD, we performed a systematic review and meta-analysis of blood oxidative stress markers in HD patients and healthy control (HC) subjects. A database search from PubMed and Web of Science identified 12 studies with 375 HD patients and 447 HC subjects in this meta-analysis. A random-effects meta-analysis showed that blood lipid peroxidation products (Hedges' g = 0.883, 95%CI = 0.637 to 1.130, p < 0.001), 8-hydroxyguanosine (Hedges' g = 1.727, 95%CI = 0.489 to 2.965, p = 0.006) levels, and the activity of glutathione peroxidase (Hedges' g = 2.026, 95%CI = 0.570 to 3.482, p = 0.006) were significantly increased in HD patients compared to controls. In contrast, reduced glutathione levels were lower in HD patients than in controls (Hedges' g = -0.611, 95%CI = -1.016 to - 0.207, p = 0.003). However, blood superoxide dismutase, cholesterol, high-density lipoproteins, low-density lipoproteins, and triglycerides did not show significant differences between cases and controls. Taken together, this study clarified the associations between blood oxidative stress markers and HD, supporting the clinical evidence that HD is accompanied by increased oxidative stress.

Traditional Chinese Medicine Decoction Combined With Antipsychotic for Chronic Schizophrenia Treatment: A Systematic Review and Meta-analysis.

Despite several studies suggesting the effectiveness of traditional Chinese medicine (TCM) in schizophrenia, there is still a lack of systematic summary and analysis on the role of TCM as adjuvant therapy in chronic schizophrenia. For this purpose, we conducted a meta-analysis to study the efficacy of TCM as an adjuvant combined with antipsychotics in the treatment of chronic schizophrenia. Until April 2020, based on the review of six electronic databases, eight articles were selected. The articles compared TCM decoction assisted antipsychotic therapies with an antipsychotic alone in the treatment of chronic schizophrenia by analyzing a total of 810 cases. The results showed that TCM combined with antipsychotics have beneficial effects on the Positive and Negative Syndrome Scale (PANSS), including the changes in total score, negative score, and the clinical effects evaluated by the PANSS scale. Subgroup analysis showed that the effects of auxiliary TCM with different efficacy on the positive and psychopathological scores were significantly different. It was found that adjuvant treatment with TCM can reduce some side effects and improve the patient's living conditions in the evaluation of the Schizophrenia Quality Of Life Scale (SQLS). Many studies have proved that TCM is safe and well-tolerated. Although the difficulties of using limited TCM remains to be generalized, it still has great potential in the adjuvant treatment of chronic schizophrenia.

Membrane-sensitive bacterial DNA extractions and absolute quantitation of recovery efficiencies.

Absolute quantification of waterborne pathogens is mandatory for microbiological risk assessment (MRA). Determination of the DNA recovery efficiency is an essential step before the quantitative molecular measurements, which has been largely ignored. In this study, we compared the DNA recovery efficiency and quality of five extraction methods, including two modified phenol-chloroform-based extractions with mechanical shearing and three commercial kits for the extraction of DNA from indigenous mixed-bacteria culture of river water. All of the methods gave relatively satisfying results from the pelleted sample through centrifugation. However, the commercial kits provided surprisingly low DNA yields for membrane-filtered samples because of DNA trapping and/or absorption on the membrane. Integrating with enzymatic lysis, bath sonication, phenol extraction, and alcohol precipitation achieved highest DNA yields and an acceptable DNA integrity for quantitative PCR. A plasmid containing the human GADPH gene fragment was demonstrated to be a suitable spiking control for determining the absolute DNA recovery efficiency. The unexpectedly low efficiencies of commercial kit extractions imply the significant underestimation of pathogenic bacteria in previous studies, which should gain enough concern in the area of pathogen monitoring in the future.

Platelet Surface CD62p and Serum Vitamin D Levels are Associated with Clopidogrel Resistance in Chinese Patients with Ischemic Stroke.

BACKGROUND: To explore the association of platelet activation markers, vitamin D, and antiplatelet drugs resistance in ischemic stroke patients. METHODS: A total of 230 patients with ischemic stroke were enrolled in this study. Platelet aggregation, platelet activation marker (CD62p), and vitamin D were measured after 7-14 days of dual antiplatelet treatment (aspirin + clopidogrel). All individuals were divided into a drug resistance group and a drug sensitive group according to the platelet maximum aggregation rate induced by antagonist adenosine diphosphate or arachidonic acid. RESULTS: In this study, the prevalence of aspirin resistance was low (1.2%), while the prevalence of clopidogrel resistance (CR) was 24.8%, so we focused on CR. The percentage of CD62p on activated platelet [(25.74 ± 4.61) versus (12.41 ± 3.93), P < .001] and the prevalence of hypertension [93.0% (53) versus 79.8% (138), P = .021] in CR group were significantly higher than those in clopidogrel sensitive (CS) group, while the vitamin D concentration [(8.96 ± 4.41) versus (13.9 ± 4.84) ng/mL, P = .003] in CR group was significantly lower compared with the CS group. No significant difference was found in soluble P-selectin between these 2 groups [(56.2 ± 16.13) versus (54.2 ± 14.87) ng/mL, P = .258], neither in calcium [(2.29 ± .12) versus (2.33 ± .13) mmol/L, P = .821]. Logistic regression analysis showed that hypertension (odds ratio [OR] = 5.348, 95% confidence intervals [CI] 1.184-23.350, P = .026), expression of platelet CD62p (OR = 1.095, 95% CI 1.052-1.201, P = .018) and vitamin D level (OR = .832, 95% CI .763-.934, P = .005) were associated with CR in ischemic stroke patients. CONCLUSIONS: CR in ischemic stroke patients is associated with several independent predictors, including increased platelet activation marker CD62p, decreased vitamin D level, and hypertension.

Prevalence of antibiotic-resistant bacteria in a lake for the storage of reclaimed water before and after usage as cooling water.

Wastewater reclamation and reuse is a promising way to relieve water scarcity by substituting for natural water consumption by industrial cooling. However, health concerns regarding cooling water originating from reclaimed water are increasing because an abundance of antibiotic-resistant bacteria (ARB) has been detected in reclaimed water. To assess the potential increase of ARB risks in reclaimed water after reuse for industrial cooling, the prevalence of six types of ARB was investigated in water and sediment samples from Lake Gaobeidian, which serves as an artificial circular storage reservoir for reclaimed water for cooling reuse. The effect of treated wastewater and cooling water drainage on the ARB distribution in water and sediment samples was also studied. The results showed that the concentration levels of six types of ARB in lake water samples were as high as those in treated wastewater. The annual median concentrations of total heterotrophic bacteria (HPC) and ARB in discharged cooling water after usage were 0.6-log and 0.4-log higher than those in treated wastewater and the cooling water intake site, respectively, indicating that the process of cooling water usage enhanced the proliferation of HPC and consequently increased the concentrations of ARB. Furthermore, the percentages of penicillin-, ampicillin-, and cephalothin-resistant bacteria in water were 30-57%, 36-48%, and 23-40% higher than those in sediment, respectively. However, the proportions of chloramphenicol-resistant bacteria in water were 35-85% lower than those in sediment. Quantitative evaluation of antibiotic resistance showed that HPC in water had a significant tolerance to penicillin and chloramphenicol, with 50% inhibitory concentrations reaching 22.90 mg L(-1) and 29.11 mg L(-1), respectively.

A fingerprint analysis method for characterization of dissolved organic matter in secondary effluents of municipal wastewater treatment plant.

Dissolved organic matter (DOM) in wastewater and reclaimed water is related to water quality, safety, and treatability. In this study, DOM was characterized through a fingerprint analysis method for DOM characterization using resin fractionation followed by size exclusion chromatography (SEC). Resin fractionation was used in the first step to divide the DOM in water samples into six resin fractions, namely, hydrophobic acids (HOA), hydrophobic bases (HOB), hydrophobic neutrals (HON), hydrophilic acids (HIA), hydrophilic bases (HIB), and hydrophilic neutrals (HIN). SEC analysis was then performed to separate each resin fraction into several (n) subfractions with different molecular weights (MW). Thus, the total DOM in the water sample was fractionated into 6n subfractions. After quantification of each subfraction by dissolved organic carbon (DOC), a fingerprint graph was constructed to express the distribution of DOM in the subfractions. The fingerprint analysis method was applied to a secondary effluent sample during ozonation. Ozonation (dose of 10 mg L(-1)) removed the DOC only by 8 % and reduced UV254 of the sample by 36 %. Fingerprint graphs also revealed that the resin fractions changed quite limitedly but transformation of subfractions occurred notably.

Modulation of astrocytic glutamine synthetase expression and cell viability by histamine in cultured cortical astrocytes exposed to OGD insults.

Histamine, a neurotransmitter or neuromodulator has been demonstrated to be neuroprotective in cerebral ischemia. However, few reports concern its function on astrocytes during cerebral ischemia. The purpose of this study was to investigate the effects of histamine on astrocytic cell damage and glutamate signaling, especially on glutamine synthetase (GS) expression in primary cultured cortical astrocytes exposed to oxygen-glucose deprivation (OGD) insult. OGD for 6h caused a severe damage of astrocytic mitochondrial function, and decreased GS expression and then increased the extracellular glutamate level. Pretreatment with histamine significantly prevented the cell damage and rescued the expression of GS in a concentration-dependent manner. The protective effect of histamine on astrocytic cell damage could be partly reversed either by H1 receptor antagonist pyrilamine or H2 receptor antagonist cimetidine. However, the regulatory effect of histamine on GS expression was antagonized only by pyrilamine. In addition, bisindolylmaleimide II, a broad-spectrum inhibitor of PKC, reversed the regulatory action of histamine on GS expression. These results indicate that histamine can effectively protect against OGD-induced cell damage in astrocytes through H1 and H2 receptors, and its regulatory effect on astrocytic GS expression may be due to the activation of H1 receptor and PKC pathway. Histamine may be an endogenous protective factor and calls for its further study as a regulator of astrocyte function during ischemic stroke.