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1.
Semin Cancer Biol ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33836253

RESUMO

Arsenic exposure in contaminated drinking water is a global health issue, as more than 200 million people are affected globally. Arsenic has been known to cause skin, liver, lung, bladder and prostate cancers. Accordingly, it has been categorized as a group I human carcinogen by the International Agency for Research on Cancer (IARC). Various natural and anthropogenic activities lead to the release of arsenic in the environment, contaminating air, water and food sources. Traditionally, genetic mutations have been the center of cancer research. However, emerging studies have now focused on the importance of epigenetics, metabolism and endoplasmic reticulum (ER) stress in cancer. Arsenic is highly capable of inducing stress in the cells via the generation of free radicals causing oxidative stress, epigenetic and genetic alterations, mitochondrial dysfunction, activation of intracellular signaling pathways, and impairment of autophagy and DNA repair systems. The cancer cells are able to utilize the unfolded protein response (UPR) to overcome these internal stresses in various stages of arsenic-induced carcinogenesis, from cancer growth to immune responses. The UPR is an evolutionarily conserved stress response that has both survival and apoptotic outcomes. PERK, IRE1α and ATF6α are the three ER stress sensors that are activated to maintain cellular proteostasis, which can also promote apoptosis on prolonged ER stress. The dual nature of UPR in different cancer types and stages is a challenge for researchers. We must investigate the role and the connections among ER stress-associated UPR, mitochondrial dysfunction and autophagy in arsenic malignancies to identify key targets for cancer prevention and therapeutics.

2.
Biomaterials ; 272: 120770, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33798957

RESUMO

Three-dimensional in vitro tumor models provide more physiologically relevant responses to drugs than 2D models, but the lack of proper evaluation indices and the laborious quantitation of tumor behavior in 3D have limited the use of 3D tumor models in large-scale preclinical drug screening. Here we propose two indices of 3D tumor invasiveness-the excess perimeter index (EPI) and the multiscale entropy index (MSEI)-and combine these indices with a new convolutional neural network-based algorithm for tumor spheroid boundary detection. This new algorithm for 3D tumor boundary detection and invasiveness analysis is more accurate than any other existing algorithms. We apply this spheroid monitoring and AI-based recognition technique ("SMART") to evaluating the invasiveness of tumor spheroids grown from tumor cell lines and from primary tumor cells in 3D culture.

3.
Semin Cancer Biol ; 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33823236

RESUMO

Environmental exposure to arsenic, a well-established carcinogen linked to a number of human cancers, is a public health concern in many areas of the world. Despite extensive studies on the molecular mechanisms of arsenic-induced carcinogenesis, how initial cellular responses, such as activation of stress kinases and the generation of reactive oxygen species, converge to affect the transcriptional and/or epigenetic reprogramming required for the malignant transformation of normal cells or normal stem cells remains to be elucidated. In this review, we discuss some recent discoveries showing how the transcription factor NRF2 and an epigenetic regulator, MDIG, contribute to the arsenic-induced generation of cancer stem-like cells (CSCs) as determined by applying CRISPR-Cas9 gene editing and chromosome immunoprecipitation followed by DNA sequencing (ChIP-seq).

4.
ChemMedChem ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792182

RESUMO

In this work, we designed a new type of nano-system (CaO 2 @TA-Fe(III)) for the enhanced CDT of tumours in which the polyphenolic compound-tannic acid (TA) and Fe 3+ formed a TA-Fe nano-coating on the surface of calcium peroxide (CaO 2 ) nanospherical aggregates. When the CaO 2 @TA-Fe(III) nanoconjugates reach the tumour site, the CaO 2 contained in the nanoconjugates produces H 2 O 2 after disintegration in tumour cells, and the carried TA rapidly reduces Fe 3+ to Fe 2+ , solving the two major shortcomings in CDT of (1) insufficient content of H 2 O 2 in cancer cells, and (2) low catalytic efficiency of the Fenton reaction. Additionally, the ∙OH produced in the Fenton reaction induces oxidative stress for the tumour cells, promoting the occurrence of the "calcium overload" process, and thereby accelerating the death of tumour cells. Experimental results in vitro and in vivo showed that CaO 2 @TA-Fe(III) nanoconjugates can effectively kill cancer cells. We believe that the CaO 2 @TA-Fe(III) nanoconjugates are a promising new nano-platform for highly effective tumour treatment.

5.
Autism Res ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33792205

RESUMO

The presence of vowel exaggeration in infant-directed speech (IDS) may adapt to the age-appropriate demands in speech and language acquisition. Previous studies have provided behavioral evidence of atypical auditory processing towards IDS in children with autism spectrum disorders (ASD), while the underlying neurophysiological mechanisms remain unknown. This event-related potential (ERP) study investigated the neural coding of formant-exaggerated speech and nonspeech in 24 4- to 11-year-old children with ASD and 24 typically-developing (TD) peers. The EEG data were recorded using an alternating block design, in which each stimulus type (exaggerated/non-exaggerated sound) was presented with equal probability. ERP waveform analysis revealed an enhanced P1 for vowel formant exaggeration in the TD group but not in the ASD group. This speech-specific atypical processing in ASD was not found for the nonspeech stimuli which showed similar P1 enhancement in both ASD and TD groups. Moreover, the time-frequency analysis indicated that children with ASD showed differences in neural synchronization in the delta-theta bands for processing acoustic formant changes embedded in nonspeech. Collectively, the results add substantiating neurophysiological evidence (i.e., a lack of neural enhancement effect of vowel exaggeration) for atypical auditory processing of IDS in children with ASD, which may exert a negative effect on phonetic encoding and language learning. LAY SUMMARY: Atypical responses to motherese might act as a potential early marker of risk for children with ASD. This study investigated the neural responses to such socially relevant stimuli in the ASD brain, and the results suggested a lack of neural enhancement responding to the motherese even in individuals without intellectual disability.

6.
Biomed Res Int ; 2021: 6653500, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791370

RESUMO

Pinene, a natural active monoterpene, is widely used as a flavoring agent, perfume, medicine, and biofuel. Although genetically engineered microorganisms have successfully produced pinene, to date, the biological yield of pinene is much lower than that of semiterpenes (isoprene) and sesquiterpenes (farnesene). In addition to the low heterologous expression of geranyl pyrophosphate synthase (GPPS) and pinene synthase (PS), cytotoxicity due to accumulation of the monoterpene also limits the production of pinene in microorganisms. In this study, we attempted to use two strategies to increase the biological yield of pinene. By deleting the random coils of GPPS and PS alone or in combination, a strain with a 335% yield increase was obtained. Additionally, upon computer-guided molecular modeling and docking of GPPS with isopentenyl pyrophosphate (IPP), its substrate, the key sites located within the catalytic pocket for substrate binding, was predicted. After screening, a strain harboring the T273R mutation of GPPS was selected among a batch of mutations of the key sites with a 154% increase in pinene yield.

7.
Anal Chem ; 93(10): 4506-4512, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33677958

RESUMO

Single-particle electrochemical collision has gained great achievements in fundamental research, but it is challenging to use in practice on account of its low collision frequency and the interference of the complex matrix in actual samples. Here, magnetic separation and DNA walker amplification were integrated to build a robust and sensitive single-particle electrochemical biosensor. Magnetic nanobeads (MBs) can specifically capture and separate targets from complex samples, which not only ensures the anti-interference capability of this method but also avoids the aggregation of platinum nanoparticles (Pt NPs) caused by numerous coexisting substances. A low amount of targets can lead to the release of more Pt NPs and the generation of more collision current transients, realizing cyclic amplification. Compared with simple hybridization, a DNA walker can improve the collision frequency by about 3-fold, greatly enhancing detection sensitivity, and a relationship between collision frequency and target concentration is used to realize quantification. The biosensor realized an ultrasensitive detection of 4.86 fM human immunodeficiency virus DNA (HIV-DNA), which is 1-4 orders of magnitude lower than that of traditional methods. The successful HIV-DNA detection in complex systems (serum and urine) demonstrated a great promising application in real samples and in the development of new single-entity biosensors.

8.
J Mol Graph Model ; 105: 107898, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33784524

RESUMO

Oncogenic protein farnesyltransferase (FTase) is a key enzyme responsible for the lipid modification of a large and important number of proteins including Ras, which has been recognized as a druggable target of diverse cancers. Here, we report a systematic scaffold-based analysis to investigate the affinity, selectivity and cross-reactivity of nonpeptide inhibitors across ontology-enriched, disease-associated FTase mutants, by integrating multiple similarity matching, binding affinity scoring and enzyme inhibition assay. It is revealed that nonpeptide inhibitors are generally insensitive to FTase mutations; many of them cannot definitely select for wild-type target over mutant enzymes. Therefore, off-target is observed as a common phenomenon for the untargeted consequence of targeted therapies with FTase inhibition. This is not unexpected if considering that the enzyme active site is highly conserved in composition, configuration and function. The off-target, on the one hand, causes nonpeptide inhibitors with adverse drug reactions and, on the other hand, makes the inhibitors as promising candidates for the new use of old drugs. To practice the latter, a number of unexpected mutant-inhibitor interactions involved in cancer signaling pathways are uncovered in the created profile, from which several nonpeptide inhibitors are identified as insensitive to a drug-resistant mutation. Structural analysis suggests that the inhibitor ligands can bind to the mutant active site in a similar manner with wild-type target, although their nonbonded interactions appear to be impaired moderately upon the mutation.

9.
Bioorg Chem ; 109: 104753, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33652163

RESUMO

Extensive phytochemical study of the methanol extract of twigs and leaves of Buxus sempervirens resulted in the identification of 17 Buxus alkaloids, including 12 new ones, namely buxusemines A-L (1-12). Their structures were delineated by detailed analysis of the HRESIMS and NMR data, as well as quantum chemical NMR calculations. Buxusemine A (1) represents the second Buxus alkaloid with a unique spiro[4.6]undecatriene moiety, buxusemines B-C (2-3) are a rarely occurring class of Buxus alkaloids featured with an additional five-membered ring through the ether or lactone linkage between C-10 and C-23, and buxusemines D-F (4-6) are another rare type of Buxus alkaloids with an epoxy motif. In the assessment of their bioactivities, buxusemine F (6) and buxanoldine (17) displayed more potent protective effects than the positive control cyclovirobuxinum D in the doxorubicin-induced cardiac injury model.

10.
BMC Pregnancy Childbirth ; 21(1): 266, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33784964

RESUMO

BACKGROUND: To assess the indications and complications of late amniocentesis and the advanced genetic test results in a tertiary university fetal medical medicine unit. METHODS: In this retrospective study, women that underwent amniocentesis at 24+ 0 to 39+ 4 weeks, between January 2014 and December 2019, were recruited. Indications, complications, genetic test results, and pregnancy outcomes were reported for each pregnancy and compared with those who underwent the traditional amniocentesis at 16+ 0 to 23+ 6 weeks (control group). Information was retrieved from patient medical records, checked by research staff, and analyzed. RESULTS: Of the 1287 women (1321 fetuses) included in the late amniocentesis group, late detected sonographic abnormalities (85.5%) were the most common indication. The overall incidence of preterm birth and intrauterine demise after amniocentesis were 2.5 and 1.3%, respectively. Sixty-nine fetuses with aneuploidy (5.3%) and seventy-two fetuses with pathogenic copy number variations (5.5%) were identified by chromosomal microarray analysis. The maximal diagnostic yield (70%) was in the subgroup of fetuses with the abnormal diagnostic test results, followed by abnormal NIPT results (35.7%) and multiple abnormalities (23.8%). And 35.4% of the pregnancies were finally terminated. CONCLUSIONS: Due to the high detection rates of advanced genetic technologies and the safety of the invasive procedure (3.9% vs 4.0%), it is reasonable to recommend late amniocentesis as an effective and reliable method to detect late-onset fetal abnormalities. However, chromosomal microarray and whole-exome sequencing may result in uncertain results like variants of uncertain significance. Comprehensive genetic counseling is necessary.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33661622

RESUMO

Sodium-ion batteries (SIBs) are the appropriate alternatives to lithium-ion batteries (LIBs) for the large-scale energy storage applications because of the abundant resources and wide distribution of sodium on earth. O3-NaCrO2 is a promising cathode material for SIBs due to its stable structure and low-cost raw materials. In this paper, we design and synthesize a powder consisting of submicrometer-sized O3-NaCrO2 spheres (s-NaCrO2) self-assembled with nanoflakes, which exhibits faster ion migration ability and strong structure robustness. The galvanostatic intermittent titration technique test reveals the higher apparent Na+ diffusion coefficient of s-NaCrO2 when compared with a normal NaCrO2 powder with an irregular particle morphology. The s-NaCrO2 shows impressive electrochemical properties with a capacity of 90 mAh g-1 at 50 C. In addition, outstanding cycling stability is shown when tested at 20 C, where a capacity of 90 mAh g-1 is maintained with a retention of 87% after 1500 cycles. Also, s-NaCrO2 is advantageous at high (50 °C) and low (-10 °C) temperatures. The full cells assembled employing Sb/C as the anode exhibit good rate capability with 85 mAh g-1 obtained at 50 C.

12.
Anesth Analg ; 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33661789

RESUMO

BACKGROUND: Modern medical education requires frequent competency assessment. The Accreditation Council for Graduate Medical Education (ACGME) provides a descriptive framework of competencies and milestones but does not provide standardized instruments to assess and track trainee competency over time. Entrustable professional activities (EPAs) represent a workplace-based method to assess the achievement of competency milestones at the point-of-care that can be applied to anesthesiology training in the United States. METHODS: Experts in education and competency assessment were recruited to participate in a 6-step process using a modified Delphi method with iterative rounds to reach consensus on an entrustment scale, a list of EPAs and procedural skills, detailed definitions for each EPA, a mapping of the EPAs to the ACGME milestones, and a target level of entrustment for graduating US anesthesiology residents for each EPA and procedural skill. The defined EPAs and procedural skills were implemented using a website and mobile app. The assessment system was piloted at 7 anesthesiology residency programs. After 2 months, faculty were surveyed on their attitudes on usability and utility of the assessment system. The number of evaluations submitted per month was collected for 1 year. RESULTS: Participants in EPA development included 18 education experts from 11 different programs. The Delphi rounds produced a final list of 20 EPAs, each differentiated as simple or complex, a defined entrustment scale, mapping of the EPAs to milestones, and graduation entrustment targets. A list of 159 procedural skills was similarly developed. Results of the faculty survey demonstrated favorable ratings on all questions regarding app usability as well as the utility of the app and EPA assessments. Over the 2-month pilot period, 1636 EPA and 1427 procedure assessments were submitted. All programs continued to use the app for the remainder of the academic year resulting in 12,641 submitted assessments. CONCLUSIONS: A list of 20 anesthesiology EPAs and 159 procedural skills assessments were developed using a rigorous methodology to reach consensus among education experts. The assessments were pilot tested at 7 US anesthesiology residency programs demonstrating the feasibility of implementation using a mobile app and the ability to collect assessment data. Adoption at the pilot sites was variable; however, the use of the system was not mandatory for faculty or trainees at any site.

13.
J Biomed Mater Res A ; 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33682365

RESUMO

Whole-organ engineering is emerging as an alternative source for xenotransplantation in end-stage diseases. Utilization of decellularized whole lung scaffolds created by detergent perfusion is an effective strategy for organ replacement. In the current study, we attempted to decellularize porcine whole lungs to generate an optimal and reproducible decellularized matrix for future clinical use. Porcine whole lungs were decellularized via perfusion of various detergents (sodium dodecyl sulfate (SDS)/Triton X-100, sodium lauryl ether sulfate (SLES)/Triton X-100, dextrose/SDS/Triton X-100 and dextrose/SLES/Triton X-100) through the pulmonary artery and bronchus of the lung. The decellularized scaffolds were evaluated for decellularization efficiency, extracellular matrix (ECM) component preservation, xenoantigen removal and compatibility. The resulting lung scaffolds obtained from treatment with the dextrose/SLES/Triton X-100 cocktail showed minimal residual cellular components and xenoantigens, including DNA and protein, and good preservation of ECM composition. Evaluation of the porcine lung ECM by specific staining and immunofluorescence confirmed that the three-dimensional ultrastructure of the ECM was noticeably preserved in the SLES-treated groups. In addition, the decellularized lung scaffolds originating from the dextrose/SLES/Triton X-100 cocktail supported cell adhesion and growth. In summary, the novel detergent SLES alleviated the damage to retain a better-preserved ECM than SDS. Sequential Triton X-100 perfusion eliminated SLES. Moreover, performing dextrose perfusion in advance further protected scaffold components, especially collagen. We developed an optimal dextrose/SLES/Triton X-100 cocktail method that can be used for the decellularization of porcine whole lung to obtain a clinical-scale bioengineered scaffold.

14.
Mol Cell Proteomics ; : 100068, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33676000

RESUMO

Signet ring cell carcinoma (SRCC) is a histological subtype of gastric cancer with distinct features in multiple aspects compared to adenocarcinomas (ACs). The lack of a systematic molecular overview of this disease has led to slow progress in its clinical practice. In the present proteomics study, gastric tissues were collected from tumors and adjacent tissues, including 14 SRCCs and 34 ACs, and laser capture microdissection (LCM) was employed to eradicate the cellular heterogeneity of the tissues. The proteomes of tissues were profiled by data independent acquisition (DIA) mass spectrometry (MS). Based on the over 6000 proteins quantified, univariate analysis and pathway enrichment revealed that some proteins and pathways demonstrated differences between SRCC and ACs. Importantly, the upregulation of a majority of complement-related proteins was notable for SRCC but not for ACs. A hypothesis, based on the proteomics evidence, was proposed that the complement cascade was evoked in the SRCC microenvironment upon infiltration, and the SRCC cells survived the complement cytotoxicity by secreting endogenous negative regulators. Moreover, an attempt was made to establish appropriate cell models for gastric SRCC through proteomic comparison of the 15 gastric cell lines and gastric tumors. The predictions of a supervised classifier suggested that none of these gastric cell lines qualified to mimic SRCC. This study discovered that the complement cascade is activated at a higher level in gastric SRCC than in ACs.

15.
Lasers Med Sci ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723687

RESUMO

The purpose of this study is to evaluate the efficacy and safety of vaginal fractional CO2 laser therapy for female sexual dysfunction (FSD). A total of 84 women at high risk of sexual dysfunction were randomly divided into two groups. Women in the laser group received vaginal fractional CO2 laser therapy. Others in the Kegel group were advised to participate in Kegel exercise training. Sexual distress and sexual function were evaluated by using the Female Sexual Distress Scale-Revised (FSDS-R) and the Chinese version Female Sexual Function Index (CVFSFI), respectively. Adverse events were recorded during the 12-month follow-up. At the end of the 6th and 12th months, the lubrication scores of the CVFSFI in the laser group (4.55±0.05, 4.58±0.09) were significantly higher than those in the Kegel group (4.19±0.15, 4.20±0.14) (P<0.05). The satisfaction scores in the laser group (4.43±0.08) were higher than those in the Kegel group (4.20±0.16) at the end of the 6th month (P<0.05). The self-contrast test in the laser group showed significant improvement in lubrication, pain, satisfaction and total scores after CO2 laser therapy (p<0.05). These improvements were maintained for 1 year. The improvement of FSDS-R in the laser group (10.0±0.2) was more evident than in the Kegel group (11.1±0.4) at the end of the 12th month. There were no major adverse events reported during laser therapy. Vaginal fractional CO2 laser therapy can effectively improve sexual function without any serious adverse events. It might be an effective and relatively safe treatment option for improving vaginal mucosa status in sexually active women with sexual dysfunction.

16.
Mol Genet Genomic Med ; : e1624, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33724704

RESUMO

BACKGROUND: Congenital hydrocephalus-3 with brain anomalies (HYC3, MIM 617967) is a rare form of congenital hydrocephalus characterized by severe hydrocephalus and cerebellar abnormalities, the onset of the disease occurs in utero even resulting in fetal death. A very limited spectrum of WDR81 pathogenic variants had been reported in three unrelated families with HYC3. This study aims at presenting novel compound heterozygous frameshift variants in WDR81 in a Chinese fetus. METHODS: Whole-exome sequencing (WES) was performed for a fetus with multiple congenital anomalies including sever hydrocephalus, cleft lip and palate, hydrops fetalis, hepatomegaly, and cerebellar hypoplasia. Sanger sequencing was performed to confirm the origin of the variants subsequently. Variants classification was based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Two novel heterozygous variants c.146_147insG (p.Thr52fs) and c.673delC (p.Leu225fs) in WDR81 were identified. Sanger sequencing revealed that the c.146_147insG mutation was maternal origin and the c.673delC mutation was paternal origin. Both variants were pathogenic according to the ACMG/AMP guidelines. CONCLUSION: The present study expands the mutation spectrum of WDR81 and help further define the genotype-phenotype correlations of HYC3. WDR81-related HYC3 were highly clinical heterogeneity. We suggested that fetal hydrocephalus with extracerebral manifestations may be suggestive of WDR81 deficiency and WES is effective for achieving a conclusive diagnosis for disorder.

17.
Food Res Int ; 140: 109995, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33648229

RESUMO

As the main raw material for commercial Wuliangye-flavor liquor, Wuliangye-flavor raw liquor (WFRL) plays an important role in the formation of flavor components. Aroma components and microbial community diversity of 4 WFRLs produced by the same fermenting cellar were investigated by headspace solid phase microextraction, liquid-liquid microextraction combined gas chromatography-mass spectrometry and phospholipid fatty acid fingerprint method. Correlations between aroma components and microbial community of WFRL were disclosed by multivariate statistical analysis techniques. Results indicated that a total of 75 aroma components were identified, including 39 esters, 11 alcohols, 9 acids, 7 aldehyde, 5 ketones and 4 others, whereas esters were dominant for the samples (67.49%). Meanwhile, Gram-positive bacteria (G+) and aerobe in the fermenting cellar increased gradually from top to bottom, compared with Gram-negative bacteria (G-), anaerobe and fungi showed the opposite trend. Furthermore, 4 WFRLs could be distinguished according to 13 differential aroma components (VIP > 1, P < 0.05). Whereas, the differential aroma components were positively correlated with G-, anaerobe and fungi, but negatively correlated with G+ and aerobe. In particular, 4 key esters including ethyl caproate, ethyl acetate, ethyl butyrate and ethyl lactate that determine the grade of WFRL were positively correlated with anaerobe and fungi. Therefore, the results can be used as a reference to understand the correlation between aroma components and microbial communities in different quality grades of WFRL.

18.
Stem Cell Res Ther ; 12(1): 164, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676566

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are derived from multiple tissues, including amniotic fluid (AF-MSCs) and the umbilical cord (UC-MSCs). Although the therapeutic effect of MSCs on sepsis is already known, researchers have not determined whether the cells from different sources require different therapeutic schedules or exert different curative effects. We assessed the biofunction of the administration of AF-MSCs and UC-MSCs in rats with caecal ligation and puncture (CLP)-induced sepsis. METHODS: CLP was used to establish a disease model of sepsis in rats, and intravenous tail vein administration of AF-MSCs and UC-MSCs was performed to treat sepsis at 6 h after CLP. Two phases of animal experiments were implemented using MSCs harvested in saline with or without filtration. The curative effect was measured by determining the survival rate. Further effects were assessed by measuring proinflammatory cytokine levels, the plasma coagulation index, tissue histology and the pathology of the lung, liver and kidney. RESULTS: We generated rats with medium-grade sepsis with a 30-40% survival rate to study the curative effects of AF-MSCs and UC-MSCs. MSCs reversed CLP-induced changes in proinflammatory cytokine levels and coagulation activation. MSCs ameliorated CLP-induced histological and pathological changes in the lung, liver and kidney. AF-MSCs and UC-MSCs functioned differently in different tissues; UC-MSCs performed well in reducing the upregulation of inflammatory cytokine levels in the lungs and inhibiting the inflammatory cell infiltration into the liver capsule, while AF-MSCs performed well in inhibiting cell death in the kidneys and reducing the plasma blood urea nitrogen (BUN) level, an indicator of renal function. CONCLUSIONS: Our studies suggest the safety and efficacy of AF-MSCs and UC-MSCs in the treatment of CLP-induced sepsis in rats and show that the cells potentially exert different curative effects on the main sepsis-affected tissues.

19.
Nucleic Acids Res ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33693773

RESUMO

We present barcoded oligonucleotides ligated on RNA amplified for multiplexed and parallel insitu analyses (BOLORAMIS), a reverse transcription-free method for spatially-resolved, targeted, in situ RNA identification of single or multiple targets. BOLORAMIS was demonstrated on a range of cell types and human cerebral organoids. Singleplex experiments to detect coding and non-coding RNAs in human iPSCs showed a stem-cell signature pattern. Specificity of BOLORAMIS was found to be 92% as illustrated by a clear distinction between human and mouse housekeeping genes in a co-culture system, as well as by recapitulation of subcellular localization of lncRNA MALAT1. Sensitivity of BOLORAMIS was quantified by comparing with single molecule FISH experiments and found to be 11%, 12% and 35% for GAPDH, TFRC and POLR2A, respectively. To demonstrate BOLORAMIS for multiplexed gene analysis, we targeted 96 mRNAs within a co-culture of iNGN neurons and HMC3 human microglial cells. We used fluorescence in situ sequencing to detect error-robust 8-base barcodes associated with each of these genes. We then used this data to uncover the spatial relationship among cells and transcripts by performing single-cell clustering and gene-gene proximity analyses. We anticipate the BOLORAMIS technology for in situ RNA detection to find applications in basic and translational research.

20.
Mol Oncol ; 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33675143

RESUMO

Despite recent progress in non-small-cell lung cancer (NSCLC) treatment, treatment outcomes remain poor, mainly because of treatment resistance or toxicity. Erastin is a ferroptosis inducer that has shown promising cytotoxic effects in various types of cancers, including NSCLC. Celastrol is a triterpene extracted from the Tripterygium wilfordii that exhibits potential anticancer activity. However, the side effects of celastrol are severe and limit its clinical application. Combination therapy is a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects. In the present study, we found that erastin synergized with celastrol to induce cell death at nontoxic concentrations. The combined treatment with celastrol and erastin significantly increased reactive oxygen species (ROS) generation, disrupted mitochondrial membrane potential, and promoted mitochondrial fission. Furthermore, cotreatment with erastin and celastrol initiated ATG5/ATG7-dependent autophagy, PINK1/Parkin-dependent mitophagy, and the expression of heat shock proteins (HSPs) in an HSF1-dependent manner. HSF1 knockdown further enhanced cell death in vitro and inhibited tumor growth in vivo. Our findings indicate that the combination of celastrol with erastin may represent a novel therapeutic regimen for patients with NSCLC and warrants further clinical evaluation.

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