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1.
Bioorg Chem ; 93: 103309, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31585266

RESUMO

The antibacterial agents and therapies today are facing serious problems such as drug resistance. Introducing dual inhibiting effect is a valid approach to solve this trouble and bring advantages including wide adaptability, favorable safety and superiority of combination. We started from potential DNA Gyrase inhibitory backbone isatin to develop oxoindolin derivatives as atypical dual Gyrase (major) and FabH (assistant) inhibitors via a two-round screening. Aiming at blocking both duplication (Gyrase) and survival (FabH), most of synthesized compounds indicated potency against Gyrase and some of them inferred favorable inhibitory effect on FabH. The top hit I18 suggested comparable Gyrase inhibitory activity (IC50 = 0.025 µM) and antibacterial effect with the positive control Novobiocin (IC50 = 0.040 µM). FabH inhibitory activity (IC50 = 5.20 µM) was also successfully introduced. Docking simulation hinted possible important interacted residues and binding patterns for both target proteins. Adequate Structure-Activity Relation discussions provide the future orientations of modification. With high potency, low initial toxicity and dual inhibiting strategy, advanced compounds with therapeutic methods will be developed for clinical application.

2.
Chemosphere ; 241: 125001, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31590020

RESUMO

Bacterial regrowth in drinking water systems is a threat to public health. In this study, ferrihydrite (Fh) adsorption was compared with advanced drinking water treatment processes (ADWTP) during one and a half years of sampling to test the reduction in assimilable organic carbon (AOC) and bacterial regrowth potential (BRP). Dissolved organic matter (DOM) was removed by Fh through ligand exchange and electrostatic interaction. The DOM removal was higher below pH 6 due to protonation of Fh surfaces. The ADWTP exhibited higher removal rates of DOM than Fh and lower phosphate removal rates than Fh. Excitation-emission matrix (EEM) and size exclusion chromatography (SEC) revealed that Fh removed aromatic DOM larger than 1000 Da, while the biological activated carbon (BAC) of ADWTP could remove DOM smaller than 1000 Da. These differences of organic compositions resulted in the lowest AOC of BAC treated water, and the lowest BRP of Fh-treated water, indicating that it was the most biostable water. Phosphate addition experiments illustrated that phosphorus was the primary rate limiting nutrient, indicating that the higher phosphate removal of Fh made it possible to produce waters with lower BRP than ADWTP. Therefore, BRP is considered to be a better indicator of bacterial regrowth than AOC when phosphorus is a rate-limiting nutrient, as is the case with the Fh treatment.

3.
Org Lett ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31596099

RESUMO

A catalytic, enantioselective formal synthesis of monoterpene indole alkaloid (-)-alstoscholarine is described. The synthesis employs an Ir-amine dual catalyzed asymmetric allylation of aldehyde 8 with 3-indolyl vinyl carbinol derivative 7 to furnish chiral aldehyde 6 as a key asymmetric step. Other key reactions include the construction of the 2-ketopyrrole moiety by Nicolaou's method and Tf2O promoted Pictet-Spengler cyclization to access Zhu's intermediate 3.

4.
J Food Drug Anal ; 27(4): 860-868, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31590757

RESUMO

The continuous re-isolation of the known and non-applicable compounds that is time-consuming and wasting resources is still a critical problem in the discovery of bioactive entities from natural resources. To efficiently address the problem, high performance liquid chromatography-diode array detector-microfractionation (HPLC-DAD-microfractionation) guided by disk agar diffusion assay was developed, and the active compounds were further identified using the tandem mass spectrometry (MS/MS)-based molecular networking. Of 150 fungal strains screened, the methanolic extracts of Phoma herbarum PPM7487, Cryptosporiopsis ericae PPM7405, and Albifimbria verrucaria PPM945 exhibited potent antimicrobial activity against Candida albicans SC5314 and Cryptococcus neoformans H99 in the preliminary agar diffusion assay. The concept of OSMAC (one strain many compounds) was employed in the fungal cultures in order to enrich the diversity of the 2nd metabolites in this study. HPLC coupled with off-line bioactivity-directed profiling of the extracts enabled a precise localization of the compounds responsible for the conspicuous antimicrobial activity. The purified active compounds were identified based mainly on MS/MS database, and further supported by 13C nuclear magnetic resonance (NMR) spectral data compared to the literatures. In addition to nineteen known compounds, a new trichothecene derivative 1, namely trichoverrin D, was isolated and identified through this protocol. The antifungal activities of all the pure isolates were evaluated, and the structure activity relationships were also inferred. This report has demonstrated the combination of HPLC microfractination and MS/MS coupled by NMR spectral dereplication for speeding up the antimicrobial natural products discovery process.

5.
Cell Death Dis ; 10(10): 775, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601791

RESUMO

Uterine angiogenesis and vascular remodeling play critical roles in determing the normal menstrual cycle and successful pregnancy. Poor uterine angiogenesis usually results in pregnancy failure. Protein O-fucosyltransferase 1 (poFUT1) is the key enzyme responsible for O-fucosylated glycan biosynthesis on glycoproteins. However, the dynamic expression and regulation of poFUT1 on the uterine angiogenesis and vascular remodeling remain unknown. Here, we showed that the enlargement of the vascular lumen in the secretory phase was greater than that in the proliferative phase of the uterine endometrium during menstrual cycle; whereas there was a narrower vessel lumen and fewer blood vessels in the decidua from miscarriage patients than in that from healthy pregnancy women. Additionally, the expression of poFUT1 was increased in the uterine endometrium during the secretory phase compared with that in the proliferation phase, and its expression was decreased in the uterus of miscarriage patients compared with that of the healthy pregnancy women. Using hESCs and a mouse model, we demonstrated that poFUT1 increased the O-fucosylation on uPA, and activated of the RhoA signaling pathway, thus facilitating uterine angiogenesis and vascular remodeling. We also provide evidence that poFUT1 promotes hESCs angiogenesis by the decreased stemness of hESCs. These findings reveal a new insight into the uterine angiogenesis and vascular remodeling. The study suggests that poFUT1 could be seen as a novel potential diagnostic and therapeutic target for miscarriage.

6.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3323-3329, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602890

RESUMO

To study the correlation between ultra high performance liquid chromatography( UPLC) fingerprint of Smilax china and its anti-pelvic inflammatory effect,and to explore the pharmacodynamic material basis of S. china against pelvic inflammatory disease.UPLC fingerprints of 10 batches of S. china from different habitats were established,and the values of SOD,MDA,TNF-α,and IL-6 in rats with pelvic inflammation were measured. The weight of each single pharmacodynamics index to the total efficacy was determined by analytic hierarchy process,and the contribution of each peak in fingerprints to the each single pharmacodynamics index and total efficacy was analyzed by the grey relational analysis. Then the structures of chemical constituents at the identified peaks were confirmed by comparing with the reference substance. The 27 common characteristic peaks of UPLC fingerprints were all related to the anti-pelvic inflammation effect of S. china,of which 13 peaks were identified as peak 2( 3,5-dihydroxy-2-methylbenzoic acid-3-O-glucoside),peak 3( chlorogenic acid),peak 5( 2,7,4-trihydroxydihydroflavone-5-O-glucoside),peak 6( 7,4-dihydroxydihydroflavonol-5-O-glucoside),peak 7( taxifolin-7-O-glucoside),peak 9( taxifolin),peak 10( polydatin),peak 11( oxyresveratrol),peak 12( astilbin),peak15( resveratrol),peak 16( quercitrin),peak 18( engeletin) and peak 24( kaempferol). The correlation degree of 21 peaks and the total efficacy was greater than 0. 8,and the top 10 ranked by correlation degree were as follows: peak 1,3,7,19,18,17,4,11,16,and 21. The results showed that the anti-pelvic inflammation effect of S. china was achieved by the combined action of pharmacodynamic substances. In order to control the quality of S. china and its prepared slices more effectively,the index components of content detection should be selected reasonably.

7.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3358-3364, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602895

RESUMO

To evaluate the effect of Tripterygium Glycosides Tablets extract in the treatment of rheumatoid arthritis( RA). Clinical trials of treating rheumatoid arthritis with Tripterygium Glycosides Tablets published by Meta-analysis were retrieved from EMbase,PubMed,Clinical Trials,Web of Science,Cochrane Library,CNKI,Wanfang,VIP,CBM and Chi CTR,and comprehensively analyzed. A total of 3 studies were enrolled,the modified Sharp score( m TSS),tender join joint erosions( JE) and joint space narrowing( JSN) of Tripterygium Glycosides Tablets group were significant superior to those of control group,including positive drugs methotrexate( MTX) and salazopyridine( SSZ)( P<0. 01). Tripterygium Glycosides Tablets had an effect in treating RA. Due to the small sample size,this study shall be verified with high-quality,large-sample-size double-blinded RCTs.

9.
Environ Sci Technol ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578063

RESUMO

Although spores/pollens are so abundant and ubiquitous in the environment, the role of those natural organic matter concerning fate and transport of organic pollutants in the environment is neglected. Lipid-free (LF) fractions and sporopollenins were isolated from seven spores/pollens collected from lower and higher biota species and were characterized by elemental analysis, CO2 adsorption techniques and advanced solid-state 13C nuclear magnetic resonance (NMR) spectroscopy. Then, the sorption isotherms of phenanthrene (Phen) on all the samples were investigated by a batch technique. The sporopollenins were a highly cross-linked polymer including alkyl carbon, poly(methylene) carbon, and aromatic carbon as well as oxygen functionalities; additionally, their sorption capacities (Koc) for Phen reached up to 1,170,000 mL/g, suggesting that some of the sporopollenins were good biopolymeric sorbents for the removal of hydrophobic organic contaminants in aquatic media. A highly significant and positive correlation between the sorption capacity of Phen and the aliphaticity of the sporopollenins suggested that their structure was critical to Phen sorption. Meanwhile, the (O+N)/C atomic ratios and polar groups were significantly and negatively correlated with the sorption capacity of Phen, indicating that accessibility also played a significant role in the sorption process. Moreover, variable correlations between the sorption capacities (Koc) and the micropore volumes of the spore/pollen fractions were observed. This study sheds light on the importance of the polarity, microporosity, and structure of sporopollenin on the sorption process of Phen.

10.
Development ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597659

RESUMO

A dense local vascular network is crucial for pancreatic endocrine cells to sense metabolites and secrete hormones, and understanding the interactions between the vasculature and the islets may allow for therapeutic modulation in disease conditions. Using live imaging in two models of vascular disruption in zebrafish, we identified two distinct roles for the pancreatic vasculature. At larval stages, expression of a dominant negative version of Vegfaa (dnVegfaa) in ß-cells led to vascular and endocrine cell disruption with a minor impairment in ß-cell function. In contrast, expression of a soluble isoform of Vegf receptor 1 (sFlt1) in ß-cells blocked the formation of the pancreatic vasculature and drastically stunted glucose response while islet architecture was not affected. Notably, these effects of dnVegfaa or sFlt1 were not observed in animals lacking vegfaa, vegfab, kdrl, kdr, or flt1 function, indicating that they interfere with multiple ligands and/or receptors. In adults, disrupted islet architecture persisted in dnVegfaa expressing animals, while sFlt1 expressing animals displayed large sheets of ß-cells along their pancreatic ducts, accompanied by impaired glucose tolerance in both models. Thus, our study reveals novel roles for the vasculature in patterning and function of the islet.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31573118

RESUMO

Weaning may cause oxidative injury, immune response impairment, apoptosis and other injuries in piglets. Oxidative and endoplasmic reticulum stress (ERS) can elicit inflammatory responses, and persistent oxidative and ERS also may lead to apoptotic cascades, which is associated with the pathogenesis of multiple diseases. ß-carotene, a natural carotenoid, has potential anti-inflammatory and antioxidant functions. However, the effect of ß-carotene on apoptosis in weaned piglets and the detailed molecular mechanism remain unclear. In this study, we found that ß-carotene decreased malondialdehyde (MDA) levels and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in piglet serum. ß-carotene could inhibit the mRNA levels of caspase-3 significantly, but had no significant inhibitory effect of the mRNA levels of caspase-9 and caspase-12 in the piglet jejunum. In addition, ß-carotene decreased the activation of GRP78, CHOP, and JNK/p38 MAPK and the ratio of Bax/Bcl-2. Furthermore, ß-carotene had a significant influence on the activation of ERS and apoptosis-related signals in TG-induced IPEC-J2. In the present study, ß-carotene pre-treatment attenuated the ratio of Bax/Bcl-2 and prevented TG-induced increases in the level of PERK-CHOP and IRE1-JNK/p38 MAPK pathway activation in a dose-dependent manner. Overall, these findings indicate that ß-carotene may protect weaning-induced apoptosis through inhibiting ERS.

12.
J Orthop Sci ; 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31575498

RESUMO

BACKGROUND: Elevated high-sensitive cardiac troponin T (cTnT) is a well-known biomarker to predict cardiac events following non-cardiac surgery. However, further information regarding high-sensitive cTnT in orthopedic surgery, especially total knee arthroplasty (TKA), is not present yet. This study aims to gain further insight into the predictive value of high-sensitive cTnT in adverse cardiac events in patients accepting TKA. METHODS: We performed a prospective study in our hospital with the aim to enrolling 789 consecutive patients. Included patients who underwent TKA had mean ages of 65 years, and 64.9% were female. High-sensitive cTnT measurements were performed for study purposes before operation and on 1st postoperative days respectively. Postoperative cardiac events (POCE) 2 months and 2 years postoperatively were used to be evaluated for present study and defined short-term and long-term POCE respectively. The cut-off value of high-sensitive cTnT predicting patients at increased risks of POCE was evaluated by the Receiver Operating Characteristic (ROC) curve analysis. RESULTS: Mean preoperative, postoperative cTnT and difference value between preoperative and postoperative cTnT (D-cTnT) were 20, 32, 12 ng/L respectively. 2-month and 2-year cardiac event rate following TKA were 2.3% and 3.4%. Using difference value between preoperative and postoperative cTnT (D-cTnT) to predict short-term cardiac events, the best cut-off was 23 ng litre-1, with an AUC of 0.84 (95% CI: 0.79-0.89, p < 0.001), which was better in comparison to preoperative and postoperative cTnT. In contrast, using preoperative cTnT to predict long-term cardiac events, the best cut-off was 25 ng litre-1 with an AUC of 0.78 (95% CI: 0.73-0.83, p < 0.001), which was better in comparison to postoperative and D-cTnT. CONCLUSIONS: D-cTnT best predicted short-term POCE in comparison to preoperative and postoperative cTnT, while preoperative cTnT level best predicted long-term POCE in comparison to postoperative cTnT and D-cTnT.

13.
Theranostics ; 9(22): 6396-6411, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588225

RESUMO

Effective therapeutic targets against post-myocardial infarction (MI) arrhythmias remain to be discovered. We aimed to investigate the role of macrophages in post-MI arrhythmias. Methods: Mononuclear cell accumulation, macrophage polarization from M0 to M1 subset, and gap junction formation were analyzed in MI patients and MI mice by flow cytometry, immunofluorescence and patch clamping. Differentially expressed genes were identified by RNA sequencing. Macrophages and cardiomyocytes were cocultured in vitro, and the effects of gap junction and KCa3.1 on electrophysiological properties were assessed by patch clamping. The effects of KCa3.1 inhibition on post-MI arrhythmias were assessed by intracardiac stimulation and ambulatory electrocardiograms in vivo. Results: Percentage of pro-inflammatory mononuclear cells were significantly elevated in patients with post-MI arrhythmias compared with MI patients without arrhythmias and healthy controls (p<0.001). Macrophages formed gap junction with cardiomyocytes in MI border zones of MI patient and mice, and pro-inflammatory macrophages were significantly increased 3 days post-MI (p<0.001). RNA sequencing identified Kcnn4 as the most differentially expressed gene encoding ion channel, and the upregulation is mainly attributed to macrophage accumulation and polarization into pro-inflammatory subset. In vitro coculture experiments demonstrated that connection with M0 macrophages via gap junction slightly shortened the action potential durations (APDs) of cardiomyocytes. However, the APD90 of cardiomyocytes connected with M1 macrophages were significantly prolonged (p<0.001), which were effectively attenuated by gap junction inhibition (p=0.002), KCa3.1 inhibition (p=0.008), KCa3.1 silencing (p<0.001) and store-operated Ca2+ channel inhibition (p=0.005). In vivo results demonstrated that KCa3.1 inhibition significantly decreased the QTc durations (p=0.031), intracardiac stimulation-induced ventricular arrhythmia durations (p=0.050) and incidence of premature ventricular contractions (p=0.030) in MI mice. Conclusion: Macrophage polarization leads to APD heterogeneity and post-MI arrhythmias via gap junction and KCa3.1 activation. The results provide evidences of a novel mechanism of post-MI heterogeneous repolarization and arrhythmias, rendering macrophages and KCa3.1 to be potential therapeutic targets.

14.
Arch Pharm (Weinheim) ; : e1900129, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31478565

RESUMO

To gain further knowledge of the structure-activity relationship and druggability of novel oxazolidinone-based UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) inhibitors as Gram-negative antibacterial agents, compounds containing the hydrophobic tails with different lengths and terminal substitutions were synthesized and their antibacterial activities against standard and clinically isolated Gram-negative strains were evaluated. We summarized their structure-activity relationships and found that oxazolidinone-based compounds exhibited a narrower antibacterial spectrum compared with threonine-based compounds. Furthermore, we parallelly compared the metabolic stabilities of the compounds with the classic threonine scaffold and the novel oxazolidinone scaffold in liver microsomes. The results indicated that the druggability of the oxazolidinone scaffold may be inferior to the classic threonine scaffold in the design of LpxC inhibitors.

15.
J Cell Mol Med ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513352

RESUMO

This study aimed to determine long non-coding RNA (lncRNA) small nucleolar RNA host gene 14 (SNHG14) expression in pancreatic cancer and to explore the potential molecular actions of SNHG14 in mediating pancreatic cancer progression. Gene expression was detected by quantitative real-time PCR. Cell proliferation, growth and invasion were detected by respective CCK-8, colony formation, and transwell invasion assays. Protein levels were measured by Western blotting. Cell apoptosis and caspase-3 activity were detected by flow cytometry and caspase-3 activity assay. The link between miR-613 and its targets was evaluated by luciferase reporter assay. In vivo tumour growth was evaluated using a xenograft model of nude mice. SNHG14 expression was up-regulated in cancerous tissues from pancreatic cancer patients. High expression of SNHG14 was associated with poor tumour differentiation, advanced TNM stage and nodal metastasis. SNHG14 overexpression enhanced cell proliferative, growth and invasive abilities, and suppressed apoptotic rates and caspase-3 activity in pancreatic cancer cells, while SNHG14 knockdown exerted opposite effects. Mechanistic studies revealed that miR-613 was targeted by SNHG14, and Annexin A2 (ANXA2) was targeted and inversely regulated by miR-613 in pancreatic cancer cells. In vivo studies showed that SNHG14 knockdown attenuated tumour growth. MiR-613 was down-regulated and ANXA2 was up-regulated in the pancreatic cancer tissues, and SNHG14 expression levels were inversely correlated with miR-613 expression levels and positively correlated with the ANXA2 mRNA expression levels. Collectively, our results suggest that SNHG14 potentiates pancreatic cancer progression through modulation of annexin A2 expression via acting as a competing endogenous RNA for miR-613.

16.
Plant Sci ; 288: 110219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31521216

RESUMO

The 14-3-3 proteins are a family of highly conserved phosphoserine-binding proteins that participate in the regulation of diverse physiological and developmental processes. In this research, twenty 14-3-3 genes in apples, which contained a highly conserved 14-3-3 domain, were identified and divided into two subgroups. Among them, MdGRF11 was further cloned and investigated. qRT-PCR analyses and GUS staining show that MdGRF11 is expressed in various organs and tissues with the highest expression levels found in the fruit. MdGRF11 was upregulated by polyethylene glycol 6000 (PEG 6000), NaCl, abscisic acid (ABA) and low temperature (4 °C) treatments. MdGRF11-overexpressing transgenic Arabidopsis and apple calli exhibited reduced sensitivity to salt and PEG 6000 treatments. Moreover, the ectopic expression of MdGRF11 improved the tolerance of transgenic tobacco to salt and drought stresses, which grew longer roots, underwent more growth, and presented higher chlorophyll levels than the wild-type control under salt and drought stress conditions. Furthermore, MdGRF11 expression remarkably reduced electrolyte leakage, malondialdehyde content levels, H2O2 and O2- accumulation under salt and drought stress conditions, which relied on the regulation of ROS-scavenging signaling to reduce oxidative damage of cells after salt and drought stress treatment. MdGRF11 also enhanced tolerance to stress by upregulating expression levels of ROS-scavenging and stress-related genes, especially improving responses to drought stress by modifying the water loss rates and stomatal aperture. Moreover, MdGRF11 could interact with MdAREB/ABF transcription factors through yeast two hybrid analyses. In conclusion, our results indicate that MdGRF11 acts as a positive regulator of salt and drought stress responses through regulating ROS scavenging and other signaling systems.

17.
Med Sci Monit ; 25: 6950-6956, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31522190

RESUMO

BACKGROUND Clear cell sarcoma (CCS) of soft tissue, or malignant melanoma of soft parts, is a rare disease. We aimed to identify prognostic factors linked to patient survival in CCS by analyzing demographic and clinical features using the Surveillance, Epidemiology, and End Results (SEER) database. This study aimed to identify prognostic factors associated with CCS that would be of clinical value. MATERIAL AND METHODS We collected data from patients diagnosed with CCS between 1973 and 2009 from the SEER database. The Kaplan-Meier method and Cox regression analysis were performed to identify prognostic factors for patient survival. RESULTS A total of 175 patients with CCS were identified from the SEER database. The 5-year survival rate was 62.9%, and the 10-year survival rate was 51.3%. Patients with CCS with local stage, and with tumor size ≤3 cm were more likely to have good survival rates. CONCLUSIONS The findings from this study showed that the identifiable prognostic factors in patients with CCS were stage and tumor size. Local stage and tumor size ≤3 cm were favorable prognostic factors for patient survival in CCS.

18.
Curr Top Med Chem ; 19(15): 1276-1288, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31526339

RESUMO

C-Met, also referred to as Hepatocyte Growth Factor Receptor (HGFR), is a heterodimeric receptor tyrosine kinase. It has been determined that c-Met gene mutations, overexpression, and amplification also occur in a variety of human tumor types, and these events are closely related to the aberrant activation of the HGF/c-Met signaling pathway. Meanwhile, high c-Met expression is closely associated with poor prognosis in cancer patients. The c-Met kinase has emerged as an attractive target for developing antitumor agents. In this review, we cover the recent advances on the small molecule c-Met inhibitors discovered from 2018 until now, with a main focus on the rational design, synthesis and structureactivity relationship analysis.

19.
J Cell Biochem ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31489709

RESUMO

Transcription factors (TFs) like a nuclear factor of activated T-cells (NFAT) and its controller calcineurin are highly expressed in primary intestinal epithelial cells (IECs) due to delamination, damage by tumor-associated flora and selective activation in the intestinal tract tumor are crucial in the progression and growth of colorectal cancer (CRC). This study sought to summarize the current findings concerning the dysregulated calcineurin/NFAT (C/N) signaling involved in CRC initiation and progression. These signalings include proliferation, T-cell functions, and glycolysis with high lactate production that remodels the acidosis, which genes in tumor cells provide an evolutionary advantage, or even increased their attack phenotype. Moreover, the relationship between C/N and gut microbiome in CRC, especially role of NFAT and toll-like receptor signaling in regulating intestinal microbiota are also discussed. Furthermore, this review will discuss the proteins and genes relating to C/N induced acidosis in CRC, which includes ASIC2 regulated C/N1 and TFs associated with the glycolytic by-product that affect T-cell functions and CRC cell growth. It is revealed that calcineurin or NFAT targeting to antitumor, selective calcineurin inhibition or targets in NFAT signaling may be useful for clinical treatment of CRC. This can further aid in the identification of specific targets via cancer patient-personalized approach. Future studies should be focused on targeting to C/N or TLR signaling by the combination of therapeutic agents to regulate T-cell functions and gut microbiome for activating potent anticancer property with the prospect of potentiating the antitumor therapy for CRC.

20.
Nat Commun ; 10(1): 4039, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492864

RESUMO

Antibiotic therapy is usually not recommended for salmonellosis, as it is associated with prolonged fecal carriage without reducing symptom duration or severity. Here we show that antibiotics encapsulated in hydrogen sulfide (H2S)-responsive glycovesicles may be potentially useful for the treatment of salmonellosis. The antibiotics are released in the presence of Salmonella, which is known to produce H2S. This approach prevents the quick absorption of antibiotics into the bloodstream, allows localized targeting of the pathogen in the gut, and alleviates disease symptoms in a mouse infection model. In addition, it reduces antibiotic-induced changes in the gut microbiota, and increases the abundance of potentially beneficial lactobacilli due to the release of prebiotic xylooligosaccharide analogs.

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