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1.
Front Nutr ; 8: 680700, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621771

RESUMO

Oral nutritional (ON) products are an effective way to treat patients with type 2 diabetes mellitus (T2DM) whose gastrointestinal functions are normal. The influence of ON formula prepared with three different proteins on T2DM was studied. The hyperglycaemic mouse model using a high-fat diet (HFD) combined with an intraperitoneal injection of streptozotocin (STZ) was used to simulate T2DM. The study was done for 15 weeks using seven groups of mice: control group (CG, normal mice, and normal food), non-treated group (BG, diabetic mice, and normal food), positive control group (PG, diabetic mice, and HFD), soybean protein group (SPG, diabetic mice, and HFD), silkworm pupa protein group (SPPG, diabetic mice, and HFD), whey protein group (LPG, diabetic mice, and HFD), and whey protein combined with silkworm pupa protein group (LCSSPG, diabetic mice, and HFD). The plasma levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were analyzed on weeks 2, 10, 12, 14, and 15. The concentration of total protein (TP) and albumin (ALB) of the plasma was increased in SPG, SPPG, and PG comparing with BG (p < 0.05). The TC, TG, and LDL-C levels were decreased, and HDL-C level was increased in SPG, PG, SPPG, PG comparing with BG (p < 0.05). Blood glucose (BLG) levels were decreased 47, 34, 24, and 21% in SPG, LCSSPG, SPPG, and PG, respectively. While BLG was not significantly changed (p ≥ 0.05) in LG after 5 weeks of treatment. Overall, the data suggested that consumption of SP, SPP, LCSSPG Oral-formula may be beneficial for the treatment of T2DM.

2.
Neurochem Res ; 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34626306

RESUMO

Neuropathic pain is one of the most common conditions requiring treatment worldwide. Salidroside (SAL), a phenylpropanoid glucoside extracted from Rhodiola, has been suggested to produce an analgesic effect in chronic pain. However, whether SAL could alleviate pain hypersensitivity after peripheral nerve injury and its mode of action remains unclear. Several studies suggest that activation of the spinal NOD-like receptor protein 3 (NLRP3) inflammasome and its related proteins contribute to neuropathic pain's pathogenesis. This study investigates the time course of activation of spinal NLRP3 inflammasome axis in the development of neuropathic pain and also whether SAL could be an effective treatment for this type of pain by modulating NLRP3 inflammasome. In the chronic constriction injury (CCI) mice model, spinal NLRP3 inflammasome-related proteins and TXNIP, the mediator of NLRP3, were upregulated from the 14th to the 28th day after injury. The TXNIP and NLRP3 inflammasome-related proteins were mainly present in neurons and microglial cells in the spinal dorsal horn after CCI. Intraperitoneal injection of SAL at 200 mg/kg for 14 consecutive days starting from the 7th day of CCI injury could ameliorate mechanical and thermal hypersensitivity in the CCI model. Moreover, SAL inhibited the activation of the TXNIP/NLRP3 inflammasome axis and mitigated the neuronal loss of spinal dorsal horn induced by nerve injury. These results indicate that SAL could produce analgesic and neuroprotective effects in the CCI model of neuropathic pain.

3.
J Immunother Cancer ; 9(10)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34625514

RESUMO

BACKGROUND: Immune checkpoint (IC) blockades (ICBs) significantly improve patients' clinical outcomes with solid tumors. Because the objective response rate of single-agent ICB is limited, it is meaningful to explore the combination of ICs for immunotherapy. METHODS: RNA sequencing data of 95 newly diagnosed patients with esophageal squamous cell carcinoma (ESCC) from The Cancer Genome Atlas (TCGA) database were used to explore the prognostic significance of ICs. The results were validated by immunohistochemistry of 58 ESCC tissue samples from our clinical center. RESULTS: The results of both TCGA and validation data suggested that high expression of programmed cell death 1 ligand 1 (PD-L1), T-cell immunoglobulin and mucin-domain-containing-3 (TIM3), and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) was associated with poor overall survival (OS) of patients with ESCC. Importantly, PD-L1/TIM3 or PD-L1/TIGIT was the optimal combination for predicting poor OS and short restricted mean survival time of patients with ESCC and was an independent prognostic factor. Moreover, a nomogram model constructed by PD-L1, TIM3, and TIGIT together with the primary tumor, regional lymph node, distant metastasis stage could provide a concise and precise prediction of 1-year and 2-year OS rates and median survival time. PD-L1/TIM3 or PD-L1/TIGIT had a positive correlation with CD8+ T cells. Notably, PD-1 and TIM3/TIGIT were primarily coexpressed on CD8+ tumor-infiltrating lymphocyte in patients with ESCC by multiplexed immunofluorescence. CONCLUSION: High expression of ICs was associated with poor OS of patients with ESCC. PD-L1/TIM3 and PD-L1/TIGIT were the optimal combinations for predicting OS, which might be potential targets for future ICBs therapy of ESCC.

4.
Neural Plast ; 2021: 7031178, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659397

RESUMO

Purpose. We investigated the disparate influence of lesion location on functional damage and reorganization of the sensorimotor brain network in patients with thalamic infarction and pontine infarction. Methods. Fourteen patients with unilateral infarction of the thalamus and 14 patients with unilateral infarction of the pons underwent longitudinal fMRI measurements and motor functional assessment five times during a 6-month period (<7 days, at 2 weeks, 1 month, 3 months, and 6 months after stroke onset). Twenty-five age- and sex-matched controls underwent MRI examination across five consecutive time points in 6 months. Functional images from patients with left hemisphere lesions were first flipped from the left to the right side. The voxel-wise connectivity analyses between the reference time course of each ROI (the contralateral dorsal lateral putamen (dl-putamen), pons, ventral anterior (VA), and ventral lateral (VL) nuclei of the thalamus) and the time course of each voxel in the sensorimotor area were performed for all five measurements. One-way ANOVA was used to identify between-group differences in functional connectivity (FC) at baseline stage (<7 days after stroke onset), with infarction volume included as a nuisance variable. The family-wise error (FWE) method was used to account for multiple comparison issues using SPM software. Post hoc repeated-measure ANOVA was applied to examine longitudinal FC reorganization. Results. At baseline stage, significant differences were detected between the contralateral VA and ipsilateral postcentral gyrus (cl_VA-ip_postcentral), contralateral VL and ipsilateral precentral gyrus (cl_VL-ip_precentral). Repeated measures ANOVA revealed that the FC change of cl_VA-ip_postcentral differ significantly among the three groups over time. The significant changes of FC between cl_VA and ip_postcentral at different time points in the thalamic infarction group showed that compared with 7 days after stroke onset, there was significantly increased FC of cl_VA-ip_postcentral at 1 month, 3 months, and 6 months after stroke onset. Conclusions. The different patterns of sensorimotor functional damage and reorganization in patients with pontine infarction and thalamic infarction may provide insights into the neural mechanisms underlying functional recovery after stroke.

5.
J Med Chem ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34665631

RESUMO

Checkpoint kinase 1 (CHK1) plays an important role in the DNA damage response pathway, being a potential anti-cancer drug target. In this study, we used a strategy for trifluoromethyl substitution to obtain orally bioavailable CHK1 inhibitors to overcome the limitations of lead compound 1, which can only be administered intravenously. After detailed investigation, we identified compound 6c as an oral CHK1 inhibitor, which demonstrated a considerably higher plasma exposure in mice. Compound 6c also showed good kinase selectivity. Moreover, it exhibited a significant antiproliferative effect in MV-4-11 cells singly and a synergistic effect in combination with gemcitabine in HT-29, A549, and RPMI-8226 cells. Additionally, compound 6c could inhibit tumor growth in the MV-4-11 xenograft mouse model. The combination of 6c and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Thus, compound 6c was found to be a selective and oral potential anticancer CHK1 inhibitor.

6.
Int Immunopharmacol ; 100: 108128, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34537483

RESUMO

PURPOSE: This study aimed to test the interaction between viral infections and immune checkpoint inhibitor (ICI) efficacy for two virus-associated tumors, head and neck squamous carcinoma (HNSCC) and hepatocellular carcinoma (HCC), by conducting a systematic review and meta-analysis. METHODS: We searched databases from inception until December 30, 2020 to identify phase 2 or 3 randomized clinical trials involving ICI treatments with data on hazard ratios (HRs) for survival according to viral infection status. We evaluated the heterogeneity between patients with and without viral infections using an interaction test. Subgroup analyses were conducted to explore variations in the efficacy of immunotherapy according to viral infection status. RESULTS: Six phase 3 trials with 3672 patients (1382 with viral infections [38%] and 2115 without viral infections [57%]) were included. Among these patients, the pooled HR for survival was 0.69 (95% confidence interval [CI], 0.60-0.79) for those with viral infections and 0.84 (95% CI, 0.77-0.91) for those without infections after ICI treatment. Patients with viral infections achieved a better prognosis after ICI therapy than those without infections (P = 0.018). This was evident in patients with hepatitis B virus-associated HCC (P = 0.016), but not in patients with hepatitis C virus-associated HCC (P = 0.081) or in patients with human papillomavirus-positive HNSCC (P = 0.67). CONCLUSION: Patients with advanced HNSCC and HCC, regardless of viral infection status, could benefit from ICI treatment. Patients with hepatitis B virus-associated HCC were more likely to benefit from ICI treatment than patients without viral infections. REGISTRATION: Our systematic review protocol was registered with the International Prospective Register of Systematic Reviews on March 27, 2020 (registration number CRD42020155326).

7.
J Med Chem ; 64(19): 14647-14663, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477384

RESUMO

CDK9 is an essential drug target correlated to the development of acute myeloid leukemia (AML). Starting from the hit compound 10, which was discovered through a screening of our in-house compound library, the structural modifications were carried out based on the bioisosterism and scaffold hopping strategies. Consequently, compound 37 displayed the optimal CDK9 inhibitory activity with an IC50 value of 5.41 nM, which was nearly 1500-fold higher than compound 10. In addition, compound 37 exhibited significant antiproliferative activity in broad cancer cell lines. Further investigation of in vivo properties demonstrated that compound 37 could be orally administrated with an acceptable bioavailability (F = 33.7%). In MV-4-11 subcutaneous xenograft mouse model, compound 37 (7.5 mg/kg) could significantly suppress the tumor progression with a T/C value of 27.80%. Compound 37 represents a promising lead compound for the development of a novel class of CDK9 inhibitors for the treatment of acute myeloid leukemia.

8.
J Med Chem ; 64(19): 14822-14847, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34538051

RESUMO

Triple-negative breast cancer (TNBC) is highly aggressive with very limited treatment options due to the lack of efficient targeted therapies and thus still remains clinically challenging. Targeting transcription-associated cyclin-dependent kinases to remodel transcriptional regulation shows great promise in cancer therapy. Herein, we report the synthesis, optimization, and evaluation of new series of heterobifunctional molecules as highly selective and efficacious CDK9 degraders, enabling potent inhibition of TNBC cell growth and rapidly targeted degradation of CDK9. Moreover, the most potent CDK9 degrader (compound 45) induces cell apoptosis in vitro and inhibits tumor growth in the MDA-MB-231 TNBC model. Furthermore, the RNA-seq, immunohistochemistry assays demonstrate that the CDK9 degrader downregulates the downstream targets, such as MYC, at the transcriptional level, resulting apoptosis in TNBC cells. Our work establishes that 45 is a highly potent and efficacious CDK9 degrader for targeting transcription regulation, which represents an effective strategy and great potential as a new targeted therapy for TNBC.

9.
BMC Plant Biol ; 21(1): 442, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34587914

RESUMO

BACKGROUND: Stone-hardening stage is crucial to the development of grape seed and berry quality. A significant body of evidence supports the important roles of MicroRNAs in grape-berry development, but their specific molecular functions during grape stone-hardening stage remain unclear. RESULTS: Here, a total of 161 conserved and 85 species-specific miRNAs/miRNAs* (precursor) were identified in grape berries at stone-hardening stage using Solexa sequencing. Amongst them, 30 VvmiRNAs were stone-hardening stage-specific, whereas 52 exhibited differential expression profiles during berry development, potentially participating in the modulation of berry development as verified by their expression patterns. GO and KEGG pathway analysis showed that 13 VvmiRNAs might be involved in the regulation of embryo development, another 11 in lignin and cellulose biosynthesis, and also 28 in the modulation of hormone signaling, sugar, and proline metabolism. Furthermore, the target genes for 4 novel VvmiRNAs related to berry development were validated using RNA Ligase-Mediated (RLM)-RACE and Poly(A) Polymerase-Mediated (PPM)-RACE methods, and their cleavage mainly occurred at the 9th-11th sites from the 5' ends of miRNAs at their binding regions. In view of the regulatory roles of GA in seed embryo development and stone-hardening in grape, we investigated the expression modes of VvmiRNAs and their target genes during GA-induced grape seedless-berry development, and we validated that GA induced the expression of VvmiR31-3p and VvmiR8-5p to negatively regulate the expression levels of CAFFEOYL COENZYME A-3-O-METHYLTRANSFERASE (VvCCoAOMT), and DDB1-CUL4 ASSOCIATED FACTOR1 (VvDCAF1). The series of changes might repress grape stone hardening and embryo development, which might be a potential key molecular mechanism in GA-induced grape seedless-berry development. Finally, a schematic model of miRNA-mediated grape seed and stone-hardening development was proposed. CONCLUSION: This work identified 30 stone-hardening stage-specific VvmiRNAs and 52 significant differential expression ones, and preliminary interpreted the potential molecular mechanism of GA-induced grape parthenocarpy. GA negatively manipulate the expression of VvCCoAOMT and VvDCAF1 by up-regulation the expression of VvmiR31-3p and VvmiR8-5p, thereby repressing seed stone and embryo development to produce grape seedless berries.

10.
Theranostics ; 11(18): 8771-8796, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522211

RESUMO

The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an important post-transcriptional gene regulator, are also the subject of both basic research and clinical trials. Both siRNA and miRNA mimics are ~21 nucleotides RNA duplexes inducing mRNA silencing. Given the well performance of siRNA, researchers ask whether miRNA mimics are unnecessary or developed siRNA technology can pave the way for the emergence of miRNA mimic drugs. Through comprehensive comparison of siRNA and miRNA, we focus on (1) the common features and lessons learnt from the success of siRNAs; (2) the unique characteristics of miRNA that potentially offer additional therapeutic advantages and opportunities; (3) key areas of ongoing research that will contribute to clinical application of miRNA mimics. In conclusion, miRNA mimics have unique properties and advantages which cannot be fully matched by siRNA in clinical applications. MiRNAs are endogenous molecules and the gene silencing effects of miRNA mimics can be regulated or buffered to ameliorate or eliminate off-target effects. An in-depth understanding of the differences between siRNA and miRNA mimics will facilitate the development of miRNA mimic drugs.

11.
Front Cell Dev Biol ; 9: 710964, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485297

RESUMO

N6-methyladenosine (m6A) is a commonly modification of mammalian mRNAs and plays key roles in various cellular processes. Emerging evidence reveals the importance of RNA m6A modification in maintaining stem cell function in normal hematopoiesis and leukemogenesis. In this review, we first briefly summarize the latest advances in RNA m6A biology, and further highlight the roles of m6A writers, readers and erasers in normal hematopoiesis and acute myeloid leukemia. Moreover, we also discuss the mechanisms of these m6A modifiers in preserving the function of hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), as well as potential strategies for targeting m6A modification related pathways. Overall, we provide a comprehensive summary and our insights into the field of RNA m6A in normal hematopoiesis and leukemia pathogenesis.

12.
Sci Rep ; 11(1): 17421, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465820

RESUMO

Corona Virus Disease 2019 (COVID-19) has spread rapidly to countries all around the world from the end of 2019, which caused a great impact on global health and has had a huge impact on many countries. Since there is still no effective treatment, it is essential to making effective predictions for relevant departments to make responses and arrangements in advance. Under the limited data, the prediction error of LSTM model will increase over time, and its prone to big bias for medium- and long-term prediction. To overcome this problem, our study proposed a LSTM-Markov model, which uses Markov model to reduce the prediction error of LSTM model. Based on confirmed case data in the US, Britain, Brazil and Russia, we calculated the training errors of LSTM and constructed the probability transfer matrix of the Markov model by the errors. And finally, the prediction results were obtained by combining the output data of LSTM model with the prediction errors of Markov Model. The results show that: compared with the prediction results of the classical LSTM model, the average prediction error of LSTM-Markov is reduced by more than 75%, and the RMSE is reduced by more than 60%, the mean [Formula: see text] of LSTM-Markov is over 0.96. All those indicators demonstrate that the prediction accuracy of proposed LSTM-Markov model is higher than that of the LSTM model to reach more accurate prediction of COVID-19.


Assuntos
COVID-19/epidemiologia , Brasil/epidemiologia , Aprendizado Profundo , Humanos , Cadeias de Markov , Redes Neurais de Computação , Projetos de Pesquisa , Federação Russa/epidemiologia , Reino Unido/epidemiologia , Estados Unidos
13.
Cell Prolif ; 54(9): e13107, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34346124

RESUMO

OBJECTIVES: In recent years, cellular senescence has attracted a lot of interest in researchers due to its involvement in non-alcoholic fatty liver disease (NAFLD). However, the mechanism of cellular senescence is not clear. The purpose of this study was to investigate the effect of curcumol on hepatocyte senescence in NAFLD and the molecular mechanisms implicated. MATERIALS AND METHODS: LVG Golden Syrian hamsters, C57BL/6J mice and human hepatocyte cell line LO2 were used. Cellular senescence was assessed by analyses of senescence marker SA-ß-gal, p16 and p21, H3K9me3, γ-H2AX and telomerase activity. RESULTS: The results showed that curcumol could inhibit hepatocyte senescence in both in vivo and in vitro NAFLD models, and the mechanism might be related to its regulation of ferritinophagy and subsequent alleviation of iron overload. Moreover, overexpression of nuclear receptor coactivator 4 (NCOA4) weakened the effect of curcumol on ferritinophagy-mediated iron overload and cellular senescence. Furthermore, we demonstrated that curcumol reduced the expression of NCOA4 by Yes-associated protein (YAP). In addition, depression of YAP could impair the effect of curcumol on iron overload and cellular senescence. CONCLUSION: Our results clarified the mechanism of curcumol inhibition of hepatocyte senescence through YAP/NCOA4 regulation of ferritinophagy in NAFLD. These findings provided a promising option of curcumol to regulate cellular senescence by target YAP/NCOA4 for the treatment of NAFLD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Ferritinas/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Coativadores de Receptor Nuclear/metabolismo , Sesquiterpenos/farmacologia , Animais , Linhagem Celular , Hepatócitos/metabolismo , Humanos , Ferro/metabolismo , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo
14.
Emerg Microbes Infect ; 10(1): 1638-1648, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34346827

RESUMO

MW33 is a fully humanized IgG1κ monoclonal neutralizing antibody, and may be used for the prevention and treatment of coronavirus disease 2019 (COVID-19). We conducted a randomized, double-blind, placebo-controlled, single-dose, dose-escalation Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of MW33. Healthy adults aged 18-45 years were sequentially enrolled into the 4, 10, 20, 40, and 60 mg/kg dose groups and infused with MW33 over 60 ± 15 min and followed for 85 days. All 42 enrolled participants completed the MW33 infusion, and 40 participants completed the 85-day follow-up period. 34 participants received a single infusion of 4 (n = 2), 10 (n = 8), 20 (n = 8), 40 (n = 8), and 60 mg/kg (n = 8) of MW33. 27 subjects in the test groups experienced 78 adverse events (AEs) post-dose, with an incidence of 79.4% (27/34). The most common AEs included abnormal laboratory test results, vascular and lymphatic disorders, and infectious diseases. The severity of AEs was mainly Grade 1 (92 AEs), and three Grade 2 and one Grade 4. The main PK parameters, maximum concentration (Cmax), and area under the concentration-time curve (AUC0-t, and AUC0-∞) in 34 subjects showed a linear kinetic relationship in the range of 10-60 mg/kg. The plasma half-life was approximately 25 days. The positive rates of serum ADAs and antibody titres were low with no evidence of an impact on safety or PK. In conclusion, MW33 was well-tolerated, demonstrated linear PK, with a lower positive rate of serum ADAs and antibody titres in healthy subjects.Trial registration: ClinicalTrials.gov identifier: NCT04427501.Trial registration: ClinicalTrials.gov identifier: NCT04533048.Trial registration: ClinicalTrials.gov identifier: NCT04627584.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , SARS-CoV-2/efeitos dos fármacos , Adulto , COVID-19/diagnóstico , COVID-19/imunologia , Análise de Dados , Feminino , Humanos , Masculino , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
15.
J Sci Food Agric ; 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34329497

RESUMO

BACKGROUND: Although the grape berries are deliberated as a non-climacteric fruit, ethylene seems to be involved in grape berry ripening. However, the precise role of ethylene in regulating the ripening of non-climacteric fruits is poorly understood. RESULTS: Exogenous ethephon (ETH) can stimulate the concentration of internal ethylene and accelerate the accumulation of anthocyanins in berries of 'Fujiminori', including malvidin-, delphinidin-, and petunidin-derivatives (3',4',5'-trihydroxylated anthocyanins) and cyanidin-derivatives (3',4'-dihydroxylated anthocyanins). The content of 3',4',5'-trihydroxylated anthocyanins was extremely higher than 3',4'-dihydroxylated anthocyanins, and ethylene did not affect the composition of anthocyanins in grape. Furthermore, we observed the expression of anthocyanin structural and regulatory genes as well as ethylene biosynthesis and response genes in response to ETH treatment. The anthocyanins accumulation is significantly associated with increased expression of anthocyanin structural (VvPAL, Vv4CH, VvCHS, VvCHI, VvF3H, and VvUFGT) and regulatory genes (VvMYBA1, VvMYBA2, and VvMYBA3), which persisted over the 12 days. In addition, exogenous ETH affected the endogenous ethylene biosynthesis (VvACO2 and VvACO4) and the downstream ethylene regulatory network (VvERS1, VvETR2, VvCTR1, and VvERF005). CONCLUSIONS: These findings bring new insights into the physiological and molecular function of ethylene during berry development and ripening in grapes. © 2021 Society of Chemical Industry.

16.
Cancer Sci ; 112(10): 4176-4186, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34327778

RESUMO

As a POU homeodomain transcription factor, POU4F2 has been implicated in regulating tumorigenic processes in various cancers. However, the role of POU4F2 in colorectal cancer (CRC) remains unclear. Here, we revealed that POU4F2 functions as a tumor promotor in CRC. Bioinformatics analysis in specimens from CRC patients and expression analysis in CRC cell lines showed that POU4F2 was upregulated at the mRNA and protein levels in CRC. Depletion of POU4F2 suppressed the metastatic phenotypes of CRC cells, including cell migration, invasion, and the expression of epithelial-mesenchymal transition (EMT) markers. Moreover, depletion of POU4F2 decreased the number of lung metastatic nodes in nude mice. Mechanistically, POU4F2 positively regulated the Hedgehog signaling pathway, as inferred from the downregulation of the expression of sonic Hedgehog homolog, patched 1, Smoothened, and GLI family zinc finger 1 in vitro and vivo following silencing of POU4F2. Furthermore, the SMO agonist SAG reversed the effects of POU4F2 knockdown in CRC. Functionally, POU4F2 contributed to the Hedgehog signaling-regulated activation of the EMT process and promotion of CRC cell migration and invasion. Collectively, these findings elucidated the role of POU4F2 as a tumor promotor in CRC through the regulation of Hedgehog signaling-mediated EMT and suggested that POU4F2 suppression might be a promising therapeutic target in inhibiting CRC metastasis.


Assuntos
Movimento Celular , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Proteínas Hedgehog/metabolismo , Invasividade Neoplásica , Fator de Transcrição Brn-3B/fisiologia , Animais , Linhagem Celular Tumoral , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/patologia , Cicloexilaminas/farmacologia , Regulação para Baixo , Inativação Gênica , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular , Receptor Patched-1/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Receptor Smoothened/agonistas , Receptor Smoothened/metabolismo , Tiofenos/farmacologia , Fator de Transcrição Brn-3B/antagonistas & inibidores , Fator de Transcrição Brn-3B/genética , Fator de Transcrição Brn-3B/metabolismo , Regulação para Cima , Dedos de Zinco
17.
Drug Des Devel Ther ; 15: 2899-2905, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262257

RESUMO

Purpose: To evaluate the administration regimen of ceftazidime/avibactam (CZA) for bloodstream infections caused by Enterobacteriaceae and Pseudomonas aeruginosa. Methods: The minimal inhibitory concentrations (MICs) of CZA against Enterobacteriaceae and P. aeruginosa isolated from blood cultures at member hospitals in BRICS (Blood Bacterial Resistant Investigation Collaborative System) in 2019 were determined by broth micro-dilution methodology. A 10,000-patient Monte Carlo simulation (MCS) was used to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) for different CZA dosage regimens to evaluate their efficacies and optimize the best initial dosage regimen. Results: Altogether, 6487 Enterobacteriaceae and P. aeruginosa strains were isolated from the blood cultures. The overall CZA resistance rate was 2.31%, of which the Enterobacteriaceae and P. aeruginosa rates were 1.57% and 14.29%, respectively. The MCS showed that the greater the MIC value, the worse the therapeutic effect. When the CZA MIC was ≤8 mg/L, the standard dose (2.5g iv q8h) achieved 90% PTA in the subset of patients with creatinine clearance (CrCl) values from 51 to 120 mL/min. Although the high-dose regimen (3.75g iv q8h) achieved 90% PTA in patients with CrCl values from 121 to 190 mL/min, implementing the low-dose regimen (1.25g iv q8h) was also effective for patients in the 51-89 mL/min CrCl range. Generally, the high-dose regimen (3.75g iv q8h) reached 90% CFR against all of the strains. Conversely, in patients with CrCl values of 121-190 mL/min, the standard dose (2.5g iv q8h) failed to reach 90% CFR against some Enterobacteriaceae members and P. aeruginosa. When the dose was reduced to the low-dose regimen (1.25g iv q8h), no patients reached 90% CFR against some Enterobacteriaceae members and P. aeruginosa. Conclusion: CZA has good antibacterial activity against Enterobacteriaceae and P. aeruginosa in bloodstream infections. Clinicians could make individualized treatment regimens in accordance with the sensitivity of the strains and the level of renal function in their patients to best predict the drug-related clinical responses.

18.
ACS Omega ; 6(25): 16259-16265, 2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34235295

RESUMO

The potential therapeutic application of oligonucleotides (ONs) that selectively suppress target genes through antisense and RNA interference mechanisms has attracted great attention. The clinical applications of ONs have overcome multiple obstacles and become one of the most active areas for the development of novel therapeutics. To achieve efficient and specific cellular internalization, conjugation of a variety of functional groups to ONs has been the subject of intensive investigations over the past decade. Among them, a promising liver-targeted N-acetylgalactosamine (GalNAc) ligand has been evaluated in multiple preclinical and clinical trials for improving the cellular uptake and tissue specific delivery of ONs. GalNAc-based delivery relies on the fact that liver hepatocytes abundantly and specifically express the asialoglycoprotein receptor that binds and uptakes circulating glycoproteins via receptor-mediated endocytosis. In recent years, encouraging progress has been made in the field of GalNAc conjugates. This review aims to provide an overview of GalNAc-mediated liver-targeted delivery of small interfering RNA and antisense oligonucleotides, and the immense effort as well as recent advances in the development of GalNAc-conjugated agents are described.

19.
ACS Omega ; 6(27): 17255-17266, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34278112

RESUMO

Coal spontaneous combustion (CSC) often occurs in environments that are poorly ventilated or under lean-oxygen environments in coal mines or coal seam outcrops. The understanding of the thermodynamic properties of CSC under lean-oxygen conditions is important to avoid safety and environmental problems. In this paper, the mass variation and critical temperature (the minimum temperature required for coal reaction in each stage) of six coals during CSC under lean-oxygen conditions were investigated using thermogravimetric methods. Furthermore, the thermodynamics parameters and kinetic compensation processes during CSC under lean-oxygen conditions were analyzed. The results showed that the oxidation and combustion of coal under lean-oxygen conditions was affected by the coal rank and oxygen concentration. The increase in the critical temperature was more significant when the oxygen concentration was reduced from 10 to 5%. The mechanism functions most likely to cause CSC at different oxygen concentrations were similar. The reaction mechanisms of high-rank coals at a low-temperature oxidation stage were more influenced by oxygen concentration than low-rank coals. Evaluations of kinetic behavior showed that activation energy decreased in a linear manner as the oxygen concentration decreased. The mathematical relationship between the activation energy and the pre-exponential factor indicated that there was a kinetic compensation process during CSC under lean-oxygen conditions. It is also worth noting that the effect of the coal rank on the thermodynamic characteristics of CSC is better than that of oxygen concentration. This work is helpful for enhancing the prediction and prevention of CSC.

20.
Nano Lett ; 21(14): 5998-6004, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34251198

RESUMO

Topological matter plays a central role in today's condensed matter research. Zirconium pentatelluride (ZrTe5) has attracted attention as a Dirac semimetal at the boundary of weak and strong topological insulators (TI). Few-layer ZrTe5 is anticipated to exhibit the quantum spin Hall effect due to topological states inside the band gap, but sample degradation inflicted by ambient conditions and processing has so far hampered the fabrication of high quality devices. The quantum Hall effect (QHE), serving as the litmus test for 2D systems to be considered of high quality, has not been observed so far. Only a 3D variant on bulk was reported. Here, we succeeded in preserving the intrinsic properties of thin films lifting the carrier mobility to ∼3500 cm2 V-1 s-1, sufficient to observe the integer QHE and a bulk band gap related zero-energy state. The magneto-transport results offer evidence for the gapless topological states within this gap.

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