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2.
Menopause ; Publish Ahead of Print2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33438891

RESUMO

OBJECTIVE: To evaluate the effects of sex hormones on amplitude of low-frequency fluctuation (ALFF) in brain regions related to cognition in perimenopausal women. METHODS: This cross-sectional study involved 25 perimenopausal women and 25 premenopausal women who underwent behavioral evaluations, sex hormone level measurements, and functional magnetic resonance imaging (fMRI). All data and ALFF analyses were preprocessed using the Data Processing Assistant for Resting-State fMRI. Statistical analyses were performed using the Resting-State fMRI Data Analysis Toolkit to explore the differences in ALFF between perimenopausal and premenopausal women. The gray matter volume (GMV) values extracted from brain regions (regions of interest) with significantly different ALFF values between the perimenopausal and premenopausal groups were compared. We analyzed the correlations of the ALFF and GMV values of these regions of interest with the results of behavioral evaluations and sex hormone levels in the two groups. RESULTS: Compared with the premenopausal group, the perimenopausal group showed significant ALFF increase in the left gyrus rectus. Regions with decreased ALFF in the perimenopausal group included the left superior temporal gyrus, left inferior frontal gyrus, and left insula. The GMV values of the left gyrus rectus and left superior temporal gyrus were reduced in perimenopausal women. Furthermore, the estradiol level was negatively correlated with the ALFF value of the left gyrus rectus in perimenopausal women. CONCLUSIONS: The ALFF and GMV values of certain brain regions related to cognitive function were changed in perimenopausal women. Such functional brain alterations may provide more information regarding the mechanism of cognitive dysfunction in perimenopausal women.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33403738

RESUMO

AIM: To investigate the safety and feasibility of taking low-concentration carbohydrate solution at 2 h before induction of anesthesia for gestational diabetes mellitus (GDM) patients. METHODS: GDM patients undergoing cesarean section were randomly assigned to experimental group (n = 43) and control group (n = 42). Two hours before induction of anesthesia, participants in experimental group orally received 300 mL low-concentration carbohydrate solution, while those in control group received equivalent warm water. Blood glucose and serum insulin were measured at 2 h before induction of anesthesia, right before induction of anesthesia, and the morning of postoperative day 1. Neonatal blood glucose level was monitored at birth. Maternal gastrointestinal function and well-being were assessed perioperatively. RESULTS: The levels of blood glucose and serum insulin right before induction of anesthesia in the experimental group were significantly higher than those in the control group. There were four cases with hypoglycemia in the experimental group and 19 cases in the control group right before induction of anesthesia (9.3% vs 45.2%, p < 0.001). The incidence of neonatal hypoglycemia was 2.3% in the experimental group and 7.1% in the control group with no significance. Hunger score of the participants between the two groups right before induction of anesthesia was significantly different. No aspiration, nausea, and vomiting occurred in both groups before, during, and after surgery. No significant difference was found in the time to the first flatus and abdominal distension between the two groups. CONCLUSION: Taking low-concentration carbohydrate solution is safe and feasible for patients with GDM undergoing elective cesarean section.

4.
J Cell Mol Med ; 25(2): 1001-1011, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33314748

RESUMO

Cardiac fibrosis, featuring abnormally elevated extracellular matrix accumulation, decreases tissue compliance, impairs cardiac function and accelerates heart failure. Mounting evidence suggests that the ubiquitin proteasome pathway is involved in cardiac fibrosis. In the present study, ubiquitin-specific protease 2 (USP2) was identified as a novel therapeutic target in cardiac fibrosis. Indeed, USP2 expression was increased in angiotensin II-induced primary cardiac fibroblasts (CFs) from neonatal rats. In addition, USP2 inhibition suppressed CFs proliferation, collagen synthesis and cell cycle progression. Furthermore, USP2 interacted with ß-catenin, thereby regulating its deubiquitination and stabilization in CFs. To sum up, these findings revealed that USP2 has a therapeutic potential for the treatment of cardiac fibrosis.

5.
Am J Cancer Res ; 10(11): 3721-3736, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33294263

RESUMO

Breast cancer (BCa) has the highest incidence and mortality among malignant diseases in female worldwide. BCa is frequently caused by estrogen receptor α (ERα), a ligand-dependent receptor that highly expressed in about 70% of breast tumors. Therefore, ERα has become a well-characterized and the most effective target for treating ERα-expressing BCa (ERα+ BCa). However, the acquire resistance was somehow developed in patients who received current ERα signaling-targeted endocrine therapies. Hence, discovery of novel anti-estrogen/ERα strategies is urgent. In the present study, we identified butein as a potential agent for breast cancer treatment by the use of a natural product library. We showed that butein inhibits the growth of ERα+ BCa both in vitro and in vivo which is associated with cell cycle arrest that partially triggered by butein-induced ERα downregulation. Mechanically, butein binds to a specific pocket of ERα and promotes proteasome-mediated degradation of the receptor. Collectively, this work reveals that butein is a candidate to diminish ERα signaling which represents a potentially novel strategy for treating BCa.

6.
NPJ Precis Oncol ; 4(1): 33, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303906

RESUMO

The correlations between microbiota dysbiosis and cancer have gained extensive attention and been widely explored. As a leading cancer diagnosis worldwide, lung cancer poses a great threat to human health. The healthy human lungs are consistently exposed to external environment and harbor a specific pattern of microbiota, sharing many key pathological and physiological characteristics with the intestinal tract. Although previous findings uncovered the critical roles of microbiota in tumorigenesis and response to anticancer therapy, most of them were focused on the intestinal microbiota rather than lung microbiota. Notably, the considerable functions of microbiota in maintaining lung homeostasis should not be neglected as the microbiome dysbiosis may promote tumor development and progression through production of cytokines and toxins and multiple other pathways. Despite the fact that increasing studies have revealed the effect of microbiome on the induction of lung cancer and different disease status, the underlying mechanisms and potential therapeutic strategies remained unclear. Herein, we summarized the recent progresses about microbiome in lung cancer and further discussed the role of microbial communities in promoting lung cancer progression and the current status of therapeutic approaches targeting microbiome to alleviate and even cure lung cancer.

7.
Aging (Albany NY) ; 12(24): 26121-26139, 2020 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-33373319

RESUMO

Isoflurane (ISO) elicits protective effects on ischemia-induced brain injury. We investigated whether sub-anesthetic (0.7%) ISO post-conditioning attenuates the inflammation and apoptosis in oxygen-glucose deprivation (OGD)-insulted co-cultures (microglia and neurons) in vitro and the brain injury of the middle cerebral arterial occlusion (MCAO) rat. We demonstrated that ISO augmented the viability of OGD-treated microglia and neurons. ISO reduced the expression and activation of COX2 and iNOS in OGD-challenged microglia. ISO repressed the production of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-8, and monocyte chemoattractant protein-1 in OGD-exposed microglia. ISO also decreased nucleosomal fragmentation and caspase-3 activity but increased mitochondrial membrane potential in OGD-stimulated microglia and neurons. Mechanistically, ISO suppressed OGD-induced microglial inflammation by blocking ROS-regulated p38 MAPK/NF-κB signaling pathway and hampered OGD-triggered microglial apoptosis in a ROS- or NO-dependent fashion. In vivo results with MCAO rats were partly consistent with the in vitro observation. These findings indicate that sub-anesthetic ISO post-conditioning abates the inflammation and apoptosis in OGD-stimulated rat microglia and the apoptosis of OGD-exposed neurons and the brain injuries of MCAO rats, suggesting it as a potentially effective therapeutic approach for ischemic brain damages.

8.
BMC Infect Dis ; 20(1): 949, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33308190

RESUMO

BACKGROUND: Intracranial infection after puncture of cerebral hematoma in patients with intracerebral hemorrhage is very common in the department of neurosurgery, yet the relevant risks remain unknown. We attempted to analyze the risk factors of intracranial infection after puncture of cerebral hematoma, to provide insights into the management of patients with intracerebral hemorrhage after puncture of cerebral hematoma. METHODS: Patients with intracerebral hemorrhage after puncture of cerebral hematoma treated in our hospital from January 2017 to January 2020 were selected, the related characteristics of intracranial infection and no infection patients were compared. Logistic regression analyses were conducted to analyze the risk factors for intracranial infection after puncture of cerebral hematoma. RESULTS: A total of 925 patients with puncture of cerebral hematoma were included. The incidence of postoperative intracranial infection was 7.03%. There were significant statistical differences between the infected group and the no infection group in the American Association of Anesthesiologists (ASA) grade, length of hospital stay, consecutive operation, duration of surgery, extra-ventricular drainage (EVD) use (all p < 0.05). There was statistically significant difference in the duration of EVD between the infection and no infection groups (p = 0.002), and there was no significant difference in the frequency of EVD insertion between the two groups (p = 0.094). The length of hospital stay≥10 days (OR1.832, 1.062-3.158), consecutive operation (OR2.158, 1.358-3.430), duration of surgery≥4 h (OR1.581, 1.031-2.425), EVD use (OR1.694, 1.074-2.670), and duration of EVD ≥ 7 days (OR2.699, 1.689-4.311) were the risk factors of intracranial infection in patients with intracerebral hemorrhage after puncture of cerebral hematoma (all p < 0.05). CONCLUSION: Clinical medical workers should take corresponding preventive measures against the different risk factors for prevention of intracranial infection in patient with puncture of cerebral hematoma.


Assuntos
Hemorragia Cerebral/cirurgia , Hematoma/cirurgia , Procedimentos Neurocirúrgicos/efeitos adversos , Punções/efeitos adversos , Infecção da Ferida Cirúrgica/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Infecção da Ferida Cirúrgica/prevenção & controle , Resultado do Tratamento , Adulto Jovem
9.
Aging (Albany NY) ; 12(22): 22892-22905, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33197885

RESUMO

Foam cell formation process is involved in the pathogenesis of atherosclerosis (AS). Activation of this biological process depends on lipid uptake by scavenger receptors, such as CD36, SR-A and SR-B1. Among these receptors, CD36 is the principal one because it dominates roughly 50% lipid uptake in monocytes. In this study, our western blotting and RT-qPCR assays revealed that USP10 inhibition promotes the degradation of CD36 protein but does not change its mRNA level. In addition, Co-IP results showed that USP10 interacts with CD36 and stabilizes CD36 protein by cleaving poly-ubiquitin on CD36. Significantly, USP10 promotes foam cell formation. Immunofluorescence and Oil red O staining assays show that inhibition or knockdown of USP10 suppresses lipid uptake and foam cell formation by macrophages. In conclusion, USP10 promotes the development and progression of atherosclerosis through stabilizing CD36 protein expression. The regulation of USP10-CD36 may provide a significant therapeutic scheme in atherosclerosis.

10.
Medicine (Baltimore) ; 99(46): e23110, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181678

RESUMO

Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) might be benefited from nephron-sparing surgery. Contrast-enhanced computed tomography is used for the diagnosis of MCRNLMP but contrast-enhanced ultrasound has lack of nephrotoxicity and several advantages over contrast-enhanced computed tomography and contrast-enhanced magnetic resonance. The purpose of the study was to compare diagnostic parameters of preoperative contrast-enhanced ultrasound against contrast-enhanced computed tomography for the detection of MCRNLMP in patients who faced curative surgery for complex cystic renal mass.Data regarding contrast-enhanced ultrasound, contrast-enhanced computed tomography, and clinicopathological results of 219 patients who underwent curative surgery for complex cystic renal mass (Bosniak classification III or IV) were retrospectively collected and analyzed. Bosniak classification for imaging modality and the 2016 WHO criteria for clinic pathology were used for detection of MCRNLMP.Contrast-enhanced ultrasound, contrast-enhanced computed tomography, and clinicopathology were detected 68, 66, and 67 as a MCRNLMP respectively. Contrast-enhanced ultrasound and contrast-enhanced computed tomography had 30.37% and 29.27% sensitivities for the detection of MCRNLMP. While 60% and 50% specificities respectively. Bosniak classification III (P = .045) and lower mean Hounsfield unit (P = .049) were associated with the prevalence of MCRNLMP. Contrast-enhanced computed tomography was detected 6 and 7, while contrast-enhanced ultrasound detected 3 and 2 complex cystic renal mass as false positive and false negative MCRNLMP respectively. A contrast-enhanced ultrasound had 0.011 to 1.0 diagnostic confidence and contrast-enhanced computed tomography had 0.045 to 0.983 diagnostic confidence for decision making of nephron-sparing surgeries.Contrast-enhanced ultrasound may have better visualization of MCRNLMP than contrast-enhanced computed tomography.Level of Evidence: III.


Assuntos
Carcinoma de Células Renais , Aumento da Imagem/métodos , Neoplasias Renais , Rim/diagnóstico por imagem , Compostos Organometálicos/farmacologia , Fosfolipídeos/farmacologia , Hexafluoreto de Enxofre/farmacologia , Tomografia Computadorizada por Raios X/métodos , Ultrassonografia/métodos , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/cirurgia , Tomada de Decisão Clínica , Pesquisa Comparativa da Efetividade , Meios de Contraste/farmacologia , Precisão da Medição Dimensional , Feminino , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia/métodos , Tratamentos com Preservação do Órgão/métodos
11.
Front Pharmacol ; 11: 586616, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192529

RESUMO

Tanshinone IIA (Tan IIA) is a major active ingredient extracted from Salvia miltiorrhiza, which has been proved to be able to inhibit metastasis of various cancers including colorectal cancer (CRC). However, the mechanisms of anti-metastatic effect of Tan IIA on CRC are not well explored. A number of studies indicate that epithelial-to-mesenchymal transition (EMT) plays an important role in CRC metastasis, and our previous studies demonstrate that ß-arrestin1could regulate EMT in CRC partly through ß-catenin signaling pathway. In this work, we investigate whether Tan IIA could regulate EMT in CRC through ß-arrestin1-mediated ß-catenin signaling pathway both in vivo and in vitro. Our results showed that Tan IIA inhibited lung metastases of CRC cells in vivo and extended the survival time of mice with CRC. In vitro, Tan IIA increased the expression of E-cadherin, decreased the expression of Snail, N-cadherin and Vimentin, thus suppressed EMT and the migratory ability of CRC cells. Further study found that the mechanism of action of Tan IIA in regulating EMT and metastasis is associated with the suppression of ß-arrestin1 expression, resulting in the increase of GSK-3ß expression, reduction of ß-catenin nuclear localization, thereby decreased the activity of ß-catenin signaling pathway. Our data revealed a new mechanism of Tan IIA on the suppression of EMT and metastasis in CRC via ß-arrestin1-mediated ß-catenin signaling pathway and provided support for using Tan IIA as anti-metastatic agents in CRC.

12.
Front Cell Dev Biol ; 8: 547314, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072741

RESUMO

The COVID-19 pandemic has been a global threat. Through rapid and effective surveillance and control, the newly confirmed patients have been fluctuated at a very low level and imported case explained most of them through March, 2020 to the present, indicating China's response has achieved a stage victory. By contrast, the epidemic of COVID-19 in other countries out of China is bursting. Different countries are adopting varied response strategy in terms of their public health system to prevent the spread. Herd immunity has been a hot topic since the outbreak of COVID-19 pandemic. Can it be a possible strategy to combat COVID-19? To fully interpret the knowledge regarding the term upon the background of COVID-19-related health crisis, we aim to systematically review the definition, describe the effective measures of acquiring herd immunity, and discuss its feasibility in COVID-19 prevention. Findings from this review would promote and strengthen the international cooperation and joint efforts when confronting with COVID-19.

13.
Iran J Biotechnol ; 18(1): e2259, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32884955

RESUMO

Background: Vibrio Splendidus Vs is an important aquaculture pathogen that can infect a broad host of marine organisms. In our previous study, an antagonistic bacterium Vibrio sp. V33 that possessed inhibitory effects on the growth and virulence of a pathogenic isolate V. splendidus Vs was identified. Objectives: Here, we further explored the antagonistic substances and antagonistic effects from the viewpoint of iron competition. Materials and Methods: The main antagonistic substances in the supernatants from Vibrio sp. V33 were identified using the bioassay-guided method. The response of V. splendidus Vs under the challenge of cell-free supernatant from Vibrio sp. V33 was determined via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and real-time reverse-transcription PCR. Results: The main antagonistic substances produced by Vibrio sp. V33 have low molecular weights, are water soluble, and are heat-stable substances. Meanwhile, the iron uptake rate of Vibrio sp. V33 was higher than that of V. splendidus Vs. In the presence of cell-free supernatant from Vibrio sp. V33, expressions of two functional genes, viuB and asbJ related to ferric uptake processes in V. splendidus Vs, were up-regulated, whereas furVs coding the ferric uptake repressor was suppressed below 0.5-fold. One gene coding phosphopyruvate hydratase does not change at mRNA level, but was up-regulated at protein level. Conclusions: Our results suggested that antagonistic effect of Vibrio sp. V33 on the pathogenic isolate V. splendidus Vs was partially due to the stronger ability of Vibrio sp. V33 to seize iron. This cell-free supernatant from Vibrio sp. V33 created an iron-limited milieu for V. splendidus Vs, which led to the changed expression profiles of genes that were related to iron uptake in V. splendidus Vs.

14.
PLoS Pathog ; 16(9): e1008328, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32936835

RESUMO

Candida albicans cells depend on the energy derived from amino acid catabolism to induce and sustain hyphal growth inside phagosomes of engulfing macrophages. The concomitant deamination of amino acids is thought to neutralize the acidic microenvironment of phagosomes, a presumed requisite for survival and initiation of hyphal growth. Here, in contrast to an existing model, we show that mitochondrial-localized NAD+-dependent glutamate dehydrogenase (GDH2) catalyzing the deamination of glutamate to α-ketoglutarate, and not the cytosolic urea amidolyase (DUR1,2), accounts for the observed alkalization of media when amino acids are the sole sources of carbon and nitrogen. C. albicans strains lacking GDH2 (gdh2-/-) are viable and do not extrude ammonia on amino acid-based media. Environmental alkalization does not occur under conditions of high glucose (2%), a finding attributable to glucose-repression of GDH2 expression and mitochondrial function. Consistently, inhibition of oxidative phosphorylation or mitochondrial translation by antimycin A or chloramphenicol, respectively, prevents alkalization. GDH2 expression and mitochondrial function are derepressed as glucose levels are lowered from 2% (~110 mM) to 0.2% (~11 mM), or when glycerol is used as primary carbon source. Using time-lapse microscopy, we document that gdh2-/- cells survive, filament and escape from primary murine macrophages at rates indistinguishable from wildtype. In intact hosts, such as in fly and murine models of systemic candidiasis, gdh2-/- mutants are as virulent as wildtype. Thus, although Gdh2 has a critical role in central nitrogen metabolism, Gdh2-catalyzed deamination of glutamate is surprisingly dispensable for escape from macrophages and virulence. Consistently, using the pH-sensitive dye (pHrodo), we observed no significant difference between wildtype and gdh2-/- mutants in phagosomal pH modulation. Following engulfment of fungal cells, the phagosomal compartment is rapidly acidified and hyphal growth initiates and sustained under consistently acidic conditions within phagosomes. Together, our results demonstrate that amino acid-dependent alkalization is not essential for hyphal growth, survival in macrophages and hosts. An accurate understanding of the microenvironment within macrophage phagosomes and the metabolic events underlying the survival of phagocytized C. albicans cells and their escape are critical to understanding the host-pathogen interactions that ultimately determine the pathogenic outcome.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Drosophila melanogaster/imunologia , Glutamato Desidrogenase/metabolismo , Macrófagos/imunologia , Aminoácidos/genética , Aminoácidos/metabolismo , Animais , Candida albicans/patogenicidade , Candidíase/metabolismo , Candidíase/microbiologia , Drosophila melanogaster/metabolismo , Drosophila melanogaster/microbiologia , Feminino , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Glutamato Desidrogenase/genética , Interações Hospedeiro-Patógeno , Concentração de Íons de Hidrogênio , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Nitrogênio , Fagossomos/imunologia , Fagossomos/metabolismo , Fagossomos/microbiologia , Virulência
15.
Cell Death Dis ; 11(8): 636, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32801299

RESUMO

Atherosclerosis-associated cardiovascular diseases are main causes leading to high mortality worldwide. Macrophage-derived foam cell formation via uptaking modified lipoproteins is the initial and core step in the process of atherosclerosis. Meanwhile, scavenger receptor is indispensable for the formation of foam cells. UCHL1, a deubiquitinase, has been widely studied in multiple cancers. UCHL1 could be an oncogene or a tumor suppressor in dependent of tumor types. It remains unknown whether UCHL1 influences cellular oxLDL uptake. Herein we show that UCHL1 deletion significantly inhibits lipid accumulation and foam cell formation. Subsequently, we found that UCHL1 inhibitor or siRNA downregulates the expression of CD36 protein whereas SR-A, ABCA1, ABCG1, Lox-1, and SR-B1 have no significant change. Furthermore, the treatment of UCHL1 inhibition increases the abundance of K48-polyubiquitin on CD36 and the suppression of lipid uptake induced by UCHL1 deficiency is attenuated by blocking CD36 activation. Our study concluded that UCHL1 deletion decreases foam cell formation by promoting the degradation of CD36 protein, indicating UCHL1 may be a potential target for atherosclerosis treatment.

16.
Recent Pat Anticancer Drug Discov ; 15(3): 257-269, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32679021

RESUMO

BACKGROUND: Maintenance chemotherapeutic regimen with low toxicity is needed for metastatic colorectal cancer. A recent patent has been issued on the spleen-strengthening and detoxification prescription (JPJDF), a traditional Chinese herbal medicinal formula with anti-angiogenesis effect. The clinical effect of JPJDF on the maintenance treatment of advanced colorectal cancer has not been evaluated. OBJECTIVE: This study aims to evaluate the effectiveness and safety of JPJDF in combination with fluoropyrimidine compared to fluoropyrimidine alone as maintenance therapy for metastatic colorectal cancer. METHODS: We applied a prospective, randomized, double-blinded, single center clinical study design. A total of 137 patients with advanced colorectal cancer were recruited. Patients received either Fluoropyrimidine (Flu-treated group, n = 68), or Fluoropyrimidine plus JPJDF (Flu-F-treated group, n = 69) as maintenance treatment after 6-cycle of FOLFOX4 or FOLFORI induction treatment. The primary endpoints were Progression-Free Survival (PFS) and Overall Survival (OS). The secondary endpoints were safety, Performance Status (PS) score and other symptoms. RESULTS: The endpoint of disease progression was observed in 91.7% of patients. The PFS was 5.0 months and 3.0 months in the Flu-F-treated and Flu-treated groups, respectively. The OS was 15.0 months and 9.0 months in the Flu-F-treated and Flu-treated groups, respectively. Some common symptoms, such as hypodynamia, anepithymia, dizziness and tinnitus and shortness of breath, were improved in the Flu-F-treated group. There was no significant difference in the common adverse reactions between the two groups. CONCLUSION: JPJDF and fluoropyrimidine have synergistic effect in the maintenance treatment of mCRC.

17.
Int J Biol Sci ; 16(12): 2192-2204, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32549765

RESUMO

The incidence and mortality of breast cancer (BCa) are the highest among female cancers. There are approximate 70% BCa that are classified as estrogen receptor alpha (ERα) positive. Therefore, targeting ERα is the most significantly therapeutic schedule. However, patients with breast cancer develop resistance to ERα or estrogen (E2) antagonists such as fulvestrant and tamoxifen. In the present study, we found that L-Tetrahydropalmatine (L-THP) significantly suppressed cell proliferation in ERα+ BCa cells via inducing cell cycle arrest rather than apoptosis. Additionally, L-THP enhanced the sensitivity of ERα+ BCa cells to tamoxifen and fulvestrant. Mechanically, the application of L-THP promotes ERα degradation through accumulating ubiquitin chains on ERα. Overexpressing ERα abrogates L-THP induced-antiproliferation in ERα+ BCa cells. Collectively, our work indicates that L-THP may represent a potentially novel therapeutic medicine for ERα+ breast cancer patient.

19.
Front Microbiol ; 11: 996, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32582050

RESUMO

Due to the increasing prevalence of pathogenic fungal infections, the emergence of antifungal resistant clinical isolates worldwide, and the limited arsenal of available antifungals, developing new antifungal strategies is imperative. In this study, we screened a library of 1068 FDA-approved drugs to identify hits that exhibit broad-spectrum antifungal activity. Robenidine, an anticoccidial agent which has been widely used to treat coccidian infections of poultry and rabbits, was identified in this screen. Physiological concentration of robenidine (8 µM) was able to significantly inhibit yeast cell growth, filamentation and biofilm formation of Candida albicans - the most extensively studied human fungal pathogen. Moreover, we observed a broad-spectrum antifungal activity of this compound against fluconazole resistant clinical isolates of C. albicans, as well as a wide range of other clinically relevant fungal pathogens. Intriguingly, robenidine-treated C. albicans cells were hypersensitive to diverse cell wall stressors, and analysis of the cell wall structure by transmission electron microscopy (TEM) showed that the cell wall was severely damaged by robenidine, implying that this compound may target the cell wall integrity signaling pathway. Indeed, upon robenidine treatment, we found a dose dependent increase in the phosphorylation of the cell wall integrity marker Mkc1, which was decreased after prolonged exposure. Finally, we provide evidence by RNA-seq and qPCR that Rlm1, the downstream transcription factor of Mkc1, may represent a potential target of robenidine. Therefore, our data suggest that robenidine, a FDA approved anti-coccidiosis drug, displays a promising and broadly effective antifungal strategy, and represents a potentially repositionable candidate for the treatment of fungal infections.

20.
Gut Microbes ; 11(5): 1423-1437, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32403971

RESUMO

The protein translocated intimin receptor (Tir) from enteropathogenic Escherichia coli shares sequence similarity with the host cellular immunoreceptor tyrosine-based inhibition motifs (ITIMs). The ITIMs of Tir are required for Tir-mediated immune inhibition and evasion of host immune responses. However, the underlying molecular mechanism by which Tir regulates immune inhibition remains unclear. Here we demonstrated that ß-arrestin 2, which is involved in the G-protein-coupled receptor (GPCR) signal pathway, interacted with Tir in an ITIM-dependent manner. For the molecular mechanism, we found that ß-arrestin 2 enhanced the recruitment of SHP-1 to Tir. The recruited SHP-1 inhibited K63-linked ubiquitination of TRAF6 by dephosphorylating TRAF6 at Tyr288, and inhibited K63-linked ubiquitination and phosphorylation of TAK1 by dephosphorylating TAK1 at Tyr206, which cut off the downstream signal transduction and subsequent cytokine production. Moreover, the inhibitory effect of Tir on immune responses was diminished in ß-arrestin 2-deficient mice and macrophages. These findings suggest that ß-arrestin 2 is a key regulator in Tir-mediated immune evasion, which could serve as a new therapeutic target for bacterial infectious diseases.

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