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1.
Brain Res ; 1767: 147558, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34116054

RESUMO

Functional and structural brain alterations have been noted in carpal tunnel syndrome (CTS), the most common entrapment peripheral neuropathy. Previous studies were mainly focused on somatosensory cortices. However, the changes of white matter diffusion properties in nonsensorimotor cortices remain uninvestigated. We utilized a modified tract-based spatial statistics (TBSS) pipeline to explore CTS-related white matter plasticity, omitting the skeletonization step and registering diffusion tensor imaging (DTI) data to a study-specific, high resolution T1 template by an optimized registration method. The modified TBSS was demonstrated to be more sensitive to detect changes in white matter integrity than the standard TBSS approach. In this study, 25 moderate/severe CTS patients and 17 age- and sex-matched healthy controls (HC) were evaluated with DTI. Fractional anisotropy (FA) and radial diffusivity (RD) were calculated for group comparison. And the relationship between diffusion parameters and clinical assessments was also analyzed. Comparing with the healthy controls, CTS patients showed significantly increased FA and decreased RD in areas of multisensory integration and motor control involving the central opercular cortex and supplementary motor area (SMA) of the dominant hemisphere. Moreover, altered diffusion parameters in the central opercular cortex of the dominant hemisphere were significantly correlated with Boston Carpal Tunnel Questionnaire (BCTQ) scores. It is considered to be a form of maladaptive neuroplastic response to CTS-associated afference and motor control deficits. Such insight may be helpful in developing new strategies for the treatment of CTS.

2.
Bioresour Technol ; 337: 125358, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34120060

RESUMO

In this study, the zeolitic imidazolate framework-67 (ZIF-67) and electrospinning polyacrylonitrile membrane were combined to prepare electrospinning carbon nanofibers composite cathode (ZIF-67/CNFs) which could enhance the oxygen reduction reaction (ORR) performance of microbial fuel cells (MFCs) cathode. The optimum electrode 3 wt% ZIF-67/CNFs revealed the excellent ORR performance with a half-wave potential of -0.03 V vs. Ag/AgCl, which was more positive than Pt/C-CC (-0.09 V vs. Ag/AgCl). The highest output voltage (607±9 mV) and maximum power density (1.191±0.017 W m-2) were obtained when the prepared ZIF-67/CNFs electrode was applied to the cathode of MFC (ZIF-67/CNFs-MFC). In addition, ZIF-67/CNFs-MFC showed the best pollutant removal effect. Geobacter was the highest proportion of microbial in ZIF-67/CNFs-MFC. The results have shown that the application of ZIF-67/CNFs electrode to MFC cathode is promising.

3.
Mol Med Rep ; 24(1)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34080650

RESUMO

Diet and exercise are the most effective approaches used to induce weight loss. D­psicose is a low­calorie sweetener that has been shown to reduce weight in obese individuals. However, the effect of D­psicose on muscle cells under oxidative stress, which is produced during exercise, requires further investigation. The present study aimed to determine the effects of D­psicose on C2C12 myogenic cells in vitro. Hydrogen peroxide (H2O2) was used to stimulate the generation of intracellular reactive oxygen species (ROS) in muscle cells to mimic exercise conditions. Cell viability was analyzed using a MTT assay and flow cytometry was used to analyze the levels of apoptosis, mitochondrial membrane potential (MMP), the generation of ROS and the cell cycle distribution following treatment. Furthermore, protein expression levels were analyzed using western blotting and cell proliferation was determined using a colony formation assay. The results of the present study revealed that D­psicose alone exerted no toxicity on C2C12 mouse myogenic cells. However, in the presence of low­dose (100 µM) H2O2­induced ROS, D­psicose induced C2C12 cell injury and significantly decreased C2C12 cell viability in a dose­dependent manner. In addition, the levels of apoptosis and the generation of ROS increased, while the MMP decreased. MAPK family molecules were also activated in a dose­dependent manner following treatment. Notably, the combined treatment induced G2/M phase arrest and reduced the proliferation of C2C12 cells. In conclusion, the findings of the present study suggested that D­psicose may induce toxic effects on muscle cells in a simulated exercise situation by increasing ROS levels, activating the MAPK signaling pathway and disrupting the MMP.

4.
Nat Commun ; 12(1): 3401, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099729

RESUMO

Following hospital discharge, patients with type A acute aortic dissection (TA-AAD) may present an increase in mortality risk. However, little is known about specific biomarkers associated with post-discharge survival, and there is a paucity of prognostic markers associated with TA-AAD. Here, we identify nine candidate proteins specific for patietns with TA-AAD in a cross-sectional dataset by unbiased protein screening and in-depth bioinformatic analyses. In addition, we explore their association with short-term and long-term mortality in a derivation cohort of patients with TA-AAD, including an internal (n = 300) and external (n = 236) dataset. An elevated osteoprotegerin (OPG)/tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) ratio was the strongest predictor of overall, 30-day, post-30-day mortality in both datasets and was confirmed to be a strong predictor of mortality in an independent validation cohort (n = 400). Based on OPG/TRAIL ratio-guided risk stratification, patients at high risk (>33) had a higher 1-year mortality (55.6% vs. 4.3%; 68.2% vs. 2.6%) than patients at low risk (<4) in both cohorts. In Conclusion, we show that an elevated OPG/TRAIL ratio is associated with a significant increase in short-term and long-term mortality in patients with TA-AAD.


Assuntos
Aneurisma Dissecante/mortalidade , Aneurisma Aórtico/mortalidade , Osteoprotegerina/sangue , Ligante Indutor de Apoptose Relacionado a TNF/sangue , Adulto , Aneurisma Dissecante/sangue , Aneurisma Dissecante/etiologia , Aneurisma Dissecante/cirurgia , Aneurisma Aórtico/sangue , Aneurisma Aórtico/complicações , Aneurisma Aórtico/cirurgia , Biomarcadores/sangue , Estudos Transversais , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Seguimentos , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco/métodos
5.
Adv Sci (Weinh) ; : e2100165, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145978

RESUMO

Design of new nanoplatforms that integrates multiple imaging and therapeutic components for precision cancer nanomedicine remains to be challenging. Here, a facile strategy is reported to prepare polydopamine (PDA)-coated molybdenum disulfide (MoS2 ) nanoflakes as a nanocarrier to load dual drug cisplatin (Pt) and 1-methyl-tryptophan (1-MT) for precision tumor theranostics. Preformed MoS2 nanoflakes are coated with PDA, modified with methoxy-polyethylene glycol (PEG)-amine, and loaded with 1-MT and Pt. The formed functional 1-MT-Pt-PPDA@MoS2 (the second P stands for PEG) complexes exhibit good colloidal stability and photothermal conversion efficiency (47.9%), dual pH-, and photothermal-sensitive drug release profile, and multimodal thermal, computed tomography and photoacoustic imaging capability. Due to the respective components of Pt, MoS2 , and 1-MT that can block the immune checkpoint associated to tumoral indoleamine 2,3-dioxygenase-induced tryptophan metabolism, tri-mode chemo-photothermo-immunotherapy of tumors can be realized. In particular, under the near infrared laser irradiation, fast release of both drugs can be facilitated to achieve cooperative tumor therapy effect, and the combined immunogenic cell death induced by the dual-mode chemo-photothermo treatment and the 1-MT-induced immune checkpoint blockade can boost enhanced antitumor immune response to generate significant cytotoxic T cells for tumor killing. The developed 1-MT-Pt-PPDA@MoS2 complexes may be used as an intelligent nanoplatform for cooperative precision imaging-guided combinational tumor therapy.

6.
BMC Neurol ; 21(1): 213, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34053436

RESUMO

BACKGROUND: DDMS is a rare disease diagnosed by clinical and radiological characteristics. But the complexity of radiological and clinical manifestations of DDMS has become a challenge diagnostically. To date, the reported cases with DDMS had highly varied clinical manifestations including seizures, contralateral hemiplegia/hemiparesis, facial asymmetry, mental retardation, etc. In addition to typical clinical findings, some new characteristics have been recently added to the spectrum of DDMS. However, few cases have been reported to be associated with neuropsychiatric symptoms according to the literature. This study aimed to investigate the neuropsychiatric manifestations associated with Dyke-Davidoff-Masson syndrome (DDMS) and related imaging findings. METHODS: This study included 7 patients diagnosed with DDMS between 2014 and 2020. The clinical characteristics, neuropsychiatric manifestations, and radiological results were retrospectively evaluated. RESULTS: Seven patients (five males and two females) with a mean age of 28.0 ± 9.73 (range 15.0-41.0) years were included. Five patients were admitted to the psychiatric unit due to psychological and behavioral disorders. Two patients were referred to the neurology unit mainly due to epilepsy. Six patients had epileptic seizures, 4 had hemiplegia, 3 had mental retardation, 2 patients had external ear deformities, and 2 had facial asymmetry. Neuropsychiatric symptoms were presented in 6 (85.7 %) cases. Cases 2-6 developed affective disorders. Deficits in verbal communication, impairment of social interaction, lack of insight, adulia and hypobulia appeared in cases 1-4. Schizophrenia with apathy, and epileptic schizoid psychosis were observed in cases 4 and 5 respectively. Case 6 had behavioral disorders, hyperactivity, tic disorder, mental retardation, anxiety, catatonic symptoms and suicidal tendency. Case 7 had seizures and mental retardation, and no psychiatric symptoms were presented. Radiological examinations showed unilateral cerebral atrophy, enlarged lateral ventricles, and various compensatory hypertrophy of the skull in all cases. The midline structure has shifted to the affected side in 5(71.4 %) cases. Atrophy of the basal ganglia or brain stem was observed in 4(57.1 %) cases. CONCLUSIONS: The hallmark imaging manifestations of DDMS facilitated the diagnosis in most cases. This study illustrated that a variety of psychoneurotic disorders and ear abnormalities were correlated with DDMS.

7.
Stem Cell Res Ther ; 12(1): 271, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957971

RESUMO

BACKGROUND: Expansion-mediated replicative senescence and age-related natural senescence have adverse effects on mesenchymal stem cell (MSC) regenerative capability and functionality, thus severely impairing the extensive applications of MSC-based therapies. Emerging evidences suggest that microRNA-34a (miR-34a) has been implicated in the process of MSC senescence; however, the molecular mechanisms with regard to how miR-34a influencing MSC senescence remain largely undetermined. METHODS: MiR-34a expression in MSCs was evaluated utilizing RT-qPCR. The functional effects of miR-34a exerting on MSC senescence were investigated via gene manipulation. Relevant gene and protein expression levels were analyzed by RT-qPCR and western blot. Luciferase reporter assays were applied to confirm that Nampt is a direct target of miR-34a. The underlying regulatory mechanism of miR-34a targeting Nampt in MSC senescence was further explored by measuring intracellular NAD+ content, NAD+/NADH ratio and Sirt1 activity. RESULTS: In contrast to Nampt expression, miR-34a expression incremented in senescent MSCs. MiR-34a overexpression in young MSCs resulted in senescence-associated characteristics as displayed by senescence-like morphology, prolonged cell proliferation, declined osteogenic differentiation potency, heightened senescence-associated-ß-galactosidase activity, and upregulated expression levels of the senescence-associated factors. Conversely, miR-34a suppression in replicative senescent and natural senescent MSCs contributed to diminished senescence-related phenotypic features. We identified Nampt as a direct target gene of miR-34a. In addition, miR-34a repletion resulted in prominent reductions in Nampt expression levels, NAD+ content, NAD+/NADH ratio, and Sirt1 activity, whereas anti-miR-34a treatment exerted the opposite effects. Furthermore, miR-34a-mediated MSC senescence was evidently rescued following the co-treatment with Nampt overexpression. CONCLUSION: This study identifies a significant role of miR-34a playing in MSC replicative senescence and natural senescence via targeting Nampt and further mediating by NAD+-Sirt1 pathway, carrying great implications for optimal strategies for MSC therapeutic applications.

8.
J Mater Chem B ; 9(21): 4319-4328, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34013937

RESUMO

A lack of sufficient tumor penetration and low delivery efficiency are the main reasons for the limited clinical applications of nanocarriers in cancer treatment. Tumor microenvironment responsive drug delivery systems have been attracting great interest in cancer therapy as the desired drug release can be achieved in the disease sites for optimal treatment efficiency. In this work, we developed a biodegradable nanohybrid drug delivery system with pH/redox/enzymatic sensitivity by the simple assembly of bovine serum albumin nano-units (about 5 nm) onto graphene oxide nanosheets in the presence of a naturally originating protein (gelatin). The nanoparticles can maintain a constant size under physiological conditions, while releasing 5 nm nano-units containing the drug upon triggering by the environment-mimicking protease highly expressed in the tumor microenvironment. Furthermore, after reaching the tumor tissue, the acidic, reductive, and enzymatic microenvironments turned on the switch for DOX release, and the combination of chemotherapy and photothermal therapy was achieved under the trigger of near-infrared light. The nanosystems have the potential to improve the penetration ability through the depth of the tumor tissue to enhance drug intracellular delivery and antitumor bioactivity.

9.
Aging (Albany NY) ; 13(8): 11433-11454, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33839696

RESUMO

Autologous chondrocyte implantation (ACI) is an effective method for treating chronic articular cartilage injury and degeneration; however, it requires large numbers of hyaline chondrocytes, and human hyaline chondrocytes often undergo dedifferentiation in vitro. Moreover, although long non-coding RNAs (lncRNAs) regulate gene expression in many pathological and physiological processes, their role in human hyaline chondrocyte dedifferentiation remains unclear. Here, we examined lncRNA and mRNA expression profiles in human hyaline chondrocyte dedifferentiation using microarray analysis. Among the many lncRNAs and mRNAs that showed differential expression, lncRNA AP001505.9 (ENST00000569966) was significantly downregulated in chondrocytes after dedifferentiation. We next performed gene ontology, pathway, and CNC (coding-non-coding gene co-expression) analyses to investigate potential regulatory mechanisms for AP001505.9. Pellet cultures were then used to redifferentiate dedifferentiated chondrocytes, and AP001505.9 expression was upregulated after redifferentiation. Finally, both in vitro and in vivo experiments demonstrated that AP001505.9 overexpression inhibited dedifferentiation of chondrocytes. This study characterizes lncRNA expression profiles in human hyaline chondrocyte dedifferentiation, thereby identifying new potential mechanisms of chondrocyte dedifferentiation worthy of further investigation.

10.
Cardiovasc Toxicol ; 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33929718

RESUMO

Fatty acid-binding protein 5 (FABP5) is an important member of the FABP family and plays a vital role in the metabolism of fatty acids. However, few studies have examined the role of FABP5 in pathological cardiac remodeling and heart failure. The aim of this study was to explore the role of FABP5 in transverse aortic constriction (TAC)-induced pathological cardiac remodeling and dysfunction in mice. Quantitative RT-PCR (qRT-PCR) and western blotting (WB) analysis showed that the levels of FABP5 mRNA and protein, respectively, were upregulated in hearts of the TAC model. Ten weeks after TAC in FABP5 knockout and wild type control mice, echocardiography, histopathology, qRT-PCR, and WB demonstrated that FABP5 deficiency aggravated cardiac injury (both cardiac hypertrophy and fibrosis) and dysfunction. In addition, transmission electron microscopy, ATP detection, and WB revealed that TAC caused severe impairment to mitochondria in the hearts of FABP5-deficient mice compared with that in control mice. When FABP5 was downregulated by siRNA in primary mouse cardiac fibroblasts, FABP5 silencing increased oxidative stress, reduced mitochondrial respiration, and increased the expression of myofibroblast activation marker genes in response to treatment with transforming growth factor-ß. Our findings demonstrate that FABP5 deficiency aggravates cardiac pathological remodeling and dysfunction by damaging cardiac mitochondrial function.

11.
Cell Mol Neurobiol ; 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33886036

RESUMO

Central nervous system injuries and diseases, such as ischemic stroke, spinal cord injury, neurodegenerative diseases, glioblastoma, multiple sclerosis, and the resulting neuroinflammation often lead to death or long-term disability. MicroRNAs are small, non-coding, single-stranded RNAs that regulate posttranscriptional gene expression in both physiological and pathological cellular processes, including central nervous system injuries and disorders. Studies on miR-124, one of the most abundant microRNAs in the central nervous system, have shown that its dysregulation is related to the occurrence and development of pathology within the central nervous system. Herein, we review the molecular regulatory functions, underlying mechanisms, and effective delivery methods of miR-124 in the central nervous system, where it is involved in pathological conditions. The review also provides novel insights into the therapeutic target potential of miR-124 in the treatment of human central nervous system injuries or diseases.

12.
Eur J Hum Genet ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824467

RESUMO

Thoracic aortic aneurysm with or without dissection (TAAD) can be broadly categorized as syndromic TAAD (sTAAD) and isolated TAAD (iTAAD). sTAAD and is highly correlated with genetics. However, although the incidence of iTAAD is much higher, its monogenic contribution is not yet clear. Here, we sequenced 15 known TAAD genes for 578 iTAAD cases from four cardiac centers in China and found that 10.6% patients with a pathogenic/likely pathogenic (P/LP) variant. Other 7.27% of patients carried variants of uncertain significance in these target genes. We further investigated the correlations among genetics, clinical features, and long-term outcomes. Genetic patients showed younger onset ages (P = 1.31E-13) and larger aortic diameter (P = 1.00E-6), with the youngest age in patients with FBN1 P/LP variants. Monogenic variants were also associated with more aortic segments involved (P = 0.043) and complicated with initial dissection (P = 4.50E-5), especially for genetic patients with non-FBN1 P/LP variants. MACEs occurred in 14.9% patients during follow-up of median 55 months. Genetic status (P = 0.001) and initial dissection (P = 3.00E-6) were two major risk factors for poor prognosis. Early onset age was associated with MACEs in non-genetic cases without initial dissection (P = 0.005). Our study revealed the monogenic contribution in known TAAD genes to iTAAD patients. The genotype-phenotype correlations may complement the risk stratification of iTAAD patients and identification of higher risk subgroups, as well as assist the development of tailored precision medicine in iTAAD.

13.
Chemistry ; 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33884685

RESUMO

Porous materials have been investigated as efficient photochromic platforms for detecting hazardous radiation, while the utilization of hydrogen bonded organic frameworks (HOFs) in this field has remained intact. Herein, two HOFs were synthesized through self-assembly of tetratopic viologen ligand and formic acid (PFC-25, PFC-26), as a new class of "all-organic" radiochromic smart material, opening a gate for HOFs in this field. PFC-26 is active upon both X-ray and UV irradiation, while PFC-25 is only active upon X-ray irradiation. The same building block yet different radiochromic behaviors of PFC-25 and PFC-26 allow us to gain a deep mechanistic understanding of the factors that control the detection specificity. Theoretical and experimental studies reveal that the degree of π-conjugation of viologen ligand is highly related to the threshold energy of triggering a charge transfer, therefore being a vital factor for the particularity of radiochromic materials. Thanks to its convenient processibility, nanoparticle size, and UV silence, PFC-25 can be further fabricated into a portable naked-eye sensor for X-ray detection, which shows obvious color change with the merits of high transmittance contrast, good sensitivity (reproducible dose threshold of 3.5 Gy), and excellent stability. The work exhibits the promising practical potentials of HOF materials in photochromic technology.

14.
J Biol Chem ; : 100483, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33647318

RESUMO

Vascular calcification is the ectopic deposition of calcium hydroxyapatite minerals in arterial wall which involves the transdifferentiation of vascular smooth muscle cells (VSMCs) toward an osteogenic phenotype. However, the underlying molecular mechanisms regulating the VSMC osteogenic switch remain incompletely understood. In this study, we examined the roles of microRNAs (miRNAs) in vascular calcification. miRNA-seq transcriptome analysis identified miR-223-3p as a candidate miRNA in calcified mouse aortas. MiR-223-3p knockout aggravated calcification in both medial and atherosclerotic vascular calcification models. Further, RNA-seq transcriptome analysis verified JAK-STAT and PPAR signaling pathways were upregulated in both medial and atherosclerotic calcified aortas. Overlapping genes in these signaling pathways with predicted target genes of miR-223-3p derived from miRNA databases, we identified signal transducer and activator of transcription 3 (STAT3) as a potential target gene of miR-223-3p in vascular calcification. In vitro experiments showed that miR-223-3p blocked interleukin-6 (IL-6)/STAT3 signaling, thereby preventing the osteogenic switch and calcification of VSMCs. In contrast, overexpression of STAT3 diminished the effect of miR-223-3p. Taken together, the results indicate a protective role of miR-223-3p that inhibits both medial and atherosclerotic vascular calcification by regulating IL-6/STAT3 signaling mediated VSMC transdifferentiation.

15.
Mol Neurobiol ; 58(5): 2447-2464, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33725319

RESUMO

Irreversible neuron loss caused by central nervous system injuries usually leads to persistent neurological dysfunction. Reactive astrocytes, because of their high proliferative capacity, proximity to neuronal lineage, and significant involvement in glial scarring, are ideal starting cells for neuronal regeneration. Having previously identified several small molecules as important regulators of astrocyte-to-neuron reprogramming, we established herein that miR-124, ruxolitinib, SB203580, and forskolin could co-regulate rat cortical reactive astrocyte-to-neuron conversion. The induced cells had reduced astroglial properties, displayed typical neuronal morphologies, and expressed neuronal markers, reflecting 25.9% of cholinergic neurons and 22.3% of glutamatergic neurons. Gene analysis revealed that induced neuron gene expression patterns were more similar to that of primary neurons than of initial reactive astrocytes. On the molecular level, miR-124-driven neuronal differentiation of reactive astrocytes was via targeting of the SOX9-NFIA-HES1 axis to inhibit HES1 expression. In conclusion, we present a novel approach to inducing endogenous rat cortical reactive astrocytes into neurons through co-regulation involving miR-124 and three small molecules. Thus, our research has potential implications for inhibiting glial scar formation and promoting neuronal regeneration after central nervous system injury or disease.

16.
Apoptosis ; 26(3-4): 219-231, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33738673

RESUMO

Acute myeloid leukemia (AML) is a malignant cancer of the hematopoietic system. Although the effectiveness of arsenic compounds has been recognized and applied clinically, some patients are still found resistant to this chemotherapy. In this study, we investigated that a synthetic thyroid hormone analog (TA), 2-iodo-4-nitro-1-(o-tolyloxy) benzene, had a strong apoptosis effect on U937 cells. U937 cells were treated with TA, and examinted the generation of reactive oxygen species (ROS), dysfunction of mitochondria, expression of pro-apoptosis and anti-apoptosis, and cleavage of caspase-3 and Poly (ADP-ribose) polymerase (PARP). Further, it is also evaluated that insight molecular mechanism and signaling pathways involved in the study. It is found that TA significantly induced apoptosis in U937 cells through production of ROS, dysfunction of mitochondria, and activation of caspase cascade. It was also observed that MAPK signaling pathway including ERK, JNK, and P38 signals are involved in the induction of apoptosis. Moreover, marked activation of autophagy and ER stress markers such as LC3, P62, Beclin1 and GRP78, CHOP were observed, respectively. Pretreatment with ER stress inhibitor tauroursodeoxycholic acid (TUDCA) and autophagy inhibitor 3-Methyladenine (3-MA) have successfully attenuated and aggravated TA-induced apoptosis, respectively. We further confirmed the active involvement of ER stress and autophagy signals. In conclusion, TA induced apoptosis through ER stress and activation of autophagy, and the latter is not conducive to TA-induced cell death. Our results may provide a new insight into the strategic development of novel therapy for the treatment of AML.

17.
BMC Cancer ; 21(1): 237, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676427

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations. Farnesyl thiosalicylic acid (FTS), also known as salirasib, is a RAS inhibitor that selectively dislodges active RAS proteins from cell membrane, inhibiting downstream signaling. FTS has demonstrated limited therapeutic efficacy in PDAC patients despite being well tolerated. METHODS: To improve the efficacy of FTS in PDAC, we performed a genome-wide CRISPR synthetic lethality screen to identify genetic targets that synergize with FTS treatment. Among the top candidates, multiple genes in the endoplasmic reticulum-associated protein degradation (ERAD) pathway were identified. The role of ERAD inhibition in enhancing the therapeutic efficacy of FTS was further investigated in pancreatic cancer cells using pharmaceutical and genetic approaches. RESULTS: In murine and human PDAC cells, FTS induced unfolded protein response (UPR), which was further augmented upon treatment with a chemical inhibitor of ERAD, Eeyarestatin I (EerI). Combined treatment with FTS and EerI significantly upregulated the expression of UPR marker genes and induced apoptosis in pancreatic cancer cells. Furthermore, CRISPR-based genetic ablation of the key ERAD components, HRD1 and SEL1L, sensitized PDAC cells to FTS treatment. CONCLUSION: Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Degradação Associada com o Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Sistemas CRISPR-Cas/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Degradação Associada com o Retículo Endoplasmático/genética , Farneseno Álcool/análogos & derivados , Farneseno Álcool/farmacologia , Farneseno Álcool/uso terapêutico , Técnicas de Inativação de Genes , Humanos , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Hidroxiureia/análogos & derivados , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Camundongos , Neoplasias Pancreáticas/patologia , Proteínas/genética , Salicilatos/farmacologia , Salicilatos/uso terapêutico , Mutações Sintéticas Letais , Ubiquitina-Proteína Ligases/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos
18.
World J Mens Health ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33663030

RESUMO

PURPOSE: Male infertility is a worldwide problem with limitations in the treatment. Phosphodiesterase-5 inhibitors (PDE5is) is the first choice for the treatment of erectile dysfunction, more and more studies show that it has a certain effect on male infertility in recent years. But there was currently no high quality of systematic review to evaluate the effects of PDE5is on semen quality. MATERIALS AND METHODS: We retrieved the electronic databases of MEDLINE, PubMed, Web of Science, EMBASE, etc. Related randomized controlled trials (RCTs) were collected and selected up to May 20, 2020. We have searched literature with terms "male infertility", "phosphodiesterase-5 inhibitors", "PDE5i", "Tadalafil", "Sildenafil", "Vardenafil", "Udenafil", "Avanafil", "semen", and "sperm". Mean value and its standard deviation were used to perform quantitative analysis. All statistical analyses were conducted by RevMan 5.3 and Stata software. RESULTS: There were a total of 1,121 participants in the nine included studies. There was a statistically significant improvement treated with PDE5is compared with sham therapy, which including sperm concentration (mean difference [MD]=1.96, 95% confidence interval [CI]=1.70-2.21, p<0.001; MD=3.22, 95% CI=1.96-4.48, p<0.001), straight progressive motility (%) Grade A (MD=3.71, 95% CI=2.21-5.20, p<0.001), sperm motility (MD=8.09, 95% CI=7.83-8.36, p<0.001), morphologically normal spermatozoa (%) (MD=0.67, 95% CI=0.20-1.15, p=0.005; MD=1.27, 95% CI=0.02-2.52, p=0.05), sperm abnormalities (%) (MD=-0.64, 95% CI=-0.81--0.47, p<0.001), and progressive motile sperm (MD=5.34, 95% CI=3.87-6.81, p<0.001). CONCLUSIONS: In this meta-analysis of nine RCTs, treatment with PDE5is could improve some indicators of male sperm.

19.
Front Cell Infect Microbiol ; 11: 643092, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33768014

RESUMO

Rheumatic heart disease refers to the long-term damage of heart valves and results from an autoimmune response to group A Streptococcus infection. This study aimed to analyze the microbiota composition of patients with rheumatic heart disease and explore potential function of microbiota in this disease. First, we revealed significant alterations of microbiota in feces, subgingival plaques, and saliva of the patients compared to control subjects using 16S rRNA gene sequencing. Significantly different microbial diversity was observed in all three types of samples between the patients and control subjects. In the gut, the patients possessed higher levels of genera including Bifidobacterium and Eubacterium, and lower levels of genera including Lachnospira, Bacteroides, and Faecalibacterium. Coprococcus was identified as a super-generalist in fecal samples of the patients. Significant alterations were also observed in microbiota of subgingival plaques and saliva of the patients compared to control subjects. Second, we analyzed microbiota in mitral valves of the patients and identified microbes that could potentially transmit from the gut or oral cavity to heart valves, including Streptococcus. Third, we further analyzed the data using random forest model and demonstrated that microbiota in the gut, subgingival plaque or saliva could distinguish the patients from control subjects. Finally, we identified gut/oral microbes that significantly correlated with clinical indices of rheumatic heart disease. In conclusion, patients with rheumatic heart disease manifested important alterations in microbiota that might distinguish the patients from control subjects and correlated with severity of this disease.

20.
Neural Plast ; 2021: 8815144, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33603780

RESUMO

Purpose: This study is aimed at investigating brain structural changes and structural network properties in complete spinal cord injury (SCI) patients, as well as their relationship with clinical variables. Materials and Methods: Structural MRI of brain was acquired in 24 complete thoracic SCI patients (38.50 ± 11.19 years, 22 males) within the first postinjury year, while 26 age- and gender-matched healthy participants (38.38 ± 10.63 years, 24 males) were enrolled as control. The voxel-based morphometry (VBM) approach and graph theoretical network analysis based on cross-subject grey matter volume- (GMV-) based structural covariance networks (SCNs) were conducted to investigate the impact of SCI on brain structure. Partial correlation analysis was performed to explore the relationship between the GMV of structurally changed brain regions and SCI patients' clinical variables, including injury duration, injury level, Visual Analog Scale (VAS), American Spinal Injury Association Impairment Scale (AIS), International Classification of Functioning, Disability and Health (ICF) scale, Self-rating Depression Scale (SDS), and Self-rating Anxiety Scale (SAS), after removing the effects of age and gender. Results: Compared with healthy controls, SCI patients showed higher SDS score (t = 4.392 and p < 0.001). In the VBM analysis, significant GMV reduction was found in the left middle frontal cortex, right superior orbital frontal cortex (OFC), and left inferior OFC. No significant difference was found in global network properties between SCI patients and healthy controls. In the regional network properties, significantly higher betweenness centrality (BC) was noted in the right anterior cingulum cortex (ACC) and left inferior OFC and higher nodal degree and efficiency in bilateral middle OFCs, while decreased BC was noted in the right putamen in SCI patients. Only negative correlation was found between GMV of right middle OFC and SDS score in SCI patients (r = -0.503 and p = 0.017), while no significant correlation between other abnormal brain regions and any of the clinical variables (all p > 0.05). Conclusions: SCI patients would experience depressive and/or anxious feelings at the early stage. Their GMV reduction mainly involved psychology-cognition related rather than sensorimotor brain regions. The efficiency of regional information transmission in psychology-cognition regions increased. Greater GMV reduction in psychology region was related with more severe depressive feelings. Therefore, early neuropsychological intervention is suggested to prevent psychological and cognitive dysfunction as well as irreversible brain structure damage.

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