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1.
Blood Adv ; 2022 Jun 21.
Article in English | MEDLINE | ID: mdl-35728062

ABSTRACT

Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in treating a variety of hematologic malignancies, but resistance to this treatment in some patients limited its wider application. Using an unbiased genome-wide CRISPR/Cas9 screening, we identified and validated loss of CD58 conferred immune evasion from CAR T cells in vitro and in vivo. CD58 is a ligand of the T cell costimulatory molecule CD2, and CD58 mutation or downregulated expression is common in hematological tumors. We found that disruption of CD58 in tumor cells induced the formation of suboptimal immunological synapse (IS) with CAR T cells, which conferred functional impairment of CAR T cells, including the attenuation of cell expansion, degranulation, cytokine secretion and cytotoxicity. In summary, we describe a potential mechanism of tumor intrinsic resistance to CAR T-cell therapy and suggest that this mechanism may be leveraged for developing therapeutic strategies to overcome resistance to CAR T-cell therapy in B-cell malignancies.

2.
Front Physiol ; 13: 890566, 2022.
Article in English | MEDLINE | ID: mdl-35721535

ABSTRACT

Aims/Introduction: Diabetic nephropathy (DN) is one of the main complications of diabetes. Genomics may reveal the essential pathogenesis of DN. We analyzed datasets to search for key genes to explore pathological mechanisms of DN. Materials and Methods: In this study, weighted gene co-expression network analysis (WGCNA) was used to divide the differential expression genes (DEGs) from GSE142025 into different modules, and enrichment pathway analysis was conducted for each module to find key genes related to cell death pathway. Then, verification was carried out through network and histopathology. Finally, the regulatory mechanisms of key gene expression, including transcription factors (TFs), miRNA and E3 ligases related to ubiquitination, were predicted through website prediction and then miRNA results were validated using GSE51674 dataset. Results: The results of WGCNA and enrichment pathway analysis indicated that ferroptosis had significantly occurred in advanced DN (AND) group. Analysis of DEGs indicated that the occurrence and development of ferroptosis are mainly through ALOX15-mediated lipid metabolism pathway, which was found in all intrinsic cells of the glomerulus detected by IHC and IF staining. Moreover, network predictions were used for searching ALOX15-related TFs and ubiquitination. Meanwhile, the network predictions combining with other dataset furtherly discovered miRNAs which regulated ALOX15 expression. This study showed that the levels of mmu-miR-142-3p increased in DN mice kidney tissues, compared with the NC group. Conclusion: Ferroptosis existed in glomerular intrinsic cells of ADN group and its potential key candidate gene was ALOX15 which may be regulated by miR-142 and miRNA-650, TFs (CREBBP, EP300, HDAC1, MTA1, SPI1, STAT6) and E3 ligases related to ubiquitination (PML, ZMIZ1, MARCHF1, MARCHF3, MARCHF8, MARCHF11).

3.
Comput Intell Neurosci ; 2022: 5354326, 2022.
Article in English | MEDLINE | ID: mdl-35720941

ABSTRACT

Multihop smart grid is built on the basis of an integrated and high-speed communication network. Through the application of advanced sensing and measurement technology, equipment technology, control method, and advanced decision support system technology, the goal of reliable, safe, economic, efficient, environment-friendly, and safe use of the power grid is realized. In order to solve the problem of excessive demand for power supply, new energy power generation and demand response are proposed. According to the above background, the demand side economic scheduling problem is a complex optimization problem, which is difficult to be solved by ordinary algorithms. The adaptive global search algorithm based on a genetic algorithm can better solve complex optimization problems. The genetic algorithm proposed in this paper can effectively manage a large number of controllable loads in the selected area. The algorithm minimizes the cost and peak to the average ratio by changing the load. Home users can arrange their maximum load when the price is low. The peak load of residential buildings decreased from 98.5 kw/h to 90 kw/h, and the peak load decreased by about 7.53%. Through appropriate load dispatching, users minimize the daily electricity charge, which is reduced from 1352 yuan to 1245 yuan per day, and the daily electricity charge is reduced by about 7.25%. In addition, the advanced measurement, communication, and control means under the framework of the smart grid also play a key role in promoting all aspects of demand side management (DSM).


Subject(s)
Algorithms , Electricity , Computer Systems , Electric Power Supplies , Technology
4.
Front Public Health ; 10: 895179, 2022.
Article in English | MEDLINE | ID: mdl-35712309

ABSTRACT

Background: Tuberculosis (TB) is an important opportunistic infection in acquired immunodeficiency diseases (AIDS). Although the frequency of CD4+CD8+ double-positive (DP) T cells has been observed to increase in pathological conditions, their role (phenotypic and functional) is poorly described, especially in human immunodeficiency virus (HIV) infection with TB (HIV/TB (HT) coinfection). Methods: The percentage and phenotypic and functional properties of peripheral blood DP T cells in patients with HT coinfection in comparison to uninfected controls and to patients with HIV or TB mono-infection were analyzed by direct intracellular cytokine staining (ICS). Results: Total and CD4lowCD8high DP T cells were significantly increased in patients with both HIV and TB mono-infection, especially in patients with HT coinfection. Compared with healthy controls (HCs), the percentage of DP T cells expressing chemokine receptor 5 (CCR5) in patients with HT coinfection was significantly higher. Compared with HCs and patients with TB, a lower percentage of tumor necrosis factor α (TNF-α) secreting DP T cells and a higher percentage of granzyme A-secreting DP T cells were observed in patients with HIV mono-infection and HT coinfection, respectively. In addition, DP T cells expressed more cytolytic markers (granzyme A and perforin) than CD4+ T cells, but similarly to CD8+ T cells in patients with HT coinfection. Conclusions: Our data suggested that HT coinfection resulted in a marked increase in DP T cells, especially the CD4lowCD8high subpopulation. DP T cells may be susceptible to HT coinfection, and have the same cytotoxic function as CD8+ T cells.


Subject(s)
Coinfection , HIV Infections , Tuberculosis , CD8-Positive T-Lymphocytes , Granzymes , HIV Infections/complications , Humans
5.
Acta Pharmacol Sin ; 2022 Jun 16.
Article in English | MEDLINE | ID: mdl-35710877

ABSTRACT

Costunolide (CTD) is a sesquiterpene lactone isolated from costus root and exhibits various biological activities including anti-inflammation. Since atherosclerosis is a chronic inflammatory disease, we herein investigated the anti-atherosclerotic effects of CTD and the underlying mechanism. Atherosclerosis was induced in ApoE-/- mice by feeding them with a high-fat diet (HFD) for 8 weeks, followed by administration of CTD (10, 20 mg ·kg-1·d-1, i.g.) for 8 weeks. We showed that CTD administration dose-dependently alleviated atherosclerosis in HFD-fed ApoE-/- mice. Furthermore, we found that CTD dose-dependently reduced inflammatory responses in aortas of the mice, as CTD prevented infiltration of inflammatory cells in aortas and attenuated oxLDL uptake in macrophages, leading to reduced expression of pro-inflammatory and pro-fibrotic molecules in aortas. Similar results were observed in oxLDL-stimulated mouse primary peritoneal macrophages (MPMs) in vitro. We showed that pretreatment with CTD (2.5, 5. 10 µM) restrained oxLDL-induced inflammatory responses in MPMs by blocking pro-inflammatory NF-κB/p65 signaling pathway. We further demonstrated that CTD inactivated NF-κB via covalent binding to cysteine 179 on IKKß, a canonical upstream regulator of NF-κB, reducing its phosphorylation and leading to conformational change in the active loop of IKKß. Our results discover IKKß as the target of CTD for its anti-inflammatory activity and elucidate a molecular mechanism underlying the anti-atherosclerosis effect of CTD. CTD is a potentially therapeutic candidate for retarding inflammatory atherosclerotic diseases.

6.
J Inflamm (Lond) ; 19(1): 7, 2022 Jun 15.
Article in English | MEDLINE | ID: mdl-35706027

ABSTRACT

BACKGROUND: Long-term inhalation of cigarette smoke is considered to be one of the main causes of bronchial epithelioid cell damage, but its underlying mechanism has to be further clarified. METHODS: Gene expression at mRNA level and protein levels were detected by qRT-PCR and western blot analysis respectively. CCK-8, TUNEL assays, ELISA, western blot analysis and commercial kits were utilized to test cell viability, apoptosis inflammatory response and oxidative stress. The correlation between fatty acid binding protein 4 (FABP4) and the p38 mitogen-activated protein kinase (MAPK)/MAPK activated kinase 2 (MK2) signaling pathway was verified by western blot analysis and rescue assays. RESULTS: Cigarette smoke extract (CSE) exposure decreased viability, induced apoptosis and inflammatory response in 16HBE cells. Moreover, the expression of FABP4 in CSE-treated 16HBE cells was up-regulated in a time and dose-dependent manner. Ablation of FABP4 in 16HBE cells significantly protected against CSE-mediated cell viability decline and apoptosis. Further, FABP4 knockdown suppressed inflammatory response by down-regulating the elevated levels of cellular inflammatory factors including TNF-α, IL-1ß, IL-6, Cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) in CSE-treated 16HBE cells. The oxidative stress induced by CSE in 16HBE cells was also inhibited by FABP4 silence as evidence by reduced ROS and MDA level but increased SOD activity caused by FABP4 silence. Finally, all the above effects of FABP4 silence on CSE-treated 16HBE cells were reversed by asiatic acid, an agonist of p38 mitogen-activated protein kinase (MAPK). CONCLUSIONS: The up-regulation of FABP4 expression mediated by CSE exerted pro-inflammatory, pro-oxidative stress and pro-apoptotic effects on bronchial epithelial cells by activating the p38 MAPK/MK2 signaling pathway. Our findings help to further understand the underlying mechanism of cigarette smoke-induced bronchial inflammation.

7.
Cancer Med ; 2022 Jun 06.
Article in English | MEDLINE | ID: mdl-35670012

ABSTRACT

BACKGROUND: Drug resistance is an important factor affecting the efficacy of chemotherapy in patients with colon cancer. However, clinical markers for diagnosing drug resistance of tumor cells are not only a few in number, but also low in specificity, and the mechanism of action of tumor cell drug resistance remains unclear. METHODS: Dipeptidase 1 (DPEP1) expression was analyzed using the cancer genome atlas (TCGA) and genotype-Tissue Expression pan-cancer data. Survival analysis was performed using the survival package in R software to assess the prognostic value of DPEP1 expression in colon cancer. Correlation and Venn analyses were adopted to identify key genes. Immunohistochemistry, western blot, qRT-PCR, Co-immunoprecipitation, and dual-luciferase reporter experiments were carried out to explore the underlying associations between DPEP1 and Achaete scute-like 2 (ASCL2). MTT assays were used to evaluate the role of DPEP1 and ASCL2 in colon cancer drug resistance. RESULTS: DPEP1 was highly expressed in colon cancer tissues. DPEP1 expression correlated negatively with disease-specific survival but not with overall survival. Bioinformatics analysis and experiments showed that the expressions of DPEP1 and ASCL2 in colon cancer tissues were markedly positively correlated. Mechanistic research indicated that DPEP1 enhanced the stability of protein ASCL2 by inhibiting its ubiquitination-mediated degradation. In turn, ASCL2 functioned as a transcription factor to activate the transcriptional activity of the DPEP1 gene and boost its expression. Furthermore, DPEP1 also could enhance the expression of colon cancer stem cell markers (LGR5, CD133, and CD44), which strengthened the tolerance of colon cancer cells to chemotherapy drugs. CONCLUSIONS: Our findings reveal that the DPEP1 enhances the stemness of tumor cells by forming a positive feedback loop with ASCL2 to improve resistance to chemotherapy drugs.

8.
Front Oncol ; 12: 912426, 2022.
Article in English | MEDLINE | ID: mdl-35664749

ABSTRACT

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. There are many uncommon and rare mutations in the EGFR gene. The efficacy of the EGFR-TKIs is largely unknown for cancers harboring uncommon or rare EGFR mutations. Case Presentation: A 69-year-old woman was diagnosed with adenocarcinoma cT4N2M1c, stage IVB. Next-generation sequencing (NGS) confirmed a rare EGFR V786M mutation. During chemotherapy, immune checkpoint inhibitor (ICI), and anti-angiogenic treatment, no radiological response was observed. Subsequent third-generation EGFR TKI showed a remarkable therapeutic effect. Structural prediction revealed that the V786M mutation induces conformational change at the dimer interface, without altering the ATP binding to the EGFR tyrosine kinase domain (TKD). Consistently, docking simulations indicated that the affinity of ATP to the V786M mutant was not disturbed, which explained the TKI sensitivity. Conclusions: Our data confirmed the activating role on EGFR V786M mutation. Together with structural predictions and clinical evidence for activity of TKIs against EGFR V786M mutations, these findings warrant further investigation.

9.
Adv Sci (Weinh) ; : e2200924, 2022 May 26.
Article in English | MEDLINE | ID: mdl-35619333

ABSTRACT

Sodium and iron make up the perfect combination for the growing demand for sustainable energy storage systems, given the natural abundance and sustainability of the two building block elements. However, most sodium-iron electrode chemistries are plagued by intrinsic low energy densities with continuous ongoing efforts to solve this. Herein, the chemical space of a series of (meta)stable, off-stoichiometric Fe-PO4 -F phases is analyzed. Some are found to display markedly improved electrochemical activity for sodium storage, as compared to the amorphous or thermodynamically stable phases of equivalent composition. The metastable crystalline Na1.2 Fe1.2 PO4 F0.6 delivers a reversible capacity of more than 140 mAh g-1 with an average discharge potential of 2.9 V (vs Na+ /Na0 ) resulting in a practical specific energy density of 400 Wh kg-1 (estimated at the material level), outperforming many developed Fe-PO4 analogs thus far, with further multiple possibilities to be explored toward improved energy storage metrics. Overall, this study unlocks the possibilities of off-stoichiometric Fe-PO4 -F cathode materials and reveals the importance to explore the oft-overlooked metastable or transient state materials for energy storage.

10.
Clin Epigenetics ; 14(1): 66, 2022 05 20.
Article in English | MEDLINE | ID: mdl-35596190

ABSTRACT

BACKGROUND: Childhood overweight/obesity is a global public health concern. It is important to identify its early-life risk factors. Maternal poor sleep is common in late pregnancy, and previous studies indicated that poor sleep may influence the offspring's adiposity status. However, very few studies in humans investigated the effect of the different sleep parameters (sleep quantity, quality, and timing) on the offspring's adiposity indicators, and long-term studies are even more scarce. In addition, the underlying mechanism remains unclear. The present study therefore aimed to examine the association between the three maternal sleep dimensions in the late pregnancy and the offspring adiposity indicators and to explore the potential mediating effect of the cord blood DNA methylation in the above association. METHODS: Included participants in the current study were 2211 healthy pregnant women with singleton gestation from the Shanghai Birth Cohort (SBC) and Shanghai Sleep Birth Cohort (SSBC). Maternal nighttime sleep duration, quality, and midpoint (an indicator of circadian rhythm) were assessed by the same instrument in both cohorts during late pregnancy, and the offspring's body mass index (BMI) and subcutaneous fat (SF) were measured at 2 years old. Additionally, in 231 SSBC samples, the genome-wide DNA methylation levels were measured using the Illumina Infinium Methylation EPIC BeadChip. The multivariate linear regression was used to determine the associations between the maternal sleep parameters and the offspring adiposity indicators. The epigenome-wide association study was conducted to identify the maternal sleep-related CpG sites. The mediation analysis was performed to evaluate the potential intermediate role of DNA methylation in the association between maternal sleep and offspring adiposity indicators. RESULTS: The mean maternal nighttime sleep duration and the sleep midpoint for combined cohorts were 9.24 ± 1.13 h and 3.02 ± 0.82, respectively, and 24.5% of pregnant women experienced poor sleep quality in late pregnancy. After adjusting for the covariates, the maternal later sleep midpoint was associated with the increased SF in offspring (Coef. = 0.62, 95% CI 0.37-0.87, p < 0.001) at 2 years old. However, no significant associations of the nighttime sleep duration or sleep quality with the offspring adiposity indicators were found. In the SSBC sample, 45 differential methylated probes (DMPs) were associated with the maternal sleep midpoint, and then, we observed 10 and 3 DMPs that were also associated with the offspring's SF and BMI at 2 years, of which cg04351668 (MARCH9) and cg12232388 significantly mediated the relationship of sleep midpoint and SF and cg12232388 and cg12225226 mediated the sleep midpoint-BMI association, respectively. CONCLUSIONS: Maternal later sleep timing in late pregnancy was associated with higher childhood adiposity in the offspring. Cord blood DNA methylation may play a mediation role in that relationship.


Subject(s)
Adiposity , Pediatric Obesity , Adiposity/genetics , Birth Weight , Body Mass Index , Child , Child, Preschool , China , DNA Methylation , Female , Humans , Pregnancy , Prospective Studies , Sleep/genetics
11.
Sci Adv ; 8(20): eabn8299, 2022 May 20.
Article in English | MEDLINE | ID: mdl-35594352

ABSTRACT

Dense networks of deformation twins endow metals and alloys with unprecedented mechanical properties. However, the formation mechanism of these hierarchical twin structures remains under debate, especially their relations with the imperfect nature of twin boundaries (TBs). Here, we investigate the intrinsic deformability of defective TBs in face-centered cubic metallic materials, where the inherent kinks on a set of primary TBs are demonstrated to facilitate the formation of secondary and hierarchical nanotwins. This defect-driven hierarchical twinning propensity is critically dependent on the kink height, which proves to be generally applicable in a variety of metals and alloys with low stacking fault energies. As a geometric extreme, a fivefold twin can be constructed via this self-activated hierarchical twinning mechanism. These findings differ from the conventional twinning mechanisms, enriching our understanding of twinning-mediated plasticity in metallic materials.

12.
Elife ; 112022 05 12.
Article in English | MEDLINE | ID: mdl-35550247

ABSTRACT

Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time- and space-dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer, knocking down which attenuates metastatic phenotypes. However, due to the limited number of known substrates in the ovarian cancer context, the molecular basis for its pro-proliferation activity remains enigmatic. Here, we employed mass spectrometry and biochemical approaches to identify insulin receptor substrate 4 (IRS4) as a novel substrate of FER. FER engaged its kinase domain to associate with the PH and PTB domains of IRS4. Using a proximity-based tagging system in ovarian carcinoma-derived OVCAR-5 cells, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85ß, the regulatory subunit of PI3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4 delayed ovarian tumor cell proliferation both in vitro and in vivo. Overall, we revealed a kinase-substrate mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.


Subject(s)
Insulin Receptor Substrate Proteins , Ovarian Neoplasms , Phosphatidylinositol 3-Kinases , Protein-Tyrosine Kinases , Proto-Oncogene Proteins c-akt , Carcinogenesis , Carcinoma, Ovarian Epithelial/metabolism , Cell Transformation, Neoplastic , Enzyme Activation , Female , Humans , Insulin Receptor Substrate Proteins/metabolism , Ovarian Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Tyrosine/metabolism
13.
Sleep ; 45(5)2022 05 12.
Article in English | MEDLINE | ID: mdl-35554573

ABSTRACT

STUDY OBJECTIVES: To investigate trajectories of early childhood sleep in the first 3 years and their association with maternal depressive symptoms. METHODS: Data were from 243 Chinese mother-child dyads. Children's sleep duration and night-waking were assessed using the Brief Infant Sleep Questionnaire (BISQ) at 42 days, 3, 6, 9, 12, 18, 24, and 36 months postpartum. The Center for Epidemiological Survey-Depression Scale (CES-D), Edinburgh Postnatal Depression Scale (EPDS), and Profile of Mood States (POMS) were used to assess maternal depressive symptoms at late pregnancy, 42 days, and 36 months postpartum, respectively. Early childhood sleep trajectories were estimated with group-based trajectory models. The association between early childhood sleep trajectories and maternal depressive symptoms was examined with binary and multinomial logistic regression models and linear regression models. RESULTS: Three trajectories of daytime sleep duration ("short", 14.4%; "medium", 60.4%; "long", 25.2%), nighttime sleep duration ("increasing", 17.6%; "stable", 76.3%; "decreasing", 6.1%), and total sleep duration ("short", 21.5%; "medium", 59.9%; "long",18.6%), and two trajectories of night-waking ("resolving", 22.9%; "persistent", 77.1%) were identified. Controlling for confounding factors, maternal depression at 42 days postpartum was associated with higher risks for short daytime sleep duration and persistent night-waking in children. Persistent night-waking in children was associated with increased maternal depressive symptoms at 36 months postpartum. CONCLUSION: Early childhood sleep follows distinct trajectories in the first 3 years of life. The trajectories of short daytime sleep duration and persistent night-waking are associated with maternal depression. The findings indicate tailored interventions should target both unfavorable early childhood sleep trajectories and maternal depression.


Subject(s)
Depression, Postpartum , Sleep Initiation and Maintenance Disorders , Child, Preschool , Depression/complications , Depression/epidemiology , Depression, Postpartum/epidemiology , Female , Humans , Infant , Mothers , Pregnancy , Prospective Studies , Sleep
14.
Transl Pediatr ; 11(4): 601-609, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35558975

ABSTRACT

Background: Dextro-transposition of the great arteries (D-TGA) is a rare congenital heart disease, as it affects only 0.02-0.05% of live births. It is the second most common cyanotic heart disease following Tetralogy of Fallot. It has a male predominance. Fetal echocardiography is an optimal method for prenatal diagnosis of fetal D-TGA. In twin pregnancies, fetal D-TGA in one twin is very rare, especially in monochorionic-diamniotic twin pregnancies. Herein, we report a case of D-TGA in one twin in two dichorionic-diamniotic twin pregnancies and one monochorionic-diamniotic twin pregnancy from January 2018 to June 2021. Case Description: One twin with D-TGA was diagnosed by fetal echocardiography in the second trimester, and the co-twin was normal in all three cases. A multidisciplinary team provided extensive counseling regarding the D-TGA twin and the co-twin, and adequate perinatal management was provided. In cases 1, 2, and 3, the mothers underwent cesarean sections at 37 weeks + 2 days, 34 weeks + 5 days, and 36 weeks + 1 day, respectively. In case 1, which involved a female D-TGA neonate with birth weight 2,410 g, an emergent atrial septostomy was performed at 20 h after birth, and the neonate underwent atrial switch operation (ASO) 24 days after birth. In case 2, involving a male D-TGA neonate with a birth weight of 2,380 g, ASO was performed 24 days after birth. In case 3, involving a female D-TGA neonate with birth weight 2,240 g, ASO was performed 19 days after birth and delayed sternal closure was performed 4 days later. All six infants showed normal development during follow-up. Conclusions: Early antenatal diagnosis of D-TGA in one fetus of a twin pregnancy is significantly important. A multidisciplinary team should carry individual evaluation and integrated management of the D-TGA twin and co-twin during the pregnancy and perinatal period. After birth, delayed ductus arteriosus closure in the D-TGA twins should be performed when necessary and individualized timings for arterial switch operation should be considered.

15.
RSC Adv ; 8(23): 12779-12784, 2018 Apr 03.
Article in English | MEDLINE | ID: mdl-35541274

ABSTRACT

A synthetic route towards symmetric and asymmetric thiophenoazomethines was accomplished by reaction of the readily available amine with various aldehydes. Investigation of a series of thiophenoazomethines obtained by this method indicates that the terminal groups and the degree of conjugation have a great effect on the electronic absorption and energy levels of the conjugated compounds, particularly the effect of terminal groups. The terminal withdrawing and donating groups of thiophenoazomethines led to the formation of an electronic push-pull, push-push and pull-pull system, which can perturb the electronic transitions between the ground and excited states. The flexible chain substituents on the thiophene units, which improve its solubility, also result in bathochromic absorption, but have limited effect on the energy level.

16.
Acta Pharm Sin B ; 12(3): 1240-1253, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35530150

ABSTRACT

The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.

17.
Child Adolesc Psychiatry Ment Health ; 16(1): 34, 2022 May 09.
Article in English | MEDLINE | ID: mdl-35534893

ABSTRACT

BACKGROUND: While recent works suggested that overweight/obesity may impair executive function (EF), the overweight/obesity-EF relationship has not been well studied in adolescents. Furthermore, no research has investigated adolescent EF impairments across the weight spectrum (e.g., underweight or thinness, normal, overweight/obesity), especially those with underweight condition, with the moderating effect of negative emotions in the weight-EF association being limitedly investigated. We aimed to determine whether overall and abdominal weight spectrum associated with EF impairments and to identity whether negative emotions moderate the weight-EF link in adolescents. METHODS: We applied a subsample of the SCHEDULE-A project. Adolescents (11-18 years) were recruited using a multi-stage cluster random sampling approach. We measured the overall and abdominal weight spectrum by body mass index z-score and waist-to-height ratio, respectively. We used the Behavior Rating Inventory of Executive Function (BRIEF) to evaluate adolescent EF in nature setting, and utilized the Depression Anxiety and Stress Scales (DASS-21) to assess three types of negative emotional status (i.e., depression, anxiety, and stress). RESULTS: Of the 1935 adolescents, 963 (49.8%) were male. We observed that abdominal, not overall, overweight was associated with the Global Executive Composite (GEC) impairment (OR = 1.59, 95% CI 1.07-2.35), particularly for inhibit, emotion control, shift, working memory, and monitor domains. Furthermore, depression moderated the abdominal overweight-GEC association (P = 0.032 for interaction term), especially for emotional control, working memory, and initiate dimensions. Moreover, we also found abdominal thinness was associated with the Metacognition Index problem (OR = 1.33, 95% CI 1.04-1.72), particularly for plan and monitor areas. CONCLUSIONS: Both abdominal overweight and thinness were associated with adolescent EF, and depression would be a modifiable target to improve EF in adolescents with abdominal overweight. Future longitudinal studies are needed to investigate the causal relationship between abdominal weight spectrum and EF, as well as the underlying mechanisms among adolescents suffering from depression.

18.
Phytomedicine ; 101: 154125, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35525236

ABSTRACT

BACKGROUND: Parkinson's disease (PD) is a multi-factorial neurodegenerative disease affecting motor function of patients. The hall markers of PD are dopaminergic neuron loss in the midbrain and the presence of intra-neuronal inclusion bodies mainly composed of aggregation-prone protein alpha-synuclein (α-syn). Ubiquitin-proteasome system (UPS) is a multi-step reaction process responsible for more than 80% intracellular protein degradation. Impairment of UPS function has been observed in the brain tissue of PD patients. PDE4 inhibitors have been shown to activate cAMP-PKA pathway and promote UPS activity in Alzheimer's disease model. α-mangostin is a natural xanthonoid with broad biological activities, such as antioxidant, antimicrobial and antitumour activities. Structure-based optimizations based on α-mangostin produced a potent PDE4 inhibitor, 4e. Herein, we studied whether 4e could promote proteasomal degradation of α-syn in Parkinson's disease models through PKA activation. METHODS: cAMP Assay was conducted to quantify cAMP levels in samples. Model UPS substrates (Ub-G76V-GFP and Ub-R-GFP) were used to monitor UPS-dependent activity. Proteasome activity was investigated by short peptide substrate, Suc-LLVY-AMC, cleavage of which by the proteasome increases fluorescence sensitivity. Tet-on WT, A30P, and A53T α-syn-inducible PC12 cells and primary mouse cortical neurons from A53T transgenic mice were used to evaluate the effect of 4e against α-syn in vitro. Heterozygous A53T transgenic mice were employed to assess the effect of 4e on the clearance of α-syn in vivo, and further validations were applied by western blotting and immunohistochemistry. RESULTS: Taken together, α-mangostin derivative 4e, a PDE4 inhibitor, efficiently activated the cAMP/PKA pathway in neuronal cells, and promoted UPS activity as evidenced by enhanced degradation of UPS substrate Ub-G76V-GFP and Ub-R-GFP, as well as elevated proteasomal enzyme activity. Interestingly, 4e dramatically accelerated degradation of inducibly-expressed WT and mutant α-syn in PC12 cells, in a UPS dependent manner. Besides, 4e consistently activated PKA in primary neuron and A53T mice brain, restored UPS inhibition and alleviated α-syn accumulation in the A53T mice brain. CONCLUSIONS: 4e is a natural compound derived highly potent PDE4 inhibitor. We revealed its potential effect in promoting UPS activity to degrade pathogenic proteins associated with PD.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Neurodegenerative Diseases , Parkinson Disease , Phosphodiesterase 4 Inhibitors , Animals , Dopaminergic Neurons/metabolism , Enzyme Activation/drug effects , Humans , Mice , Mice, Transgenic , Neurodegenerative Diseases/metabolism , Parkinson Disease/metabolism , Phosphodiesterase 4 Inhibitors/metabolism , Phosphodiesterase 4 Inhibitors/pharmacology , Proteasome Endopeptidase Complex/metabolism , Rats , Ubiquitin/metabolism , Xanthones , alpha-Synuclein/metabolism
19.
Angew Chem Int Ed Engl ; : e202205312, 2022 May 06.
Article in English | MEDLINE | ID: mdl-35514288

ABSTRACT

Infinite coordination-polymer particles (CPPs) are promising materials for solar energy conversion with high efficiency. However, the range of organic ligands that may be used to create CPPs is limited, as are strategies for modification, thereby hindering the applications of such material. In this paper, competitive evolution-morphological and structural change from Zn-based crystallites to amorphous particles is described. Controlled contribution of organic linkers selectively derived six Zn-CPPs with multivariate characters. Based on the diversity of these substructures, hollow zinc oxide particles were initially formed by self-pyrolysis of CPPs and effectively modified by ultrathin doped nanosheets. The obtained double-sided heterojunctions offer fully-covered active sites, bringing together efficient light-excited charge-transfer nanochannels, which exhibit an excellent solar H2 -releasing activity (e.g., 4512.5 µmol h-1 g-1 ) and stable cyclability.

20.
RSC Adv ; 9(27): 15582-15592, 2019 May 14.
Article in English | MEDLINE | ID: mdl-35514830

ABSTRACT

Rotator cuff tear (RCT) is a major challenging shoulder disease because the fibrocartilage zone is hard to regenerate in the enthesis. Electrospun membranes with aligned nanofibers can guide the ordered tissue regeneration and kartogenin (KGN) is able to stimulate chondrocyte differentiation of mesenchymal stem cells. In this study, we fabricated a functional engineered scaffold for regenerating tendon-bone enthesis in RCTs by taking advantage of both the structural guiding ability of aligned nanofibers and the biology effects of KGN. Polycaprolactone (PCL) fibrous membranes with aligned nanofibers loaded with or without KGN were fabricated using electrospinning and characterized using scanning electron microscopy (SEM). The release of KGN from PCL membranes and the effects of KGN on differentiation of mesenchymal stem cells were investigated. Results indicated that 100 µM KGN-loaded PCL (KGN-PCL) membranes significantly stimulated chondrogenic and tenogenic differentiation of rat bone marrow stromal cells. In addition, after PCL and 100 µM KGN-PCL membranes were applied to an acute rat RCT model, KGN-PCL membranes promoted fibrocartilage formation and collagen organization as well as increased cross-sectional area and load failure. In conclusion, PCL electrospun fibrous membranes with aligned nanofibers and KGN could be an effective tissue engineering scaffold to enhance tendon-bone healing in RCTs.

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