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1.
FASEB J ; 36 Suppl 12022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35553340

RESUMO

The inhibition of calcineurin (PP2B) with tacrolimus (FK506) or cyclosporin A (CsA), two frequently used immunosuppressive drugs after organ transplantation, has been shown to stimulate cation-coupled Cl- cotransporters such as NCC and NKCC2. Also, the stimulation of NCC induced by CsA or FK506 may be responsible for PP2B-inhibition-induced hypertension and hyperkalemia. The aim of the present study is to test whether acute application of FK506 or CsA also stimulates the basolateral K+ channels in the distal convoluted tubule (DCT) thereby activating NCC expression/activity. We first used patch-clamp technique to examine the effect of FK506 or CsA on the basolateral Kir4.1/Kir5.1 activity in the DCT. Acutely addition of FK506 (5-10 uM) stimulates the 40 pS K+ (Kir4.1/Kir5.1 heterotetramer) channel activity in the DCT and increases the NPo from 1.6 to 2.6. Moreover, acutely addition of FK506 (10 uM) increases the whole-cell K+ currents from 1180 pA to 2050 pA in the DCT cells. As consequence of the stimulation of Kir4.1/Kir5.1, K-currents (IK ) reversal potential (an index of the membrane potential) becomes more negative in FK506 treated DCT than untreated (-73 mV vs -62 mV). To examine whether FK506-induced stimulation of Kir4.1/Kir5.1 in the DCT requires the FKBP12 (12 kDa FK506 binding protein), we then examined the effect of FK506 on the basolateral K+ channels in the DCT1 of kidney-tubule-specific (Ks)-FKBP12 KO mice. The control and Ks-FKBP12 KO mice were treated with FK506 (0.75 mg/Kg BW) by peritoneal injection 30 min before experiments. The stimulatory effect of FK506 on Kir4.1/Kir5.1 of the DCT is observed only in the control but is absent in Ks-FKBP12 KO mice, suggesting the effect of FK506 is due to the inhibition of PP2B. Moreover, we have used the whole-cell recording technique to examine the effect of CsA on the Ba2+ -sensitive K+ currents in the control and FKBP12-deficient mice because CsA-induced inhibition of PP2B requires binding to cyclophilin but not to FKBP12. We observed that CsA treatment (3 mg/Kg BW by peritoneal injection 30 min before experiments) significantly increases the whole-cell K+ currents in both control and Ks-FKBP12 KO mice. Fluorescence image shows that CsA treatment for 30 min increased the expression of Kir4.1 and pNCC (Serine 71) in the basolateral membrane and apical membrane, respectively. To determine whether the activation of the basolateral K+ channel activity in the DCT is essential for FK506-induced stimulation of NCC expression, we next examined the effect of FK506 treatment on the expression of pNCC and tNCC in the control (Kcnj10flox/flox ) and in kidney-tubule-specific (Ks-Kir4.1) KO mice. Acute FK506 treatment (peritoneal injection of FK506 at 0.75 mg/Kg BW) robustly increases the expression of pNCC and tNCC. However, the stimulatory effect of FK506 on NCC is blunted in Ks-Kir4.1 KO mice, suggesting the role of Kir4.1 in mediating PP2B-inhibition induced stimulation of NCC. We conclude that acute inhibition of PP2B stimulates the basolateral Kir4.1/Kir5.1 activity of the DCT and NCC and that the acute effect of PP2B inhibition on NCC is partially achieves by stimulation of the basolateral Kir4.1/Kir5.1.

2.
FASEB J ; 36 Suppl 12022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35556422

RESUMO

BACKGROUND: Mineralocorticoid receptor (MR) antagonists are recommended for patients with resistant hypertension independent of circulating aldosterone levels. Aldosterone, secreted in response to salt depletion or hyperkalemia, activates MR to increase epithelial sodium channel (ENaC) activity. While glucocorticoids can also activate MR, they are metabolized by 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), protecting MR from illicit glucocorticoid occupation. 11ß-HSD2 is expressed at increasing levels from the DCT through the collecting duct. Here, we hypothesized that glucocorticoid occupies MR to stimulate ENaC in the DCT2 and early connecting tubule. METHODS: We studied aldosterone synthase knockout (AS-/- ) mice provided by Dr. JM Luther. Kidney-specific MR knockout (MR-/- ) mice were used for validation of Western blot for ENaC and immunofluorescence for MR. We measured plasma and urinary electrolytes at baseline, and following dietary salt restriction with or without administration of the MR antagonist eplerenone. RESULTS: AS-/- mice displayed higher plasma K+ levels than AS+/+ mice but not salt wasting under baseline. Under low salt (LS) diet, AS-/- mice exhibited higher urine Na+ excretion, but preserved body weight. Cleaved αENaC and γENaC abundances were lower in AS-/- than AS+/+ mice, and were not increased in AS-/- mice after LS diet. Notably, we found nuclear localization of MR was preserved in DCT2 of AS-/- mice. Administration of the MR blocker eplerenone to AS-/- mice fed LS diet led to hyperkalemia and decreased body weight with higher Na+ excretion, mimicking the phenotype of MR-/- mice. CONCLUSIONS: Our results provide evidence that MR is occupied in the absence of aldosterone, suggesting glucocorticoid-binding to MR preserves sodium homeostasis in the DCT2 of AS-/- mice. This likely explains the milder phenotype of AS-/- mice compared with MR-/- mice.

3.
J Gastrointest Oncol ; 13(2): 462-477, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35557566

RESUMO

Background: Esophageal cancer is one of the most common gastrointestinal malignancies worldwide, with high morbidity and mortality in China. The clinical importance of the interaction between hypoxia and immune status in the tumor microenvironment has been established in esophageal squamous cell carcinoma (ESCC). This study aims to develop a new hypoxia- and immune-based gene signature to predict the survival of ESCC patients. Methods: The RNA-sequencing and clinical data of 173 cases of ESCC and 271 normal tissues were obtained from The Cancer Genome Atlas (TCGA) data portal and the Genotype-Tissue Expression (GTEx) database. Hypoxia-related genes (HRGs) and immune-related genes (IRGs) were retrieved from publicly shared data. Differentially expressed gene (DEG) analyses were carried out by the DESeq2 method using the edgeR package in R. Based on the intersection of the DEGs and HRGs/IRGs, differentially expressed HRGs (DEHRGs) and differentially expressed IRGs (DEIRGs) were obtained. DEHRGs and DEIRGs associated with prognosis were evaluated using univariate Cox proportional hazards analysis. A prognostic risk score model was constructed according to the genes acquired through Cox regression. Univariate analysis and Cox proportional hazards analysis were used to determine the independent prognostic factors related to prognosis. A nomogram was developed to predict the 1-, 2-, and 3-year overall survival (OS) probability. Results: A total of 73 intersecting genes were obtained as DEHRGs and a total of 548 intersecting genes were obtained as DEIRGs. The risk score was established using 8 genes (FABP7, TLR1, SYTL1, APLN, OSM, EGFR, IL17RD, MYH9) acquired from univariate Cox analysis. Based on this 8-gene-based risk score, a risk prognosis classifier was constructed to classify the samples into high- and low-risk groups according to the median risk score. The nomogram model was constructed to predict the OS of ESCC patients. Conclusions: The hypoxia- and immune-based gene signature might serve as a prognostic classifier for clinical decision-making regarding individualized management, follow-up plans, and treatment strategies for ESCC patients.

4.
Biochem Biophys Res Commun ; 612: 63-69, 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35504091

RESUMO

Eugenol (4-allyl -2- methoxyphenol), reportedly, a native compound that widely exists in a variety of plants, shows diverse biological activities such as anti-bacteria, anti-inflammation and anti-oxidation. This work was to delve into the effects and molecular mechanisms of eugenol on the phenotypes of fibroblast-like synovial cells from rheumatoid arthritis (RA). Fibroblast-like synovial cells treated with tumor necrosis factor-α (TNF-α) for 24 h received eugenol treatment. In this study, we found eugenol could inhibit TNF-α-induced proliferation, migration, invasion, angiogenesis and inflammatory response of fibroblast-like synovial cells, and promote apoptosis. Eugenol's target genes were significantly associated with vascular endothelial growth factor (VEGF) and NF-kappaB (NF-κB) signaling pathway. Eugenol reversed the promoting effect of TNF-α on the expression of NF-κB signaling pathway-related proteins as well as prostaglandin-endoperoxide synthase 2 (PTGS2, also known as COX-2) protein. In addition, the NF-κB pathway inhibitor Bay11-7082 markedly restrained the viability, migration, aggressiveness, and angiogenic and inflammatory responses of TNF-α-induced fibroblast-like synovial cells and promoted apoptosis. In conclusion, eugenol may represent a novel drug to suppress the progression of RA by inhibiting NF-κB signaling pathway and COX-2 expression in fibroblast-like synovial cells.

5.
Anal Chim Acta ; 1209: 339864, 2022 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-35569874

RESUMO

Latent fingerprints (LFPs) powders play a crucial part in the detection of LFPs by powder-dusting methods in forensic sciences, due to the facile, onsite, and easy-to-operate properties. However, conventional LFPs powders suffer from some drawbacks, such as high toxicity, low contrast, sensitivity and selectivity. Herein, a novel fluorescent composite powder was synthesized and used for the detection of LFPs. The resultant composite powder shows an enhanced fluorescence due to the protection of the emission of fluorescent carbonized nanoparticles (FCNPs) from being quenched in the solid state. Subsequently, the fluorescent composite powder was successfully applied to detect LFPs on various substrates. This work provides a promising strategy for developing FCNPs-based fluorescent powders for the detection of LFPs in forensic science.

6.
Ann Transl Med ; 10(8): 440, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35571433

RESUMO

Background: The optimal treatment strategy for patients with early glottic (T1-2N0M0) squamous cancer remains unclear. Methods: A retrospective population-based analysis was performed using the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was used to balance treatment arms, and Cox regression analysis was used to determine prognostic factors for survival. Kaplan-Meier analysis, log-rank tests, and competing risk analysis were used to compare survival outcomes between treatment modalities (surgery vs. radiotherapy). Results: Among the 3,994 eligible patients in this study, surgery was associated with improved cancer-specific survival (CSS) and overall survival (OS) compared with radiotherapy (log-rank test, P<0.05). This survival trend favoring surgery was consistent in the T1a, well/moderately differentiated grade, male, and all age subgroups. However, after the baseline characteristics were balanced with PSM, the survival outcomes (CSS and OS) did not differ significantly between the surgery and radiotherapy groups. Interestingly, surgery was associated with a 39% reduced risk of cancer-related death compared with radiotherapy in patients aged ≥70 years (hazard ratio 0.61; 95% CI: 0.43-0.87; P=0.006). However, this survival trend favoring surgery was not observed in younger patients (age <70 years), T stage subgroups, male or female subgroups, or in any of the pathological grade subgroups. Conclusions: In patients with early glottic squamous cell carcinoma undergoing surgery or radiotherapy, there is no sufficient evidence favoring one method over another in terms of survival. However, surgery is recommended in patients aged ≥70 years because, in this group, it was associated with improved survival outcomes compared with radiotherapy.

7.
Front Vet Sci ; 9: 878467, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35573414

RESUMO

Secreted immunoglobulin A (SIgA), IgG, and IgM play a crucial role in forming the intestinal mucosal immune barrier, and parasites could disturb the host's immune response by releasing various immunomodulatory molecules. Moniezia benedeni is an important pathogen parasitizing in the sheep small intestine. It is aimed to explore the residence characteristics of IgA+, IgG+, and IgM+ cells in the sheep small intestine, and the influence of Moniezia benedeni infection on them. Control group (n = 6) and infected group (n = 6) were selected, respectively, and the three subtype cells residing in the small intestine were systematically observed and analyzed. The results showed that in the Control group, the three types of positive cells were all distributed diffusely, and the total densities in jejunum, duodenum and ileum was gradually declined in turn. Notably, the change trend of IgA+ and IgG+ cells densities were both congruent with the total densities, and the differences among them were significant, respectively (P < 0.05); the IgM+ cells density was the highest in duodenum, followed by jejunum and ileum, there was no significant difference between duodenum and jejunum (P > 0.05), but both significantly higher than in ileum (P < 0.05). In the Infected group, their total densities in duodenum, jejunum and ileum were gradually declined in turn. Notably, the IgA+ and IgM+ cells densities change trend was the same as the total densities, and the differences among them were significant, respectively (P < 0.05). The IgG+ cells density in duodenum was the highest, followed by ileum and jejunum and there was significantly difference among them (P < 0.05). The comparison results between Control and Infected groups showed that from the duodenum, jejunum to ileum, IgA+, IgG+, and IgM+ cells were all reduced significantly, respectively. The results suggest that the three types of positive cells were resided heterogeneously in the small intestinal mucosa, that is, significant region-specificity; Moniezia benedeni infection could not change their diffuse distribution characteristics, but strikingly, reduce their resident densities, and the forming mucosal immune barrier were significantly inhibited. It provided powerful evidence for studying on the molecular mechanism of Moniezia benedeni evasion from immune surveillance by strongly inhibiting the host's mucosal immune barrier.

8.
Front Oncol ; 12: 854137, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35574329

RESUMO

Background: Breast cancer is one of the most commonly diagnosed cancers, and the fourth leading cause of cancer deaths in females worldwide. Sarcopenia is related to adverse clinical outcomes in patients with malignancies. Muscle index is a key parameter in evaluating sarcopenia. However, there is no data investigating the association between muscle index and distant metastasis in breast cancer. The aim of this study was to explore whether muscle index can effectively predict distant metastasis and death outcomes in breast cancer patients. Study Design: The clinical data of 493 breast cancer patients at the Harbin Medical University Cancer Hospital between January 2014 and December 2015 were retrospectively analyzed. Quantitative measurements of pectoralis muscle area and skeletal muscle area were performed at the level of the fourth thoracic vertebra (T4) and the eleventh thoracic vertebra (T11) of the chest computed tomography image, respectively. The pectoralis muscle index (PMI) and skeletal muscle index (SMI) were assessed by the normalized muscle area (area/the square of height). Survival analysis was performed using the log-rank test and Cox proportional hazards regression analysis. Result: The patients with metastases had lower PMI at T4 level (PMI/T4) and SMI at T11 level (SMI/T11) compared with the patients without metastases. Moreover, there were significant correlations between PMI/T4 and lymphovascular invasion, Ki67 expression, multifocal disease, and molecular subtype. In addition, multivariate analysis revealed that PMI/T4, not SMI/T11, was an independent prognostic factor for distant metastasis-free survival (DMFS) and overall survival (OS) in breast cancer patients. Conclusions: Low PMI/T4 is associated with worse DMFS and OS in breast cancer patients. Future prospective studies are needed.

9.
Plant Divers ; 44(2): 201-212, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35505987

RESUMO

The B3 transcription factors (TFs) in plants play vital roles in numerous biological processes. Although B3 genes have been broadly identified in many plants, little is known about their potential functions in mediating seed development and material accumulation. Castor bean (Ricinus communis) is a non-edible oilseed crop considered an ideal model system for seed biology research. Here, we identified a total of 61 B3 genes in the castor bean genome, which can be classified into five subfamilies, including ABI3/VP1, HSI, ARF, RAV and REM. The expression profiles revealed that RcABI3/VP1 subfamily genes are significantly up-regulated in the middle and later stages of seed development, indicating that these genes may be associated with the accumulation of storage oils. Furthermore, through yeast one-hybrid and tobacco transient expression assays, we detected that ABI3/VP1 subfamily member RcLEC2 directly regulates the transcription of RcOleosin2, which encodes an oil-body structural protein. This finding suggests that RcLEC2, as a seed-specific TF, may be involved in the regulation of storage materials accumulation. This study provides novel insights into the potential roles and molecular basis of B3 family proteins in seed development and material accumulation.

10.
Macromol Rapid Commun ; : e2200276, 2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35567333

RESUMO

The development of wide-bandgap polymer donors having complementary absorption and compatible energy levels with near-infared (NIR) absorbing nonfullerene acceptors is highly important for realizing high-performance organic solar cells (OSCs). Herein, a new thiophene-fused diazabenzo[k]fluoranthene derivative has been successfully synthesized as the electron-deficient unit to construct an efficient donor-acceptor (D-A) type alternating copolymer donor, namely PABF-Cl, using the chlorinated benzo[1,2-b:4,5-b']dithiophene as the copolymerization unit. PABF-Cl exhibits a wide optical bandgap of 1.93 eV, a deep highest occupied molecular level of -5.36 eV, and efficient hole transport. As a result, OSCs with the best power conversion efficiency of 11.8% has been successfully obtained by using PABF-Cl as the donor to blend with a NIR absorbing BTP-eC9 acceptor. Our work thus provides a new design of electron-deficient unit for constructing high performance D-A type polymer donors. This article is protected by copyright. All rights reserved.

11.
J Biomed Sci ; 29(1): 29, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534851

RESUMO

BACKGROUND: Castration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite androgen depletion therapy. The Jumonji C-containing histone lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as critical coactivators of AR to promote tumor growth in prostate cancer and are candidate therapeutic targets to overcome AR mutations/alterations-mediated resistance in CRPC. METHODS: In this study, using a structure-based approach, we identified a natural product, myricetin, able to block the demethylation of histone 3 lysine 9 trimethylation by KDM4 members and evaluated its effects on CRPC. A structure-based screening was employed to search for a natural product that inhibited KDM4B. Inhibition kinetics of myricetin was determined. The cytotoxic effect of myricetin on various prostate cancer cells was evaluated. The combined effect of myricetin with enzalutamide, a second-generation AR inhibitor toward C4-2B, a CRPC cell line, was assessed. To improve bioavailability, myricetin encapsulated by poly lactic-co-glycolic acid (PLGA), the US food and drug administration (FDA)-approved material as drug carriers, was synthesized and its antitumor activity alone or with enzalutamide was evaluated using in vivo C4-2B xenografts. RESULTS: Myricetin was identified as a potent α-ketoglutarate-type inhibitor that blocks the demethylation activity by KDM4s and significantly reduced the proliferation of both androgen-dependent (LNCaP) and androgen-independent CRPC (CWR22Rv1 and C4-2B). A synergistic cytotoxic effect toward C4-2B was detected for the combination of myricetin and enzalutamide. PLGA-myricetin, enzalutamide, and the combined treatment showed significantly greater antitumor activity than that of the control group in the C4-2B xenograft model. Tumor growth was significantly lower for the combination treatment than for enzalutamide or myricetin treatment alone. CONCLUSIONS: These results suggest that myricetin is a pan-KDM4 inhibitor and exhibited potent cell cytotoxicity toward CRPC cells. Importantly, the combination of PLGA-encapsulated myricetin with enzalutamide is potentially effective for CRPC.


Assuntos
Antineoplásicos , Produtos Biológicos , Flavonoides , Neoplasias de Próstata Resistentes à Castração , Androgênios/farmacologia , Androgênios/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Flavonoides/farmacologia , Glicolatos , Glicóis/farmacologia , Glicóis/uso terapêutico , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/farmacologia , Masculino , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores Androgênicos/uso terapêutico
12.
J Ethnopharmacol ; 294: 115365, 2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35597411

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a chronic non-specific intestinal inflammatory disease, the pathogenesis of which is strongly associated with the compromised intestinal barrier. Paeoniae Radix Alba (PRA), the root of Paeonia lactiflora Pall., is a well-known traditional Chinese medicine and an adaptogen used in Hozai, exhibiting appreciable anti-inflammatory and immunomodulatory activity. Nevertheless, the role and mechanism of PRA in UC have yet to be elucidated. AIM OF THE STUDY: This study was set out to examine the ameliorative effects of the aqueous extract of PRA (i.e., PRA dispensing granule, PRADG) on dextran sulfate sodium (DSS)-induced colitis. MATERIALS AND METHODS: The chemical components of PRADG was analyzed by HPLC. Colitis model mice were induced by free access to water containing 2.5% DSS for 10 consecutive days, and concurrently, PRADG (0.1025 and 0.41 g/kg) or Salazosulfapyridine (SASP, 450 mg/kg) was given orally from day 1-10. Body weight, disease activity index (DAI), colon length, histologic scoring, and inflammatory response were assessed. Additionally, IL-23/IL-17 axis and tight junction (TJ) proteins, as well as gut microbiota were also investigated under the above-mentioned regimen. RESULTS: Eight main chemical constituents of CPT were revealed with HPLC analysis. Noticeably, PRADG could effectively lower body weight loss as well as DAI scores, alleviate colon shortening, and reduce the levels of proinflammatory cytokines in mice with colitis. Further exploration found that increment of TJ proteins expression (ZO-1, occludin and claudin-1) and inhibition of IL-23/IL-17 axis-modulated inflammation were observed in PRADG-treated mice. Additionally, the diversity of gut microbiota and the relative abundance of beneficial bacteria were increased following PRADG treatment. CONCLUSIONS: PRADG could be sufficient to ameliorate colitis by regulating the intestinal physical barrier, immune responses, and gut microbiota in mice. Our findings highlight that PRADG might be a prospective remedy for UC.

13.
J Sep Sci ; 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35503988

RESUMO

An herbal prescription is usually composed of several herbal medicines. The complex and diverse components bring great challenges to its bioactivity study. To comprehensively analyze the bioactivity of an herbal prescription, a new strategy based on peak-by-peak cutting and knock-out chromatography was proposed. In this strategy, active compounds were screened out via peak-by-peak cutting from an herbal extract, and the influence of a compound on the overall activity of the herbal extract was evaluated by knock-out chromatography. Qiliqiangxin capsule is an herbal prescription composed of 11 herbal medicines for the treatment of chronic heart failure. A total of 71 peaks were collected through peak-by-peak cutting, and each peak was identified by high-resolution mass spectrum. The bioassay against 1,1-diphenyl-2-picrylhydrazyl showed that two types of compounds namely salvianolic acids and caffeoylquinic acids were potent scavengers. Knock-out chromatography suggested that the removement of one single compound had no obvious influence on the overall activity of Qiliqiangxin capsule. After all the main peaks in Qiliqiangxin capsule were knocked out, the remaining part still exhibited a potent activity, indicating a high activity stability of Qiliqiangxin capsule. The proposed strategy is helpful for the comprehensive analysis of the bioactivity of other herbal prescriptions. This article is protected by copyright. All rights reserved.

14.
J Biol Chem ; : 102002, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35504351

RESUMO

P2X receptors are a class of non-selective cation channels widely distributed in the immune and nervous systems, and their dysfunction is a significant cause of tumors, inflammation, leukemia, and immune diseases. P2X7 is a unique member of the P2X receptor family with many properties that differ from other subtypes in terms of primary sequence, the architecture of N- and C-terminals, and channel function. Here, we suggest that the observed lengthened ß2- and ß3-sheets and their linker (loop ß2,3), encoded by redundant sequences, play an indispensable role in the activation of the P2X7 receptor. We show that deletion of this longer structural element leads to the loss of P2X7 function. Furthermore, by combining mutagenesis, chimera construction, surface expression, and protein stability analysis, we found that the deletion of the longer ß2,3-loop affects P2X7 surface expression, but more importantly, that this loop affects channel gating of P2X7. We propose that the longer ß2,3-sheets may have a negative regulatory effect on a loop on the head domain and on the structural element formed by E171 and its surrounding regions. Understanding the role of the unique structure of the P2X7 receptor in the gating process will aid in the development of selective drugs targeting this subtype.

15.
Hypertension ; : 101161HYPERTENSIONAHA12219159, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35506380

RESUMO

BACKGROUND: MR (mineralocorticoid receptor) antagonists are recommended for patients with resistant hypertension even when circulating aldosterone levels are not high. Although aldosterone activates MR to increase epithelial sodium channel (ENaC) activity, glucocorticoids also activate MR but are metabolized by 11ßHSD2 (11ß-hydroxysteroid dehydrogenase type 2). 11ßHSD2 is expressed at increasing levels from distal convoluted tubule (DCT) through collecting duct. Here, we hypothesized that MR maintains ENaC activity in the DCT2 and early connecting tubule in the absence of aldosterone. METHODS: We studied AS (aldosterone synthase)-deficient (AS-/-) mice, which were backcrossed onto the same C57Bl6/J strain as kidney-specific MR knockout (KS-MR-/-) mice. KS-MR-/- mice were used to compare MR expression and ENaC localization and cleavage with AS-/- mice. RESULTS: MR was highly expressed along DCT2 through the cortical collecting duct (CCD), whereas no 11ßHSD2 expression was observed along DCT2. MR signal and apical ENaC localization were clearly reduced along both DCT2 and CCD in KS-MR-/- mice but were fully preserved along DCT2 and were partially reduced along CCD in AS-/- mice. Apical ENaC localization and ENaC currents were fully preserved along DCT2 in AS-/- mice and were not increased along CCD after low salt. AS-/- mice exhibited transient Na+ wasting under low-salt diet, but administration of the MR antagonist eplerenone to AS-/- mice led to hyperkalemia and decreased body weight with higher Na+ excretion, mimicking the phenotype of MR-/- mice. CONCLUSIONS: Our results provide evidence that MR is activated in the absence of aldosterone along DCT2 and partially CCD, suggesting glucocorticoid binding to MR preserves sodium homeostasis along DCT2 in AS-/- mice.

16.
Photochem Photobiol ; 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35506756

RESUMO

Blue light is a crucial environmental cue for fungi. Hypocrellin A (HA) is a photoactive perylenequinone from Shiraia with strong antimicrobial and anticancer properties. In this study, effects of the illumination of blue-light-emitting diode (LED) at 470 nm on Shiraia sp. S8 were investigated. Blue light at 50-200 lx and 4-6 h day-1 could enhance HA content in the mycelia, but suppress it at 300-400 lx or with longer exposure (8-24 h day-1 ). The intermittent blue light (6 h day-1 ) at 200 lx not only enhanced the fungal conidiation but also stimulated HA production without any growth retardation. The generation of fungal reactive oxygen species was induced to upregulate HA biosynthetic gene expressions. When the culture was maintained under the intermittent blue light for 8 days, HA production reached 242.76 mg L-1 , 2.27-fold of the dark control. On the other hand, both the degradation of HA and downregulation of HA biosynthetic genes occurred under long exposure time (8-24 h day-1 ), leading to the suppression of HA production. These results provide a basis for understanding the regulation of blue light on the biosynthesis of fungal photoactivated perylenequinones, and the application of a novel light elicitation to Shiraia mycelium cultures for enhanced HA production.

17.
Int J Biol Macromol ; 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35526771

RESUMO

Chondroitin sulfate (CCS) was purified from discarded codfish (Gadus macrocephalus) bones, and its chemical structure and anticoagulant activity were assessed. CCS was obtained via enzymatic lysis and ion-exchange column chromatography, with a yield of approximately 0.15%. High-performance gel performance chromatography revealed CCS to be a largely homogeneous polysaccharide with a relatively low molecular weight of 12.3 kDa. FT-IR spectroscopy, NMR spectroscopy, and SAX-HPLC indicated that CCS was composed of monosulfated disaccharides (ΔDi4S 73.85% and ΔDi6S 19.06%) and nonsulfated disaccharides (ΔDi0S 7.09%). In vitro anticoagulation analyses revealed that CCS was able to significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT) (p < 0.05). At a CCS concentration of 5 µg/mL and 25 µg/mL, APTT and TT were approximately 1.08 and 1.12 times higher, respectively, compared to the negative control group. The results indicated that CCS might offer value as a dietary fiber supplement with the potential to prevent the incidence of coagulation-related thrombosis.

18.
Front Neurosci ; 16: 850193, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35527820

RESUMO

In response to external threatening signals, animals evolve a series of defensive behaviors that depend on heightened arousal. It is believed that arousal and defensive behaviors are coordinately regulated by specific neurocircuits in the central nervous system. The ventral tegmental area (VTA) is a key structure located in the ventral midbrain of mice. The activity of VTA glutamatergic neurons has recently been shown to be closely related to sleep-wake behavior. However, the specific role of VTA glutamatergic neurons in sleep-wake regulation, associated physiological functions, and underlying neural circuits remain unclear. In the current study, using an optogenetic approach and synchronous polysomnographic recording, we demonstrated that selective activation of VTA glutamatergic neurons induced immediate transition from sleep to wakefulness and obviously increased the amount of wakefulness in mice. Furthermore, optogenetic activation of VTA glutamatergic neurons induced multiple defensive behaviors, including burrowing, fleeing, avoidance and hiding. Finally, viral-mediated anterograde activation revealed that projections from the VTA to the central nucleus of the amygdala (CeA) mediated the wake- and defense-promoting effects of VTA glutamatergic neurons. Collectively, our results illustrate that the glutamatergic VTA is a key neural substrate regulating wakefulness and defensive behaviors that controls these behaviors through its projection into the CeA. We further discuss the possibility that the glutamatergic VTA-CeA pathway may be involved in psychiatric diseases featuring with excessive defense.

19.
Appl Psychol Meas ; 46(3): 185-199, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35528270

RESUMO

Cognitive diagnosis computerized adaptive testing (CD-CAT) aims to identify each examinee's strengths and weaknesses on latent attributes for appropriate classification into an attribute profile. As the cost of a CD-CAT misclassification differs across user needs (e.g., remedial program vs. scholarship eligibilities), item selection can incorporate such costs to improve measurement efficiency. This study proposes such a method, minimum expected risk (MER), based on Bayesian decision theory. According to simulations, using MER to identify examinees with no mastery (MER-U0) or full mastery (MER-U1) showed greater classification accuracy and efficiency than other methods for these attribute profiles, especially for shorter tests or low quality item banks. For other attribute profiles, regardless of item quality or termination criterion, MER methods, modified posterior-weighted Kullback-Leibler information (MPWKL), posterior-weighted CDM discrimination index (PWCDI), and Shannon entropy (SHE) performed similarly and outperformed posterior-weighted attribute-level CDM discrimination index (PWACDI) in classification accuracy and test efficiency, especially on short tests. MER with a zero-one loss function, MER-U0, MER-U1, and PWACDI utilized item banks more effectively than the other methods. Overall, these results show the feasibility of using MER in CD-CAT to increase the accuracy for specific attribute profiles to address different user needs.

20.
Zhongguo Dang Dai Er Ke Za Zhi ; 24(4): 411-416, 2022 Apr 15.
Artigo em Chinês | MEDLINE | ID: mdl-35527417

RESUMO

OBJECTIVES: To study the expression level of plasma miR-106b-5p in primary immune thrombocytopenia (ITP) and its correlation with the levels of T helper 17 cell (Th17) and regulatory T cell (Treg) and the Th17/Treg ratio. METHODS: A total of 79 children with ITP (ITP group) and 40 healthy children (control group) were selected as subjects. According to the treatment response, the 79 children with ITP were divided into three groups: complete response (n=40), partial response (n=18), and non-response (n=21). Quantitative real-time PCR was used to measure the expression level of miR-106b-5p. Flow cytometry was used to measure the frequencies of Th17 and Treg, and the Th17/Treg ratio was calculated. The correlation of the expression level of plasma miR-106b-5p with the frequencies of Th17 and Treg and the Th17/Treg ratio was analyzed. RESULTS: Compared with the control group, the ITP group had significantly higher levels of miR-106b-5p, Th17, and Th17/Treg ratio (P<0.05) and a significantly lower level of Treg (P<0.05). After treatment, the ITP group had significant reductions in the levels of miR-106b-5p, Th17, and Th17/Treg ratio (P<0.05) and a significant increase in the level of Treg (P<0.05). Compared with the partial response and non-response groups, the complete response group had significantly lower levels of miR-106b-5p, Th17, and Th17/Treg ratio (P<0.05) and a significantly higher level of Treg (P<0.05). The correlation analysis showed that in the children with ITP, the expression level of plasma miR-106b-5p was positively correlated with the Th17 level and the Th17/Treg ratio (r=0.730 and 0.816 respectively; P<0.001) and was negatively correlated with the Treg level (r=-0.774, P<0.001). CONCLUSIONS: A higher expression level of miR-106b-5p and Th17/Treg imbalance may be observed in children with ITP. The measurement of miR-106b-5p, Th17, Treg, and Th17/Treg ratio during treatment may be useful to the evaluation of treatment outcome in children with ITP.


Assuntos
MicroRNAs , Púrpura Trombocitopênica Idiopática , Linfócitos T Reguladores , Células Th17 , Criança , Humanos , Contagem de Linfócitos , MicroRNAs/genética , Púrpura Trombocitopênica Idiopática/genética
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