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1.
J Am Heart Assoc ; 11(19): e026581, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36172956

RESUMO

Background A beneficial role for prostanoids in hypertension is suggested by clinical studies showing nonsteroidal anti-inflammatory drugs, which block the production of all prostanoids, cause sodium retention and exacerbate hypertension. Among prostanoids, prostaglandin E2 and its E-prostanoid receptor 4 receptor (EP4R) have been implicated in blood pressure control. Our previous study found that conditional deletion of EP4R from all tissues in adult mice exacerbates angiotensin II-dependent hypertension, suggesting a powerful effect of EP4R to resist blood pressure elevation. We also found that elimination of EP4R from vascular smooth muscle cells did not affect the severity of hypertension, suggesting nonvascular targets of prostaglandin E mediate this antihypertensive effect. Methods and Results Here we generated mice with cell-specific deletion of EP4R from macrophage-specific EP4 receptor knockouts or kidney epithelial cells (KEKO) to assess the contributions of EP4R in these cells to hypertension pathogenesis. Macrophage-specific EP4 receptor knockouts showed similar blood pressure responses to alterations in dietary sodium or chronic angiotensin II infusion as Controls. By contrast, angiotensin II-dependent hypertension was significantly augmented in KEKOs (mean arterial pressure: 146±3 mm Hg) compared with Controls (137±4 mm Hg; P=0.02), which was accompanied by impaired natriuresis in KEKOs. Because EP4R expression in the kidney is enriched in the collecting duct, we compared responses to amiloride in angiotensin II-infused KEKOs and Controls. Blockade of the epithelial sodium channel with amiloride caused exaggerated natriuresis in KEKOs compared with Controls (0.21±0.01 versus 0.15±0.02 mmol/24 hour per 20 g; P=0.015). Conclusions Our data suggest EP4R in kidney epithelia attenuates hypertension. This antihypertension effect of EP4R may be mediated by reducing the activity of the epithelial sodium channel, thereby promoting natriuresis.


Assuntos
Hipertensão , Receptores de Prostaglandina E Subtipo EP4 , Amilorida/uso terapêutico , Angiotensina II/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Dinoprostona/metabolismo , Células Epiteliais , Canais Epiteliais de Sódio/genética , Hipertensão/tratamento farmacológico , Rim , Macrófagos/metabolismo , Camundongos , Prostaglandinas , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Sódio/metabolismo , Cloreto de Sódio na Dieta/metabolismo
2.
Biomater Adv ; 135: 212746, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35929218

RESUMO

Pectin-based drug delivery systems hold great potential for oral insulin delivery, since they possess excellent gelling property, good mucoadhesion and high stability in the gastrointestinal (GI) tract. However, lack of enterocyte targeting ability and premature drug release in the upper GI tract of the susceptible ionic-crosslinked pectin matrices are two major problems to be solved. To address these issues, we developed folic acid (FA)-modified pectin nanoparticles (INS/DFAN) as insulin delivery vehicles by a dual-crosslinking method using calcium ions and adipic dihydrazide (ADH) as crosslinkers. In vitro studies indicated insulin release behaviors of INS/DFAN depended on COOH/ADH molar ratio in the dual-crosslinking process. INS/DFAN effectively prevented premature insulin release in simulated GI fluids compared to ionic-crosslinked nanoparticles (INS/FAN). At an optimized COOH/ADH molar ratio, INS/DFAN with FA graft ratio of 18.2% exhibited a relatively small particle size, high encapsulation efficiency and excellent stability. Cellular uptake of INS/DFAN was FA graft ratio dependent when it was at/below 18.2%. Uptake mechanism and intestinal distribution studies demonstrated the enhanced insulin transepithelial transport by INS/DFAN via FA carrier-mediated transport pathway. In vivo studies revealed that orally-administered INS/DFAN produced a significant reduction in blood glucose levels and further improved insulin bioavailability in type I diabetic rats compared to INS/FAN. Taken together, the combination of dual crosslinking and FA modification is an effective strategy to develop pectin nano-vehicles for enhanced oral insulin delivery.


Assuntos
Diabetes Mellitus Experimental , Nanopartículas , Administração Oral , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Portadores de Fármacos/uso terapêutico , Ácido Fólico/uso terapêutico , Insulina , Insulina Regular Humana/uso terapêutico , Pectinas/uso terapêutico , Ratos
3.
Carbohydr Polym ; 292: 119677, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35725172

RESUMO

Polysaccharides from fungi have many bioactivities. Previous studies showed that galactomannans from Penicillium oxalicum antagonize galectin-8-mediated activity. Here, two intracellular and two extracellular galactomannans were purified and their structures were comparatively characterized by NMR, partial acid hydrolysis and methylation. All four of them were identified to be galactomannans with similar mannan backbones having 1,2-/1,6-linkages (~3:1) and various amounts of galactofuranan side chains. The interaction of those polysaccharides with galectin-8 was assessed by hemagglutination and biolayer interferometry. These results show that side chains are important for the interaction, and the more the side chains, the stronger the interaction. But the side chains alone did not show act on galectin-8, which indicated that the cooperation between backbone and side chains is another necessary factor for this interaction. Our findings provide important information about structure-activity relationships and the galactofuranose-containing galactomannans might be as potential therapeutic of galectin-8 related diseases.


Assuntos
Mananas , Penicillium , Galactose/análogos & derivados , Galectinas , Mananas/química , Mananas/farmacologia , Polissacarídeos/química
4.
Food Res Int ; 157: 111402, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35761656

RESUMO

The purpose of this study is to explore the effects of IVTNWDDMEK and VGPAGPRG, two angiotensin I-converting enzyme (ACE) inhibitory peptides purified from Volutharpa ampullacea perryi, on ACE's two domains and on nitric oxide (NO), endothelin-1(ET-1) production in human vascular endothelial cells (HUVECs). In addition, we sought to investigate the effects of these two peptides on HUVECs injury induced by H2O2. The results indicated that the inhibition of the ACE C-domain was significantly higher than that of the ACE N-domain by these two peptides. Molecular dynamics (MD) analysis revealed that the hydrogen bonds interactions between ACE and two peptides, the chelation between peptides and Zn2+ both play important role, which might contribute significantly to the ACE inhibitory activity. Two peptides significantly increase NO and ET-1 production in a dose-dependent manner and protects against hydrogen peroxide-induced HUVEC cell injury. The reported results also show that two peptides up-regulated the expression of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1), and reduce the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA). Our study indicated that IVTNWDDMEK and VGPAGPRG could be potent ACE inhibitors and Volutharpa ampullacea perryi is a good source of bioactive peptides, which provided a theoretical basis for the broad application of two selected peptides as functional food with anti-hypertensive activity.


Assuntos
Gastrópodes , Peróxido de Hidrogênio , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Anti-Hipertensivos/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Peptídeos/química
5.
Pharmaceutics ; 14(6)2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35745765

RESUMO

(1) Background: The glucocorticoid receptor (GR) plays a key role in lipid metabolism, but investigations of GR activation as a potential therapeutic approach have been hampered by a lack of selective agonists. Ginsenoside compound K (CK) is natural small molecule with a steroid-like structure that offers a variety of therapeutic benefits. Our study validates CK as a novel GR agonist for the treatment of obesity. (2) Methods: By using pulldown and RNA interference, we determined that CK binds to GR. The anti-obesity potential effects of CK were investigated in obese mice, including through whole-body energy homeostasis, glucose and insulin tolerance, and biochemical and proteomic analysis. Using chromatin immunoprecipitation, we identified GR binding sites upstream of lipase ATGL. (3) Results: We demonstrated that CK reduced the weight and blood lipids of mice more significantly than the drug Orlistat. Proteomics data showed that CK up-regulated autophagy regulatory proteins, enhanced fatty acid oxidation proteins, and decreased fatty acid synthesis proteins. CK induced lipophagy with the initial formation of the phagophore via AMPK/ULK1 activation. However, a blockade of autophagy did not disturb the increase in CK on lipase expression, suggesting that autophagy and lipase are independent pathways in the function of CK. The pulldown and siRNA experiments showed that GR is the critical target. After binding to GR, CK not only activated lipophagy, but also promoted the binding of GR to the ATGL promoter. (4) Conclusions: Our findings indicate that CK is a natural food candidate for reducing fat content and weight.

6.
J Ethnopharmacol ; 295: 115379, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35595221

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xiao-Xu-Ming Decoction (XXMD) is a classical Chinese medicinal compound for the treatment of ischemic stroke, which has good efficacy in clinical studies and also plays a neuroprotective role in pharmacological studies. AIM OF THE STUDY: The purpose of this study is to investigate the potential and integral interventional effects of XXMD on cerebral ischemia/reperfusion rat model. MATERIALS AND METHODS: In this study, 1H NMR metabolomics was used, combined with neurological functional assessments, cerebral infarct area measurements, and pathological staining including Nissl staining, immunofluorescence staining of NeuN and TUNEL, and immunohistochemical staining of MCT2, to analyze the metabolic effects of XXMD in the treatment of an ischemia/reperfusion rat model. RESULTS: It's observed that XXMD treatment could improve the neurological deficit scores and reduce the cerebral infarct areas on cerebral ischemia/reperfusion rat model. The pathological staining results performed that XXMD treatment could improve the decrease of Nissl bodies and the expression of NeuN and MCT2, reduce the high expression of TUNEL. In 1H NMR study, it revealed that the metabolic patterns among three experimental groups were different, the level of lactate, acetate, NAA, glutamate, and GABA were improved to varying degrees in different brain area. CONCLUSION: Our findings indicated that XXMD has positive effect on neuroprotection and improvement of metabolism targeting cerebral ischemic injury in rats, which showed great potential for ischemic stroke.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Infarto Cerebral/tratamento farmacológico , Medicamentos de Ervas Chinesas , Isquemia/tratamento farmacológico , Metabolômica , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Reperfusão , Traumatismo por Reperfusão/metabolismo
7.
Cell Death Dis ; 13(4): 340, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35418167

RESUMO

Renal inflammation is a critical pathophysiological characteristic of diabetic kidney disease (DKD). The mechanism of the inflammatory response is complicated, and there are few effective treatments for renal inflammation that can be used clinically. Insulin-like growth factor-binding protein 5 (IGFBP5) is an important secretory protein that is related to inflammation and fibrosis in several tissues. Studies have shown that the IGFBP5 level is significantly upregulated in DKD. However, the function of IGFBP5 and its mechanism in DKD remain unclear. Here, we showed that IGFBP5 levels were significantly increased in the kidneys of diabetic mice. Ablation of IGFBP5 alleviated kidney inflammation in DKD mice. Mechanistically, IGFBP5 increased glycolysis, which was characterized by increases in lactic acid and the extracellular acidification rate, by activating the transcription factor early growth response 1 (EGR1) and enhancing the expression of PFKFB3 in endothelial cells. Furthermore, a mutation in PFKFB3 attenuated renal inflammation in DKD mice. Taken together, we provided evidence that IGFBP5 enhanced kidney inflammation through metabolic reprogramming of glomerular endothelial cells. Our results provide new mechanistic insights into the effect of IGFBP5 on kidney and highlight potential therapeutic opportunities for IGFBP5 and the metabolic regulators involved in DKD.


Assuntos
Proteínas de Transporte , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Células Endoteliais/metabolismo , Glicólise , Humanos , Inflamação/metabolismo , Camundongos , Fosfofrutoquinase-2/genética , Fosfofrutoquinase-2/metabolismo
8.
Int J Biol Macromol ; 209(Pt A): 1439-1449, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35461867

RESUMO

Heterogalactans with weight-average molecular weights ~20 kDa were purified from several species of mushroom: Hypsizygus marmoreus, Pleurotus ostreatus, Pholiota nameko, Agrocybe cylindracea, Hygrophorus lucorum and Hericium erinaceus, and structurally characterized and assessed for antioxidant activity in vitro. Methylation analysis, combined with NMR spectral analysis, indicates that these glycans have a common backbone composed of (1 â†’ 6)-linked-α-D-galactopyranosyl residues that are substituted at O-2. The (1 â†’ 6)-α-D-galactans, branched primarily with ß-D-mannopyranosyl (Manp) or α-L-fucopyranosyl (Fucp) residues, have been assigned to mannogalactans or fucogalactans, respectively, as well as to ß-D-Manp and α-L-Fucp residues attached in tandem to the main chain as fucomannogalactans. In addition, 3-O-methylated-α-D-galactopyranosyl (3-O-Me-Galp) residues within the mannogalactan chains, exhibit strong reducing power and radical scavenging activity suggesting that this sugar moiety functions as an antioxidant. Our results provide important structural information on mushroom heterogalactans and prompt further investigations into their structure-activity relationships.


Assuntos
Agaricales , Pleurotus , Antioxidantes/farmacologia , Peso Molecular , Pleurotus/química , Polissacarídeos/química
9.
Front Pharmacol ; 13: 746265, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35359863

RESUMO

Introduction: Daprodustat, a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), its efficacy and safety remain unclear. Thus, we conducted this meta-analysis aiming at investigating its efficacy and safety on the treatment of patients with chronic kidney disease (CKD)-related anemia. Methods: We systematically searched for relevant studies in PubMed, Embase, Cochrane Library and Clinical Trial Registries databases from inception until December 2021. We selected randomized controlled trials comparing daprodustat with recombinant human erythropoietin (rhEPO) in anemia patients with CKD with or without dialysis. Results: Seven studies including 7933 patients met the inclusion criteria. For both nondialysis-dependent (NDD-) CKD and dialysis-dependent (DD-) CKD patients, the pooled results showed that there was no significant difference in the changes in hemoglobin levels between the daprodustat and rhEPO groups (mean difference (MD) = -0.01, 95% confidence interval (CI) = -0.38, 0.35, p = 0.95; MD = 0.15, 95% CI = -0.29, 0.60, p = 0.50; respectively). In addition, a significant increase in transferrin saturation (TSAT), total iron binding capacity (TIBC) and total iron was observed in daprodustat groups compared with rhEPO groups in DD-CKD patients (p < 0.05). As for safety, the overall frequency of adverse events was similar between the daprodustat and rhEPO groups in DD-CKD patients (relative risk (RR) = 0.99, 95%CI = 0.92, 1.06, p = 0.76), and the trial sequential analysis (TSA) confirmed this result. But for NDD-CKD patients, the incidence of adverse events in the daprodustat groups was significantly higher than that of rhEPO groups (RR = 1.04, 95%CI = 1.01,1.07, p = 0.02), while the TSA corrected this result. No trend of increasing incidence of serious adverse events was found in all daprodustat treated patients, but the TSA could not confirm this result. Conclusion: Although daprodustat was noninferior to rhEPO in correcting anemia in both NDD-CKD and DD-CKD patients, it seemed to have a better effect on optimizing iron metabolism in DD-CKD patients. Daprodustat may be a promising alternative for the treatment of anemia in patients with CKD. However, due to the lack of included studies, future researches are needed to further evaluate the therapeutic effect of daprodustat. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021229636.

10.
Int Immunopharmacol ; 107: 108679, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35279514

RESUMO

PURPOSE: Spleen deficiency diarrhea (SDD) is one of the most common types of diarrhea and is linked to intestinal barrier dysfunction and intestinal flora disorders. Atractyloside-A (AA) is one of the main components of Atractylodes Lancea(Thunb.) DC., which acts on the gastrointestinal tract and has therapeutic effects on diarrhea. Folium sennae is a medicinal plant inducing diarrhea; thus, it is one of the effective methods to obtain a diarrhea model. However, the mechanism of action of AA in the treatment of SDD induced by Folium sennae is unclear. METHODS: The intestinal thrapeutic effect of AA on SDD in mice was evaluated by colon pathology. RNA sequencing (RNA-seq) was used to analyze the colonic transcriptome profiles. In addition, 16S rDNA sequencing and fecal microbiota transplantation (FMT) were carried out to verify the role of AA in the regulation of the intestinal flora. RESULTS: The findings revealed that AA alleviated SDD by ameliorating the pathological symptoms while suppressing intestinal inflammatory responses through the TLR4/MyD88/NF-kB signaling and reversing the impairment of mucin synthesis. Furthermore, AA improved the integrity of the intestinal barrier. RNA-seq identified 436 common DEGs out of 1033 DEGs between SDD and AA, and 1933 DEGs between SDD and Ctrl, which are highly enriched in the NF-κB and TNF pathways. Moreover, AA altered the composition of the intestinal flora and FMT reduced SDD. CONCLUSION: AA exerted a therapeutic effect on SDD through the regulation of the intestinal flora and the inflammation by interfering with the TLR4/MyD88/NF-κB signaling pathway.


Assuntos
Microbioma Gastrointestinal , NF-kappa B , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Atractilosídeo , Diarreia/tratamento farmacológico , Homeostase , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Baço/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
11.
ACS Biomater Sci Eng ; 8(4): 1726-1734, 2022 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-35302761

RESUMO

Acute kidney injury (AKI) has emerged as a major public health problem affecting millions of people worldwide without specific and satisfactory therapies due to the lack of an effective delivery approach. In the past few decades, hydrogels present infinite potential in localized drug delivery, while their poor adhesion to moist tissue and isotropic diffusion character always restrict the therapeutic efficiency and may lead to unwanted side effects. Herein, we proposed a novel therapeutic strategy for AKI via a customizable artificial kidney capsule (AKC) together with a mesenchymal stem cell (MSC)-laden hydrogel. Specifically, an elastic capsule owning an inner chamber with the same size and shape as the kidney is designed and fabricated through three-dimensional (3D) modeling and printing, serving as an outer wrap for kidney and cell-laden hydrogels. According to the in vitro experiment, the excellent biocompatibility of gelatin-based hydrogel ensures viability and proliferation of MSCs. In vivo mice experiments proved that this concept of AKC-assisted kidney drug delivery could efficiently reduce epithelial cell apoptosis and minimize the damage of the renal tubular structure for mice suffering AKI. Such a strategy not only provides a promising alternative in the treatment of AKI but also offers a feasible and versatile approach for the repair and recovery of other organs.


Assuntos
Injúria Renal Aguda/terapia , Hidrogéis/uso terapêutico , Rins Artificiais , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Rabdomiólise/complicações , Injúria Renal Aguda/etiologia , Animais , Humanos , Hidrogéis/administração & dosagem , Hidrogéis/química , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Impressão Tridimensional , Rabdomiólise/tratamento farmacológico
13.
Cell Death Dis ; 12(12): 1119, 2021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-34845199

RESUMO

Nicotinamide, the amide form of Vitamin B3, is a common nutrient supplement that plays important role in human fetal development. Nicotinamide has been widely used in clinical treatments, including the treatment of diseases during pregnancy. However, its impacts during embryogenesis have not been fully understood. In this study, we show that nicotinamide plays multiplex roles in mesoderm differentiation of human embryonic stem cells (hESCs). Nicotinamide promotes cardiomyocyte fate from mesoderm progenitor cells, and suppresses the emergence of other cell types. Independent of its functions in PARP and Sirtuin pathways, nicotinamide modulates differentiation through kinase inhibition. A KINOMEscan assay identifies 14 novel nicotinamide targets among 468 kinase candidates. We demonstrate that nicotinamide promotes cardiomyocyte differentiation through p38 MAP kinase inhibition. Furthermore, we show that nicotinamide enhances cardiomyocyte survival as a Rho-associated protein kinase (ROCK) inhibitor. This study reveals nicotinamide as a pleiotropic molecule that promotes the derivation and survival of cardiomyocytes, and it could become a useful tool for cardiomyocyte production for regenerative medicine. It also provides a theoretical foundation for physicians when nicotinamide is considered for treatments for pregnant women.


Assuntos
Miócitos Cardíacos/efeitos dos fármacos , Niacinamida/uso terapêutico , Fosfotransferases/antagonistas & inibidores , Células-Tronco Pluripotentes/metabolismo , Medicina Regenerativa/métodos , Complexo Vitamínico B/uso terapêutico , Animais , Diferenciação Celular , Feminino , Humanos , Niacinamida/farmacologia , Complexo Vitamínico B/farmacologia , Peixe-Zebra
14.
BMC Bioinformatics ; 22(1): 562, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814825

RESUMO

BACKGROUND: The gain or loss of large chromosomal regions or even whole chromosomes is termed as genomic scarring and can be observed as copy number variations resulting from the failure of DNA damage repair. RESULTS: In this study, a new algorithm called genomic scar analysis (GSA) has developed and validated to calculate homologous recombination deficiency (HRD) score. The two critical submodules were tree recursion (TR) segmentation and filtering, and the estimation and correction of the tumor purity and ploidy. Then, this study evaluated the rationality of segmentation and genotype identification by the GSA algorithm and compared with other two algorithms, PureCN and ASCAT, found that the segmentation result of GSA algorithm was more logical. In addition, the results indicated that the GSA algorithm had an excellent predictive effect on tumor purity and ploidy, if the tumor purity was more than 20%. Furtherly, this study evaluated the HRD scores and BRCA1/2 deficiency status of 195 clinical samples, and the results indicated that the accuracy was 0.98 (comparing with Affymetrix OncoScan™ assay) and the sensitivity was 95.2% (comparing with BRCA1/2 deficiency status), both were well-behaved. Finally, HRD scores and 16 genes mutations (TP53 and 15 HRR pathway genes) were analyzed in 17 cell lines, the results showed that there was higher frequency in HRR pathway genes in high HRD score samples. CONCLUSIONS: This new algorithm, named as GSA, could effectively and accurately calculate the purity and ploidy of tumor samples through NGS data, and then reflect the degree of genomic instability and large-scale copy number variations of tumor samples.


Assuntos
Variações do Número de Cópias de DNA , Reparo do DNA , Recombinação Homóloga , Algoritmos , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/genética , Ploidias
15.
RSC Med Chem ; 12(11): 1968-1976, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34825192

RESUMO

Bergenin, which is isolated from Bergenia species, exhibits various pharmacological properties. In the search for new types of immunosuppressants, a series of bergenin derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by the CCK-8 assay. The experimental data demonstrated that compounds 7 and 13 showed the strongest inhibition effects on mouse splenocyte proliferation (IC50 = 3.52 and 5.39 µM, respectively). Further studies revealed that the inhibitory effect may come from the suppression of both IFN-γ and IL-4 cytokines. Alkylated derivatives of bergenin with n-hexyl and n-heptyl on the two phenolic hydroxyl groups showed better inhibitory activities. The hydrophobicity of bergenin derivatives, the configuration of the 4-OH in bergenin, and the ability to form hydrogen bonds of the substituents on the C-4 position are important to the immunosuppressive activity. This work proved that the modifications of bergenin may represent a new route to the discovery of a new class of immunosuppressive agents.

16.
Artigo em Inglês | MEDLINE | ID: mdl-34754310

RESUMO

OBJECTIVE: To explore the autonomic nerve rhythm and the correlation between palpitations below the heart (PBTH) and autonomic nerve function in patients with PBTH based on heart rate variability (HRV). METHODS: The outpatients or ward patients of Wenzhou Hospital of Traditional Chinese Medicine were collected and divided into two groups: the PBTH group and the normal group. The HRV of each group was detected. Single-factor statistical methods, Spearman correlation analysis, and logistic regression were used to describe and analyze the rhythm and characteristics of autonomic nerves in patients with PBTH and the correlation between PBTH and autonomic nerve function. RESULTS: (1) In the comparison of HRV in different time periods in the same group, the SDNN, RMSSD, pNN50, TP, and HF in the PBTH group at night were significantly higher than those in the daytime (P < 0.01), while the LF/HF ratio was significantly lower than that in the daytime (P < 0.01). (2) In the comparison of HRV between the two groups in the same time period, the RMSSD and pNN50 of the PBTH group during the daytime period were significantly higher than those of the normal control group (P < 0.05), and the LF/HF was significantly lower than that of the normal group (P < 0.05). (3) In the Spearman correlation analysis, PBTH was significantly correlated with RMSSD, pNN50, and LF/HF ratio in the daytime period, with correlation coefficients of 0.424, 0.462, and -0.524, respectively (P < 0.05). (4) Logistic regression analysis showed that the decrease of LF/HF ratio during the daytime period was an independent risk factor for PBTH in TCM (OR = 0.474, 95% CI: 0.230-0.977, P < 0.05). CONCLUSIONS: The changes in parasympathetic nerve function in patients with PBTH have a circadian rhythm, which is characterized by increased activity during the nighttime. At the same time, the autonomic nerve activity of people with PBTH during the daytime is unbalanced, and the decrease of LF/HF ratio during the day is an independent high risk factor for PBTH.

18.
Front Med (Lausanne) ; 8: 724456, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34532333

RESUMO

Background: Roxadustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), has been used to treat anemia in patients with chronic kidney disease (CKD). However, its safety and efficacy remain controversial. Methods: The PubMed, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, and Clinical Trial Registries databases were searched for relevant studies published up to April 2021. We identified randomized controlled trials (RCTs) comparing roxadustat with placebo or erythropoiesis-stimulating agents (ESAs) in anemia patients with CKD with or without dialysis. Results: Eleven studies including 6,631 patients met the inclusion criteria. In non-dialysis-dependent (NDD-) and dialysis-dependent (DD-) CKD patients, the total adverse events were not significantly different between the roxadustat and control (placebo for NDD-CKD patients and ESA for DD-CKD patients) groups [relative risk (RR) = 1.02, 95% confidence interval (CI) = 1.00, 1.04, P = 0.08, and RR = 1.22, 95% CI = 0.91, 1.64, P = 0.18, respectively], and the trial sequential analysis (TSA) confirmed the result in the NDD-CKD groups. No significant differences in hyperkalemia and infection incidences were found between roxadustat and placebo in the DD-CKD groups. The pooled results showed that roxadustat significantly increased the hemoglobin response rate compared with placebo in the NDD-CKD group and had an effect similar to that of ESA in the DD-CKD group. However, iron metabolism parameters did not seem to be obviously optimized by roxadustat. Conclusion: Roxadustat can be safely used in CKD patients. Oral roxadustat was more effective than placebo as a therapy for anemia in NDD-CKD patients and non-inferior to ESA in correcting anemia in DD-CKD patients. However, additional clinical trials are still needed to further prove whether roxadustat can optimize iron metabolism.

19.
Med Sci Monit ; 27: e932422, 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34564688

RESUMO

BACKGROUND Perioperative neuro-cognitive disorders (PND) are preoperative and postoperative complications of multiple nervous systems, typically manifested as decreased memory and learning ability after surgery. It was used to replace the original definition of postoperative cognitive dysfunctions (POCD) from 2018. Our previous studies have shown that sevoflurane inhalation can lead to cognitive dysfunction in Sprague-Dawley rats, but the specific mechanism is still unclear. MATERIAL AND METHODS Thirty-six male Sprague-Dawley rats were randomly divided into 6 groups (n=6): the SD group was given 24-h acute sleep deprivation; Sevoflurane was inhaled for 2 h in the Sevo group. Two mL propofol was injected into the tail vein of rats in the Prop group. The rats in the SD+Sevo group and SD+Prop group were deprived of sleep before intervention in the same way as before. RESULTS We noted significant behavioral changes in rats treated with SIK3 inhibitors or tau phosphorylation agonists before propofol injection or sevoflurane inhalation, with associated protein levels and dendritic spine density documented. Sevoflurane anesthesia-induced cognitive impairment following acute sleep deprivation was more pronounced than sleep deprivation-induced cognitive impairment alone and resulted in increased brain SIK3 levels, increased phosphorylation of total tau and tau, and decreased acetylation modifications. After using propofol, the cognitive function returned to baseline levels with a series of reversals of cognitive dysfunction. CONCLUSIONS These results suggest that sevoflurane inhalation via the SIK3 pathway aggravates cognitive impairment after acute sleep deprivation and that propofol anesthesia reverses the effects of sleep deprivation by affecting modifications of tau protein.


Assuntos
Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Disfunção Cognitiva/fisiopatologia , Plasticidade Neuronal/efeitos dos fármacos , Propofol/farmacologia , Sevoflurano/farmacologia , Privação do Sono/fisiopatologia , Animais , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Privação do Sono/complicações
20.
STAR Protoc ; 2(3): 100740, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34467226

RESUMO

Metabolic homeostasis is critical for cell pluripotency and differentiation in human embryonic stem cells (hESCs). It has been reported that metabolic changes specifically regulate cellular signaling during hESC differentiation. This protocol describes procedures for both cell culture and detection of intracellular and extracellular metabolites in hESCs by liquid chromatography-mass spectrometry. Metabolites in glycolysis, citric acid cycle, pentose phosphate pathway, and other metabolic processes can be detected using this approach. For complete details on the use and execution of this protocol, please refer to Song et al., (2019), Yang et al., (2019), Meng et al., (2018), and Chen et al., (2011b).


Assuntos
Técnicas de Cultura de Células/métodos , Espaço Extracelular , Células-Tronco Embrionárias Humanas , Espaço Intracelular , Metabolômica/métodos , Diferenciação Celular , Células Cultivadas , Cromatografia Líquida , Espaço Extracelular/química , Espaço Extracelular/metabolismo , Glicólise/fisiologia , Células-Tronco Embrionárias Humanas/química , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Espaço Intracelular/química , Espaço Intracelular/metabolismo , Espectrometria de Massas , Metaboloma/fisiologia
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