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1.
Neural Regen Res ; 18(1): 162-169, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35799537

RESUMO

We previously prepared nerve growth factor poly-lactide co-glycolid sustained-release microspheres to treat rat sciatic nerve injury using the small gap sleeve technique. Multiple growth factors play a synergistic role in promoting the repair of peripheral nerve injury; as a result, in this study, we added basic fibroblast growth factors to the microspheres to further promote nerve regeneration. First, in an in vitro biomimetic microenvironment, we developed and used a drug screening biomimetic microfluidic chip to screen the optimal combination of nerve growth factor/basic fibroblast growth factor to promote the regeneration of Schwann cells. We found that 22.56 ng/mL nerve growth factor combined with 4.29 ng/mL basic fibroblast growth factor exhibited optimal effects on the proliferation of primary rat Schwann cells. The successfully prepared nerve growth factor-basic fibroblast growth factor-poly-lactide-co-glycolid sustained-release microspheres were used to treat rat sciatic nerve transection injury using the small gap sleeve bridge technique. Compared with epithelium sutures and small gap sleeve bridging alone, the small gap sleeve bridging technique combined with drug-free sustained-release microspheres has a stronger effect on rat sciatic nerve transfection injury repair at the structural and functional level.

2.
Neural Regen Res ; 18(2): 244-252, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35900398

RESUMO

Subarachnoid hemorrhage (SAH) is a dominant cause of death and disability worldwide. A sharp increase in intracranial pressure after SAH leads to a reduction in cerebral perfusion and insufficient blood supply for neurons, which subsequently promotes a series of pathophysiological responses leading to neuronal death. Many previous experimental studies have reported that excitotoxicity, mitochondrial death pathways, the release of free radicals, protein misfolding, apoptosis, necrosis, autophagy, and inflammation are involved solely or in combination in this disorder. Among them, irreversible neuronal apoptosis plays a key role in both short- and long-term prognoses after SAH. Neuronal apoptosis occurs through multiple pathways including extrinsic, mitochondrial, endoplasmic reticulum, p53 and oxidative stress. Meanwhile, a large number of blood contents enter the subarachnoid space after SAH, and the secondary metabolites, including oxygenated hemoglobin and heme, further aggravate the destruction of the blood-brain barrier and vasogenic and cytotoxic brain edema, causing early brain injury and delayed cerebral ischemia, and ultimately increasing neuronal apoptosis. Even there is no clear and effective therapeutic strategy for SAH thus far, but by understanding apoptosis, we might excavate new ideas and approaches, as targeting the upstream and downstream molecules of apoptosis-related pathways shows promise in the treatment of SAH. In this review, we summarize the existing evidence on molecules and related drugs or molecules involved in the apoptotic pathway after SAH, which provides a possible target or new strategy for the treatment of SAH.

3.
Biotechnol Bioeng ; 119(3): 845-856, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34928500

RESUMO

Biocatalysis in high-concentration organic solvents (OSs) offers many advantages, but realizing this process remains a huge challenge. An R-selective ω-amine transaminase variant (AcATAM2 ) exhibited high activity toward 50 g/L pro-sitagliptin ketone 1-[1-piperidinyl]-4-[2,4,5-trifluorophenyl]-1,3-butanedione (PTfpB). However, AcATAM2 displayed unsatisfactory organic-cosolvent resistance against high-concentration dimethyl sulfoxide (DMSO), which is required to enhance the solubility of the hydrophobic substrate PTfpB. Located in the substrate-binding tunnel, enzyme gates are structural elements that undergo reversible conformational transitions, thus affecting the accessibility of the binding pocket to solvent molecules. Depending on the conformation of the enzyme gates, one can define an open or closed conformation on which the enzyme activity in OSs may depend. To enhance the DMSO resistance of AcATAM2 , we identified the beneficial residues at the "enzyme gate" region via computational analysis, alanine scanning, and site-saturation mutagenesis. Two beneficial variants, namely, AcATAM2 F56D and AcATAM2 F56V , not only displayed improved enzyme activity but also exhibited enhanced DMSO resistance (the half-life value increased from 25.71 to 42.49 h under 60% DMSO). Molecular dynamic simulations revealed that the increase in DMSO resistance was mainly caused by the decrease in the number of DMSO molecules in the substrate-binding pocket. Moreover, in the kilogram-scale experiment, the conversion of 80 g/L substrate was increased from 50% (AcATAM2 ) to 85% (M2F56D in 40% DMSO) with a high e.e. of >99% within 24 h.


Assuntos
Dimetil Sulfóxido , Simulação de Dinâmica Molecular , Biocatálise , Dimetil Sulfóxido/química , Solventes/química , Transaminases/genética
4.
Chemosphere ; 307(Pt 2): 135774, 2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35921888

RESUMO

The objective of this study was to visualize trends and current research status of hydrothermal biochar research through a bibliometric analysis by using CiteSpace software. The original article data were collected from the Web of Science core database published between 2009 and 2020. A visual analysis network of national co-authored, institutional co-authored and author co-authored articles was created, countries, institutions and authors were classified accordingly. By visualizing the cited literature and journal co-citation networks, the main subject distribution and core journals were identified respectively. By visualizing journal co-citations, the main research content was identified. Further the cluster analysis revealed the key research directions of knowledge structure. Keyword co-occurrence analysis and key occurrence analysis demonstrate current research hotspots and new research frontiers. Through the above analysis, the cooperation and contributions of hydrothermal biochar research at different levels, from researchers to institutions to countries to macro levels, were explored, the disciplinary areas of knowledge and major knowledge sources of hydrothermal biochar were discovered, and the development lineage, current status, hotspots and trends of hydrothermal biochar were clarified. The results obtained from the study can provide a reference for scholars to gain a deeper understanding of hydrothermal biochar.

5.
Redox Biol ; 55: 102413, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35932693

RESUMO

Ferroptosis is a newly recognized form of regulated cell death that is characterized by severe lipid peroxidation initiated by iron overload and the generation of reactive oxygen species (ROS). However, the role of iron in ionizing radiation (IR)-induced intestinal injury has not been fully illustrated yet. In this study, we found that IR induced ferroptosis in intestinal epithelial cells, as indicated by the increase in intracellular iron levels and lipid peroxidation, upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA, reduced glutathione peroxidase 4 (GPX4) mRNA and glutathione (GSH) levels, and significant mitochondrial damage. In addition, the iron chelator deferoxamine (DFO) attenuated IR-induced ferroptosis and intestinal injury in vitro and in vivo. Intriguingly, pharmacological inhibition of autophagy with 3-methyladenine (3-MA) mitigated IR-induced ferritin downregulation, iron overload and ferroptosis. IR increased the levels of nuclear receptor coactivator 4 (NCOA4) mRNA and protein. NCOA4 knockdown significantly inhibited the reduction of ferritin, decreased the level of intracellular free iron, and mitigated ferroptosis induced by IR in HIEC cells, indicating that NCOA4-mediated autophagic degradation of ferritin (ferritinophagy) was required for IR-induced ferroptosis. Furthermore, cytoplasmic iron further activated mitoferrin2 (Mfrn2) on the mitochondrial membrane, which in turn increased iron transport into the mitochondria, resulting in increased ROS production and ferroptosis. In addition, mice fed with an iron-deficient diet for 3 weeks showed a significant reversal in the intestinal injury induced by abdominal IR exposure. Taken together, ferroptosis is a novel mechanism of IR-induced intestinal epithelial cytotoxicity, and is dependent on NCOA4-mediated ferritinophagy.

6.
Theriogenology ; 191: 16-21, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35939900

RESUMO

Phospholipase C zeta (PLCζ) is an important inducer of Ca2+ oscillations in mammalian sperm. To explore the influence of PLCζ on early embryonic Ca2+ fluctuations during sperm-egg binding, this study used PLCζ from sheep sperm to construct an early embryonic Ca2+ fluctuation model. First, sheep MII oocytes were cultivated and screened using microinjection technology. Then, a pEGFP-N1-PLCζ plasmid was constructed to activate oocytes in the test group. Ionomycin combined with 6-Dimethylaminopurine (6-DMAP) was used for the control group to explore the effects on early embryonic development and regulation of Ca2+ fluctuations during development. The results demonstrated that both the PLCζ and ionomycin combined with 6-DMAP activation methods induced sheep oocyte parthenogenetic activation and development in early embryos. In comparisons, the cleavage rate of ionomycin combined with 6-DMAP activation was significantly higher than that of PLCζ (60.9% ± 19.4% vs 76.1% ± 0.7%, respectively; p < 0.001), and the blastocyst rates were 16.2% ± 0.62% and 21.1% ± 0.92%, respectively (p < 0.05). Additionally, when comparing the distribution of Ca2+ in early embryos at different stages, Ca2+ in both treatment groups was mainly distributed in the cytoplasm, but the temporal pattern of Ca2+ fluctuations differed. PLCζ resulted in Ca2+ peaks that appeared at the cleavage and morula stages of early embryos, and Ca2+ returned to normal levels at the morula stage. However, the Ca2+ concentration after ionomycin combined with 6-DMAP activation was always much higher than that with PLCζ, and its single peak appeared later than in the PLCζ group. In summary, the PLCζ gene promoted stable regulatory effects on Ca2+ fluctuations at different stages during early embryonic development.

7.
Clin Rheumatol ; 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35945466

RESUMO

INTRODUCTION: Disease Activity Score-28 (DAS28) with erythrocyte sedimentation rate (DAS28ESR), DAS28 with C-reactive protein (DAS28CRP), and simplified disease activity index (SDAI) are widely used to assess disease activity as low, moderate, or high or in remission in patients with rheumatoid arthritis (RA). However, these indicators can generate inconsistent results, influencing treatment decisions and limiting comparisons across studies. We aimed to establish equations for conversion from DAS28ESR and DAS28CRP to SDAI. METHODS: We conducted a retrospective study, including 933 outpatients who were simultaneously assessed using DAS28ESR, DAS28CRP, and SDAI. The patients were divided into a training set (70%) and a validation set (30%). We developed equations to convert DAS28ESR and DAS28CRP values into SDAI values by bisquare-weighted robust regression to obtain SDAI-DAS28ESR and SDAI-DAS28CRP. In addition to using kappa values to assess consistency, differences in disease activity classification between SDAI-DAS28ESR and SDAI-DAS28CRP were examined by the Stuart-Maxwell test and the Bowker test. RESULTS: Two quadratic equations were developed as follows: SDAI-DAS28ESR = 1.168 × (DAS28ESR)^2 - 2.432 × (DAS28ESR) + 2.649 and SDAI-DAS28CRP = 1.2 × (DAS28CRP)^2 - 0.3522 × (DAS28CRP) - 0.6014. After applying the equations, the Stuart-Maxwell test and the Bowker test were no longer significant between SDAI-DAS28ESR and SDAI or between SDAI-DAS28CRP and SDAI. The kappa values increased from 0.57 to 0.73 between SDAI-DAS28ESR and SDAI and 0.76 to 0.86 between SDAI-DAS28CRP and SDAI. CONCLUSION: SDAI-DAS28ESR and SDAI-DAS28CRP are interchangeable with the SDAI on the group level, which will facilitate comparisons among studies. In addition, the equations improved consistency between indicators. Key Points • There is disagreement in assessing disease activity in patients with rheumatoid arthritis between Disease Activity Score-28 (DAS28) with erythrocyte sedimentation rate (DAS28ESR), DAS28 with C-reactive protein (DAS28CRP), and simplified disease activity index (SDAI). • We developed and validated two quadratic equations to convert DAS28ESR and DAS28CRP into SDAI. We found there was no longer significant difference in disease activity between indicators after applying the equations. • This work may allow comparisons across studies which use different indicators.

8.
Analyst ; 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35946518

RESUMO

In this work, the first endoplasmic reticulum-targeted near-infrared fluorescent probe, ISO-Chy, with a dicyanoisophorone derivative as a fluorophore is reported by introducing the recognition group of 4-bromobutyl for chymotrypsin detection. The probe can be easily synthesized and has shown satisfactory sensitivity and selectivity to chymotrypsin. Meanwhile, ISO-Chy has a large Stokes shift (135 nm) to minimize self-absorption and interference from autofluorescence and then generate significant fluorescence enhancement upon incubation with chymotrypsin. Additionally, ISO-Chy has an excellent ability to target the endoplasmic reticulum, along with preferable Pearson's correlation coefficients (Rr) of 0.9411 and 0.9522 in P815 cells and HepG2 cells, respectively. Moreover, ISO-Chy was successfully utilized to visualize endogenous chymotrypsin in P815 cells and HepG2 cells and was first used to detect chymotrypsin activity in HepG2 tumor-bearing mice. These findings indicate that ISO-Chy could be an effective tool for detecting endogenous chymotrypsin activity, supporting its use for investigating chymotrypsin function in pathologic processes.

9.
Front Public Health ; 10: 946563, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937210

RESUMO

Objective: This cross-sectional research aims to develop reliable predictive short-term prediction models to predict the number of RTIs in Northeast China through comparative studies. Methodology: Seasonal auto-regressive integrated moving average (SARIMA), Long Short-Term Memory (LSTM), and Facebook Prophet (Prophet) models were used for time series prediction of the number of RTIs inpatients. The three models were trained using data from 2015 to 2019, and their prediction accuracy was compared using data from 2020 as a test set. The parameters of the SARIMA model were determined using the autocorrelation function (ACF) and the partial autocorrelation function (PACF). The LSTM uses linear as the activation function, the mean square error (MSE) as the loss function and the Adam optimizer to construct the model, while the Prophet model is built on the Python platform. The root mean squared error (RMSE), mean absolute error (MAE) and Mean Absolute Percentage Error (MAPE) are used to measure the predictive performance of the model. Findings: In this research, the LSTM model had the highest prediction accuracy, followed by the Prophet model, and the SARIMA model had the lowest prediction accuracy. The trend in medical expenditure of RTIs inpatients overlapped highly with the number of RTIs inpatients. Conclusion: By adjusting the activation function and optimizer, the LSTM predicts the number of RTIs inpatients more accurately and robustly than other models. Compared with other models, LSTM models still show excellent prediction performance in the face of data with seasonal and drastic changes. The LSTM can provide a better basis for planning and management in healthcare administration. Implication: The results of this research show that it is feasible to accurately forecast the demand for healthcare resources with seasonal distribution using a suitable forecasting model. The prediction of specific medical service volumes will be an important basis for medical management to allocate medical and health resources.


Assuntos
Infecções Respiratórias , Mídias Sociais , China/epidemiologia , Estudos Transversais , Gastos em Saúde , Recursos em Saúde , Humanos
10.
Biomed Res Int ; 2022: 2743679, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937384

RESUMO

Background: Time in range (TIR) is one of the basic indicators to assess glycemic control. In this study, the TIR of DPN patients was used as the observation index to further evaluate the correlation between TIR and DPN, so as to provide new ideas for preventing the occurrence of DPN and delaying its disease progression. Methods: A total of 120 patients with T2DM (T2DM) who were hospitalized in the Endocrinology Department of our hospital from October 2018 to February 2020 were included and divided into two groups according to whether the nerve conduction velocity was normal or not, the diabetic peripheral neuropathy group (DPN) and the other groups. No diabetic peripheral neuropathy group (NDPN). According to the corresponding inclusion and exclusion criteria, the baseline data were recorded, and test indicators such as homocysteine and blood lipids were collected at the same time, and TIR was collected by a transient blood glucose meter. To explore the relationship between TIR and other indicators and peripheral neuropathy in T2DM. Results: A total of 120 T2DM patients participated in the study, including 82 in the DPN group and 38 in the NDPN group. There were no statistically significant differences in basic indicators such as age, height, and weight between the two groups. Glycated hemoglobin (HbA1c) and homocysteine (Hcy) in DPN group were higher than those in NDPN group, while TIR and HDL-C were lower than those in NDPN group (P < 0.05). Logistic regression analysis showed that HbA1c and Hcy were risk factors for DPN, and TIR and HDL-C were protective factors for DPN, with statistical significance (P < 0.05). The prediction results of TIR, Hcy, HDL-C, and HbA1c on diabetic peripheral neuropathy were analyzed by ROC curve, and the prediction results of the five variables were all statistically significant (P < 0.05) and have a better prediction effect. Conclusion: (1) The results of TIR level suggest that the longer the blood sugar is in the good control range, the more beneficial it is to reduce the occurrence of DPN. (2) TIR and HDL-C are protective factors for DPN, and HbA1c and Hcy are risk factors for DPN. (3) The results of ROC curve analysis showed that TIR, Hcy, HbA1c, and HDL-C had a good predictive effect on the occurrence of DPN.


Assuntos
Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Glicemia/análise , Hemoglobina A Glicada/análise , Homocisteína , Humanos , NAD , Estudos Retrospectivos
11.
Front Neurosci ; 16: 905709, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937868

RESUMO

Background: The "postural instability/gait difficulty" (PIGD) and "tremor-dominant" (TD) motor subtypes of Parkinson's disease (PD) differ in their clinical manifestations. The neurological basis of these differences is unclear. Methods: We performed voxel-based morphometric analysis and measured amplitudes of low-frequency fluctuation (ALFF) on 87 PIGD patients and 51 TD patients. We complemented this neuroanatomical comparison with seed-to-voxel analysis to explore differences in functional connectivity. Results: The PIGD group showed significantly smaller gray matter volume in the medial frontal gyrus (mainly on the right side) than the TD group. Across all patients, gray matter volume in the medial frontal gyrus correlated negatively with severity of PIGD symptoms after controlling for age (r = -0.250, p = 0.003), but this correlation was not observed in separate analyses of only PIGD or TD patients. The PIGD group showed greater functional connectivity of the right superior frontal gyrus with the left lingual gyrus, right lateral occipital cortex, and right lingual gyrus. ALFF did not differ significantly between the two groups. Conclusion: Postural instability/gait difficulty may be associated with smaller gray matter volume in medial frontal gyrus than TD, as well as with greater functional connectivity between the right superior frontal gyrus and occipital cortex. These results may help explain the clinical differences between the two motor subtypes of PD.

12.
Phys Rev Lett ; 129(4): 043601, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35939014

RESUMO

A scheme for observing photon blockade in a single bosonic mode with weak nonlinearity is proposed and numerically verified. Using a simple bi-tone drive, sub- and super-Poissonian light can be generated with high fidelity. With a periodically poled lithium niobate microcavity, a sub-Poissonian photon source with kHz count rate can be realized. Our proposed scheme is robust against parameter variations of the cavity and extendable to any bosonic system with anharmonic energy levels.

13.
Cancer Sci ; 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35940591

RESUMO

Aneuploidy is the hallmark of malignancy. Our previous study successfully detected nonhematogenic circulating aneuploidy cells (CACs) in types of gliomas. The current prospective clinical study aims to further precisely subcategorize aneuploid CACs, including CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells, and thoroughly investigate the clinical utilities of these different subtypes of cells. Co-detection and analysis of CTCs and circulating tumor-derived endothelial cells (CTECs) expressing CD133, glial fibrillary acidic protein (GFAP), or epidermal growth factor receptor variant III (EGFR vIII) were performed by integrated subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) in 111 preoperative primary diffuse glioma patients. Aneuploid CACs could be detected in most de novo glioma patients. Among detected CACs, 45.6% were CD31- /CD45- aneuploid CTCs and the remaining 54.4% were CD31+ /CD45- aneuploid CTECs. Positive detection of CTECs significantly correlated with disruption of the blood-brain barrier. The median number of large CTCs (L CTCs, >5 µm, 2) in low-grade glioma (WHO grade 2) was less than high-grade glioma (WHO grades 3 and 4) (3, p = 0.044), but this difference was not observed in small CTCs (S CTCs, ≤5 µm), CTECs or CACs (CTCs + CTECs). The numbers of CTCs, CTECs, or CACs in patients with contrast-enhancing (CE) lesions considerably exceeded that of non-CE lesions (p < 0.05). Receiver operating characteristic curves demonstrated that CD31+ CTECs, especially L CTECs, exhibited a close positive relationship with CE lesions. Survival analysis revealed that the high number of CD31- CTCs could be an adverse factor for compromised progression-free survival and overall survival. Longitudinal surveillance of CD31- CTCs was suitable for evaluating the therapeutic response and for monitoring potential emerging treatment resistance.

14.
J Dairy Sci ; 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35940922

RESUMO

Ketosis is a common metabolic disorder in peripartal dairy cows that is caused by excessive mobilization of fat and incomplete hepatic metabolism of fatty acids (FFA). Recent data in nonruminant models revealed that sortilin 1 (SORT1) is involved in a variety of lipid metabolism-related diseases. It plays important roles in the regulation of triglyceride (TAG) and total cholesterol (TC) levels. In this study, we first used liver biopsies from healthy cows (serum ß-hydroxybutyrate concentration <0.6 mM) and cows diagnosed with clinical ketosis (serum ß-hydroxybutyrate concentration >3.0 mM) to assess alterations in cholesterol synthesis, transport, and excretion. Then, to assess mechanistic links between SORT1 and fatty acid-mediated cholesterol metabolism, hepatocytes isolated from 4 healthy female calves (1 d old, 35-45 kg) were challenged with or without a mixture of free fatty acids (FFA; 1.2 mM) to induce metabolic stress. Hepatocytes were then treated with empty adenovirus vectors (with green fluorescent protein; Ad-GFP) or with SORT1-overexpressing adenovirus (Ad-SORT1) for 6 h or with SORT1 inhibitor (SORT1i) for 2 h, followed by a challenge with (Ad-GFP+FFA, Ad-SORT1+FFA, or SORT1i+FFA) or without (Ad-GFP, Ad-SORT1, or SORT1i) 1.2 mM FFA mixture for 12 h. Data analysis of calf hepatocyte treatment comparisons were assessed by 2-way ANOVA, and multiplicity for each experiment was adjusted using the Bonferroni procedure. Expression levels of factors related to cholesterol synthesis, transport, and excretion in liver tissue of cows with ketosis was lower. Hepatocytes challenged with FFA had lower concentrations of TC and mRNA and protein abundances of sterol regulatory element-binding protein 2 (SREBF2), acetyl acyl coenzyme A-cholesterol acyltransferase 2 (ACAT2), ATP-binding cassette transporter A1 (ABCA1), ABC subfamily G member 5 (ABCG5), and ABC subfamily G member 8 (ABCG8). Compared with FFA challenge alone, SORT1i + FFA led to greater protein abundance of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR), ACAT2, and ABCG5, and greater mRNA abundance of ABCG5. Compared with FFA challenge alone, SORT1 overexpression led to lower protein abundance of SREBF2. In contrast, protein abundance of ABCA1 was greater. Overall, our data suggested that exogenous FFA induced abnormal cholesterol metabolism in hepatocytes, whereas a high abundance of SORT1 affected cholesterol esterification and potentially influx into bile. Thus, downregulation of hepatic SORT1 might be a cholesterol-regulated protective mechanism in the presence of a marked increase in FFA.

15.
Andrologia ; : e14545, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35942817

RESUMO

Adrenomedullin (ADM) has beneficial effects on Leydig cells under pathological conditions, including lipopolysaccharide (LPS)-induced orchitis. Our previous studies demonstrated that ADM exerts a restorative effect on steroidogenesis in LPS-treated primary rat Leydig cells by attenuating oxidative stress, inflammation and apoptosis. In this study, we aim to investigate whether ADM inhibits Leydig cell dysfunction by rescuing steroidogenic enzymes in vivo. Rats were administered with LPS and injected with Ad-ADM, an adeno-associated virus vector that expressed ADM. Then, rat testes were collected for 3ß-hydroxysteroid dehydrogenase (3ß-HSD) immunofluorescence staining. Steroidogenic enzymes or steroidogenic regulatory factors or protein, including steroidogenic factor-1 (SF-1), liver receptor homologue-1 (LRH1), Nur77, steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side chain cleavage enzyme (P450scc), 3ß-HSD, cytochrome P450 17α-hydroxylase/17, 20 lyase (CYP17) and 17ß-hydroxysteroid dehydrogenase (17ß-HSD), were detected via gene expression profiling and western blot analysis. Plasma testosterone concentrations were measured. Results showed that ADM may inhibit Leydig cell dysfunction by rescuing steroidogenic enzymes and steroidogenic regulatory factors in vivo. The reduction in the number of Leydig cells after LPS exposure was reversed by ADM. ADM rescued the gene or protein levels of SF-1, LRH1, Nur77, StAR, P450scc, 3ß-HSD, CYP17 and 17ß-HSD and plasma testosterone concentrations. To summarize ADM could rescue some important steroidogenic enzymes, steroidogenic regulatory factors and testosterone production in Leydig cells in vivo.

16.
Front Endocrinol (Lausanne) ; 13: 905171, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909556

RESUMO

The current research and existing facts indicate that type 2 diabetes mellitus (T2DM) is characterized by gut microbiota dysbiosis and disturbed microbial metabolites. Oral glucose-lowering drugs are reported with pleiotropic beneficial effects, including not only a decrease in glucose level but also weight loss, antihypertension, anti-inflammation, and cardiovascular protection, but the underlying mechanisms are still not clear. Evidence can be found showing that oral glucose-lowering drugs might modify the gut microbiome and thereby alter gastrointestinal metabolites to improve host health. Although the connections among gut microbial communities, microbial metabolites, and T2DM are complex, figuring out how antidiabetic agents shape the gut microbiome is vital for optimizing the treatment, meaningful for the instruction for probiotic therapy and gut microbiota transplantation in T2DM. In this review, we focused on the literatures in gut microbiota and its metabolite profile alterations beneficial from oral antidiabetic drugs, trying to provide implications for future study in the developing field of these drugs, such as combination therapies, pre- and probiotics intervention in T2DM, and subjects with pregestational diabetes and gestational diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Microbiota , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Disbiose , Glucose/farmacologia , Humanos
17.
J Oncol ; 2022: 1710272, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909903

RESUMO

Background: Immunotherapy represented by PD-1 blockades had become the standard of care for advanced non-small cell lung cancer (NSCLC) gradually. Unfortunately, several PD-1 inhibitor-related studies excluded elderly patients with NSCLC over 75 years of age, resulting in relatively limited evidence regarding the efficacy and safety of PD-1 in elderly patients with NSCLC clinically. Objective: This study aimed to identify the effectiveness and safety of PD-1 blockade monotherapy among elderly patients with advanced NSCLC. Methods: Elderly patients with advanced NSCLC (≥65 years) who received PD-1 blockade monotherapy from September 2018 to December 2021 were screened retrospectively, and a total of 68 elderly patients with NSCLC were eligible for inclusion ultimately. The PD-1 blockades in the study were the available PD-1 monoclonal antibodies that had been approved for marketing in China, including camrelizumab, sintilimab, pembrolizumab, and nivolumab. The effectiveness and safety of the patients was collected retrospectively. Additionally, the correlation between prognosis and baseline characteristic subgroups was analyzed to identify the potential risk factors for progression-free survival (PFS). Results: The median age of the 68 elderly patients with advanced NSCLC was 73 years (range: 65-82 years). Best overall response during PD-1 blockade administration suggested that no patients were found with complete response, partial response was found in 14 patients, stable disease was noted in 29 patients, and 25 patients had progressive disease, yielding an objective response rate (ORR) of 20.6% (95%CI: 11.7%-32.1%) and a disease control rate (DCR) of 63.2% (95%CI: 50.7%-74.6%). Furthermore, prognostic analysis exhibited that the median progression-free survival (PFS) of the 68 patients with advanced NSCLC was 3.5 months (95%CI: 2.4-4.6) and the median overall survival (OS) was 10.5 months (95%CI: 6.3-14.7). Additionally, a total of 48 patients were observed with the treatment-related adverse reaction (70.6%) of the 68 elderly patients with NSCLC, and the incidence of grade 3 or above adverse reactions was 16.2%. Specifically, the most common adverse reactions were fatigue, diarrhea, rash, and abnormal liver function with the incidence of 25.0%, 22.1%, 16.2%, and 14.7%, respectively. Exploratory analysis between PFS and baseline characteristic subgroups suggested that ECOG performance status and number of metastatic lesions might be independent factors for PFS. Conclusion: PD-1 blockade monotherapy exhibited potential effectiveness and acceptable toxicity for elderly patients with NSCLC. ECOG performance status and number of metastatic lesions might be potential risk factors to predict the PFS of elderly patients with advanced NSCLC.

18.
Org Lett ; 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35930056

RESUMO

A novel four-component reaction of alkynes, amines, azides, and 2H-azirines has been developed for the first time by the efficient formation of four C-N bonds in one step under mild conditions, rapidly preparing polyfunctionalized triazoles with molecular diversity involving three different intermediates of copper-acetylide, copper-allenylidene, and copper-vinyl nitrene. Propargylic ester is disclosed as a "three-in-one" building block possessing triplicate cycloaddition and nucleophilic and electrophilic properties, which could enable such a four-component transformation by high yields, broad substrate scope, and functionalization.

19.
Front Immunol ; 13: 781148, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911767

RESUMO

The intestinal microbiota regulate the brain function of the host through the production of a myriad of metabolites and are associated with various neurological diseases. Understanding the intestinal microbiome of patients with prolonged disorders of consciousness (DoC) is important for the evaluation and treatment of the disease. To investigate the differences in the intestinal microbiome and short-chain fatty acids (SCFAs) among patients in a vegetative state (VS), a minimally conscious state (MCS), and emerged from MCS (EMCS), as well as the influence of antibiotics on these patients, 16S ribosomal RNA (16S rRNA) sequencing and targeted lipidomics were performed on fecal samples from patients; in addition, analysis of the electroencephalogram (EEG) signals was performed to evaluate the brain function of these patients. The results showed that the intestinal microbiome of the three groups differed greatly, and some microbial communities showed a reduced production of SCFAs in VS patients compared to the other two groups. Moreover, reduced microbial communities and five major SCFAs, along with attenuated brain functional connectivity, were observed in MCS patients who were treated with antibiotics compared to those who did not receive antibiotic treatment, but not in the other pairwise comparisons. Finally, three genus-level microbiota-Faecailbacterium, Enterococcus, and Methanobrevibacter-were considered as potential biomarkers to distinguish MCS from VS patients, with high accuracy both in the discovery and validation cohorts. Together, our findings improved the understanding of patients with prolonged DoC from the intestinal microbiome perspective and provided a new reference for the exploration of therapeutic targets.


Assuntos
Microbioma Gastrointestinal , Antibacterianos , Estado de Consciência/fisiologia , Ácidos Graxos Voláteis/metabolismo , Humanos , Metabolismo dos Lipídeos , Estado Vegetativo Persistente , RNA Ribossômico 16S/genética
20.
Front Physiol ; 13: 926795, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35923240

RESUMO

Coprophagy is an instinctive behavior in rabbit with important effects on growth and reproductive performance. The underlying mechanism of this effect in rabbit is unknown. Here, we used Elizabeth circle as a coprophagy preventing model in female rabbits and assess feed intake, growth, and reproductive performance. We found that preventing coprophagy did not affect feed intake but decreased body weight and weight of several organs and tissues and resulted in complete reproductive failure during the late pregnancy period, accompanied by reduced levels of plasma progesterone. RNA-seq analysis of rabbit ovarian tissues revealed that preventing coprophagy affected significantly 241 genes (DEGs), with the large majority being downregulated. Bioinformatic analyses revealed that those DEGs are mostly involved in apoptosis, immune response, and metabolic pathways. Among DEGs, the lysosomal cysteine protease cathepsin B (CTSB) was significantly downregulated in the coprophagy prevention group. Further studies using siRNA and adenovirus overexpression systems revealed that CTSB promotes the proliferation of rabbit granulosa cells (GCS) and prevents apoptosis. Measurement of transcripts coding for proteins related to apoptosis revealed a minor transcriptomic effect of CTSB, indicating that its effect is likely post-transcriptional. Overexpression of CTSB increased secretion of progesterone and estradiol, partly via upregulation of CYP19A1 while inhibition of CTSB decreased progesterone secretion partly via downregulation of the StAR gene. In conclusion, our study demonstrated the detrimental effect on reproduction by preventing coprophagy with a main role for this response played by CTSB on the granulosa cells of the ovary.

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