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1.
Clin Kidney J ; 15(6): 1093-1099, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35664283

RESUMO

Background: The longitudinal relationship of albuminuria with incident frailty remains unknown. Therefore we aimed to evaluate the relation of albuminuria with the risk of incident frailty in older adults. Methods: A total of 1115 participants ≥65 years of age (average age 80.3 years) who were free of frailty in the Chinese Longitudinal Healthy Longevity Survey were included. The outcome was incident frailty, defined as a frailty index ≥0.25 during follow-up. Cox proportional hazards models were used to assess the association of the urinary albumin:creatinine ratio (UACR) with frailty. Results: During a median follow-up duration of 5.3 years, 295 (26.5%) participants developed incident frailty. Overall, the UACR was significantly positively associated with the risk of incident frailty (P for trend = 0.005), with a significantly higher risk of incident frailty in participants in the quartile 4 of UACR {≥13.43 mg/g; hazard ratio [HR] 1.64 [95% confidence interval (CI) 1.13-2.37]} compared with those in quartile 1 (<0.73 mg/g). Consistently, when UACRs were assessed as clinical categories, compared with participants with UACR <10 mg/g, those with UACR ≥30 mg/g had a higher HR of incident frailty [HR 1.61 (95% CI 1.17-2.20)]. Accounting for the competing risk of death also did not substantially change the results. In addition, a stronger positive association between UACR and incident frailty was found in those with a higher high-sensitivity C-reactive protein level (hs-CRP) (P for interaction = 0.045). Conclusion: Albuminuria was positively associated with the risk of incident frailty, particularly in those with higher hs-CRP, emphasizing the importance of managing both albuminuria and inflammation for primary prevention of frailty.

2.
Genes Dis ; 9(4): 1038-1048, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35685465

RESUMO

The microRNAs (miRNAs) play an important role in regulating myogenesis by targeting mRNA. However, the understanding of miRNAs in skeletal muscle development and diseases is unclear. In this study, we firstly performed the transcriptome profiling in differentiating C2C12 myoblast cells. Totally, we identified 187 miRNAs and 4260 mRNAs significantly differentially expressed that were involved in myoblast differentiation. We carried out validation of microarray data based on 5 mRNAs and 5 miRNAs differentially expressed and got a consistent result. Then we constructed and validated the significantly up- and down-regulated mRNA-miRNA interaction networks. Four interaction pairs (miR-145a-5p-Fscn1, miR-200c-5p-Tmigd1, miR-27a-5p-Sln and miR-743a-5p-Mob1b) with targeted relationships in differentiated myoblast cells were demonstrated. They are all closely related to myoblast development. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated cell cycle signals important for exploring skeletal muscle development and disease. Functionally, we discovered that miR-743a targeting gene Mps One Binder Kinase Activator-Like 1B (Mob1b) gene in differentiated C2C12. The up-regulated miR-743a can promote the differentiation of C2C12 myoblast. While the down-regulated Mob1b plays a negative role in differentiation. In addition, the expression profile of miR-743a and Mob1b are consistent with skeletal muscle recovery after Cardiotoxin (CTX) injury. Our study revealed that miR-743a-5p regulates myoblast differentiation by targeting Mob1b involved in skeletal muscle development and regeneration. Our findings made a further exploration for mechanisms in myogenesis and might provide potential possible miRNA-based target therapies for skeletal muscle regeneration and disease in the near future.

3.
Front Nutr ; 9: 871556, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685874

RESUMO

Using oat-corn-konjac extruded mixed powder, oat bran micro powder, skim milk powder, Pueraria whole powder, and pumpkin powder as raw materials, a formula powder with high dietary fiber was prepared, and its effect on obesity in mice with a high-fat diet was investigated. After 7 days of adaptive feeding, the mice were divided into blank group, high-fat diet group, formula powder + high-fat diet group, and weight-loss drug + high-fat diet group. After 8 weeks of treatment, the body weight of mice were observed and measured to determine the composition of tract flora, liver leptin content, insulin content, and activities of AMP-activated protein kinase (AMPK), lipoprotein lipase (LPL), fatty acid synthetase (FAS), sterol-regulatory element-binding proteins (SREBPs), and acetyl CoA carboxylase 1 (ACC1). The results indicated that treatment with the formula powder could reduce the body weight of mice and increase the abundance of Bifidobacterium, Akkermansia, and Romboutsia compared to the group given a high-fat diet. Moreover, the leptin and insulin contents of the experimental group decreased from 5.67 µg/L to 0.12 µg/L and from 12.71 µg/L to 7.13 µg/L, respectively, compared to the control group, which was not significantly different from the blank group (P > 0.05). Also, the activities of AMPK and LPL increased, and the activities of FAS, SREBPs, and ACC1 were significantly decreased (P < 0.05). Some pathogenic bacteria were significantly positively correlated with leptin and FAS and significantly negatively correlated with LPL. Some beneficial bacteria were positively correlated with LPL. Therefore, the formula powder used in this study could reduce the body weight of mice, increase the abundance of some beneficial bacteria in the colonic intestinal microbiota, and improve the activities of enzymes related to lipid metabolism in the liver. This study provides a theoretical reference for the pathway by which high-fiber diet improves liver and intestinal metabolic abnormalities.

4.
J Mark Access Health Policy ; 10(1): 2078474, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35693379

RESUMO

Background: The economic impact of adverse events (AEs) for poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian or breast cancer has not been widely evaluated. Objective: Compare PARPi-related AE management costs from a US payer perspective. Methods: The frequency of treatment-related grade 3-4 AEs was obtained from published clinical trials of PARPis for the treatment of advanced ovarian cancer (AOC), platinum-sensitive recurrent ovarian cancer (PSROC), and metastatic breast cancer (MBC). AE management costs per patient (2020 USD) per treatment course were calculated by multiplying the AE unit costs by the frequency of AEs for each arm of each trial. Sensitivity analyses were conducted according to the lower and upper limits of the 95% confidence interval for AE rates and unit costs, respectively. Scenarios were also performed to explore the uncertainty of outcomes. Results: Total AE management costs in AOC were: $3,904, olaparib; $5,595, olaparib plus bevacizumab; and $12,215, niraparib. In PSROC, total costs were: $3,894, olaparib; $6,001, rucaparib; and $11,492, niraparib, and in MBC: $3,574, olaparib; and $9,489, talazoparib. Hematological toxicities were the key drivers of AE management costs for PARPis. Conclusions: The main AEs among PARPis were hematological. Olaparib was associated with lower AE costs compared to other PARPis.

5.
Front Cell Dev Biol ; 10: 890574, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35693947

RESUMO

Telomerase activity is essential for the self-renewal and potential of embryonic, induced pluripotent, and cancer stem cells, as well as a few somatic stem cells, such as human urine-derived stem cells (USCs). However, it remains unclear how telomerase activity affects the regeneration potential of somatic stem cells. The objective of this study was to determine the regenerative significance of telomerase activity, particularly to retain cell surface marker expression, multipotent differentiation capability, chromosomal stability, and in vivo tumorigenic transformation, in each clonal population of human primary USCs. In total, 117 USC specimens from 10 healthy male adults (25-57 years of age) were obtained. Polymerase chain reaction amplification of a telomeric repeat was used to detect USCs with positive telomerase activity (USCsTA+). A total of 80 USCsTA+ (70.2%) were identified from 117 USC clones, but they were not detected in the paired normal bladder smooth muscle cell and bone marrow stromal cell specimens. In the 20-40 years age group, approximately 75% of USC clones displayed positive telomerase activity, whereas in the 50 years age group, 59.2% of the USC clones expressed positive telomerase activity. USCsTA+ extended to passage 16, underwent 62.0 ± 4.8 population doublings, produced more cells, and were superior for osteogenic, myogenic, and uroepithelial differentiation compared to USCsTA-. Importantly, USCs displayed normal chromosome and no oncological transformation after being implanted in vivo. Overall, as a safe cell source, telomerase-positive USCs have a robust regenerative potential in cell proliferation and multipotent differentiation capacity.

6.
ACS Nano ; 2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35696325

RESUMO

The phenomena of ice formation and growth are of great importance for climate science, regenerative medicine, cryobiology, and food science. Hence, how to control ice formation and growth remains a challenge in these fields and attracts great interest from widespread researchers. Herein, the ice regulation ability of the two-dimensional MXene Ti3C2Tx in both the cooling and thawing processes is explored. Molecularly speaking, the ice growth inhibition mechanism of Ti3C2Tx MXene is ascribed to the formation of hydrogen bonds between functional groups of -O-, -OH, and -F distributed on the surface of Ti3C2Tx and ice/water molecules, which was elucidated by the molecular dynamics simulation method. In the cooling process, Ti3C2Tx can decrease the supercooling degree and inhibit the sharp edge morphology of ice crystals. Moreover, taking advantage of the outstanding photothermal conversion property of Ti3C2Tx, rapid ice melting can be achieved, thus reducing the phenomena of devitrification and ice recrystallization. Based on the ice restriction performance of Ti3C2Tx mentioned above, Ti3C2Tx is applied for cryopreservation of stem-cell-laden hydrogel constructs. The results show that Ti3C2Tx can reduce cryodamage to stem cells induced by ice injury in both the cooling and thawing processes and finally increase the cell viability from 38.4% to 80.9%. In addition, Ti3C2Tx also shows synergetic antibacterial activity under laser irradiation, thus realizing sterile cryopreservation of stem cells. Overall, this work explores the ice inhibition performance of Ti3C2Tx, elucidates the physical mechanism, and further achieves application of Ti3C2Tx in the field of cell cryopreservation.

7.
Int J Mol Sci ; 23(11)2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35682680

RESUMO

Myogenesis is a central step in prenatal myofiber formation, postnatal myofiber hypertrophy, and muscle damage repair in adulthood. RNA-Seq technology has greatly helped reveal the molecular mechanism of myogenesis, but batch effects in different experiments inevitably lead to misinterpretation of differentially expressed genes (DEGs). We previously applied the robust rank aggregation (RRA) method to effectively circumvent batch effects across multiple RNA-Seq datasets from 3T3-L1 cells. Here, we also used the RRA method to integrate nine RNA-Seq datasets from C2C12 cells and obtained 3140 robust DEGs between myoblasts and myotubes, which were then validated with array expression profiles and H3K27ac signals. The upregulated robust DEGs were highly enriched in gene ontology (GO) terms related to muscle cell differentiation and development. Considering that the cooperative binding of transcription factors (TFs) to enhancers to regulate downstream gene expression is a classical epigenetic mechanism, differentially expressed TFs (DETFs) were screened, and potential novel myogenic factors (MAF, BCL6, and ESR1) with high connection degree in protein-protein interaction (PPI) network were presented. Moreover, KLF5 cooperatively binds with the three key myogenic factors (MYOD, MYOG, and MEF2D) in C2C12 cells. Motif analysis speculates that the binding of MYOD and MYOG is KLF5-independent, while MEF2D is KLF5-dependent. It was revealed that KLF5-binding sites could be exploited to filter redundant MYOD-, MYOG-, and MEF2D-binding sites to focus on key enhancers for myogenesis. Further functional annotation of KLF5-binding sites suggested that KLF5 may regulate myogenesis through the PI3K-AKt signaling pathway, Rap1 signaling pathway, and the Hippo signaling pathway. In general, our study provides a wealth of untapped candidate targets for myogenesis and contributes new insights into the core regulatory mechanisms of myogenesis relying on KLF5-binding signal.


Assuntos
Desenvolvimento Muscular , Fosfatidilinositol 3-Quinases , Diferenciação Celular/genética , Desenvolvimento Muscular/genética , Mioblastos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Transcrição/metabolismo
8.
Aging Dis ; 13(3): 884-898, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35656097

RESUMO

COVID-19 emerged in Wuhan in December 2019 and soon became a worldwide pandemic. We collected and analyzed the data from 1077 patients with COVID-19 who were admitted to the west campus of Wuhan Union Hospital from January 16 to April 16, 2020. Sixty (5.6%) of the 1077 COVID-19 patients were diagnosed with acute kidney injury (AKI) during hospitalization, and 18 of them (30%) had AKI on chronic kidney disease (AKI/CKD). COVID-19 patients with AKI had a worse prognosis, with higher intensive care unit (ICU) admission (28.3%) and fatality (65%) rates than patients without AKI (3.4% and 10.7%, respectively). Among the COVID-19 patients, AKI was more likely to occur in male patients, the elderly, patients with more severe disease states and those with comorbidities (such as hypertension, diabetes, coronary heart disease (CHD), chronic obstructive pulmonary disease (COPD) and CKD). COVID-19 patients with AKI were more likely to develop respiratory failure, gastrointestinal bleeding, acute liver injury, acute myocardial injury, heart failure, acute respiratory distress syndrome (ARDS), cerebrovascular accident, and disseminated intravascular coagulation (DIC) than those without AKI. Compared with patients without AKI, COVID-19 patients with AKI had lower platelet counts, lymphocyte counts, albumin levels and serum calcium levels but had elevated leukocyte counts, neutrophil counts and serum potassium levels. Inflammatory indicators, such as C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT), were significantly higher in patients with AKI than in those without AKI. COVID-19 patients with AKI also exhibited a longer prothrombin time (PT), a longer activated partial thromboplastin time (APTT), and a higher D-dimer level than those without AKI. Survival analysis revealed that COVID-19 patients with AKI had a reduced survival rate compared with those without AKI. Furthermore, COVID-19 patients with AKI/CKD had a lower survival rate than those with AKI or CKD only. Multiple logistic regression indicated that the predictors of AKI in COVID-19 patients included complications, such as respiratory failure and acute myocardial injury, and higher creatinine and PCT levels during hospitalization.

9.
BMC Endocr Disord ; 22(1): 144, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35641932

RESUMO

BACKGROUND: The objective of this study is to retrospectively analyze the correlation between the thyroid hormones and nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) patients with normal thyroid function. METHODS: Totally 586 T2DM patients with normal thyroid function participated in this research and were divided into T2DM without NAFLD (240 cases) group and T2DM with NAFLD (346 cases) group. The NAFLD fibrosis score (NFS) > 0.676 was defined as progressive liver fibrosis and used to categorize the patients into T2DM without progressive liver fibrosis group (493 cases) and T2DM with progressive liver fibrosis group (93 cases). RESULTS: The results indicated that the levels of free triiodothyronine (FT3), total triiodomethylamine (TT3) and FT3/free thyroxine ratio (FT3/FT4) were significantly higher while the FT4 level was lower in T2DM with NAFLD group than that in T2DM without NAFLD group (p < 0.05). The levels of FT3, FT4, TT3 and TT4 in patients with progressive liver fibrosis were significantly lower in patients with progressive liver fibrosis than that in patients without progressive liver fibrosis (p < 0.05). Logistic regression analysis showed a positive connection between FT3/FT4 ratio and NAFLD (p = 0.038), a negative relationship between FT4 level and NAFLD (p = 0.026), between the levels of FT4, TT3 and total thyroxine (TT4) and the risk of progressive hepatic fibrosis (p = 0.022, p = 0.007, p = 0.046). CONCLUSION: There is a certain correlation between thyroid hormone levels and NAFLD in T2DM patients, suggesting that the assessment of thyroid hormone levels in T2DM patients with normal thyroid function could be helpful in the prevention and treatment of NAFLD.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/complicações , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Estudos Retrospectivos , Fatores de Risco , Glândula Tireoide , Hormônios Tireóideos , Tiroxina
10.
Dev Cell ; 57(12): 1496-1511.e6, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35675813

RESUMO

Diabetic patients show elevated plasma IL18 concentrations. IL18 has two receptors: the IL18 receptor (IL18r) and the Na-Cl co-transporter (NCC). Here, we report that IL18 is expressed on islet α cells, NCC on ß cells, and IL18r on acinar cells in human and mouse pancreases. The deficiency of these receptors reduces islet size, ß cell proliferation, and insulin secretion but increases ß cell apoptosis and exocrine macrophage accumulation after diet-induced glucose intolerance or streptozotocin-induced hyperglycemia. Together with the glucagon-like peptide-1 (GLP1), IL18 uses the NCC and GLP1 receptors on ß cells to trigger ß cell development and insulin secretion. IL18 also uses the IL18r on acinar cells to block hyperglycemic pancreas macrophage expansion. The ß cell-selective depletion of the NCC or acinar-cell-selective IL18r depletion reduces glucose tolerance and insulin sensitivity with impaired ß cell proliferation, enhanced ß cell apoptosis and macrophage expansion, and inflammation in mouse hyperglycemic pancreas. IL18 uses NCC, GLP1r, and IL18r to maintain islet ß cell function and homeostasis.

11.
Biomaterials ; 287: 121615, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35679644

RESUMO

The emerging field of cultured meat faces several technical hurdles, including the scale-up production of quality muscle and adipose progenitor cells, and the differentiation and bioengineering of these cellular materials into large, meat-like tissue. Here, we present edible, 3D porous gelatin micro-carriers (PoGelat-MCs), as efficient cell expansion scaffolds, as well as modular tissue-engineering building blocks for lab-grown meat. PoGelat-MC culture in spinner flasks, not only facilitated the scalable expansion of porcine skeletal muscle satellite cells and murine myoblasts, but also triggered their spontaneous myogenesis, in the absence of myogenic reagents. Using 3D-printed mold and transglutaminase, we bio-assembled pork muscle micro-tissues into centimeter-scale meatballs, which exhibited similar mechanical property and higher protein content compared to conventional ground pork meatballs. PoGelat-MCs also supported the expansion and differentiation of 3T3L1 murine pre-adipocytes into mature adipose micro-tissues, which could be used as modular assembly unit for engineered fat-containing meat products. Together, our results highlight PoGelat-MCs, in combination with dynamic bioreactors, as a scalable culture system to produce large quantity of highly-viable muscle and fat micro-tissues, which could be further bio-assembled into ground meat analogues.

12.
HLA ; 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35681275

RESUMO

The importance of anti-HLA antibodies in transplantation settings, such as HLA-mismatched or haploidentical hematopoietic stem cell transplantation and platelet refractoriness, is widely recognized. In previous reports, it was mentioned that several cut-off values of donor-specific anti-HLA antibodies mean fluorescence intensity (MFI) were related to graft rejection in the environment of HLA mismatched stem cell transplantation and the aim of this study was to investigate the prevalence and risk factors of anti-HLA antibodies according to those cut-off values of MFI. A total of 3805 patients with hematologic disease were prospectively enrolled and analyzed. When using MFI of anti-HLA antibodies ≥500, ≥1000, ≥1500, ≥2000, ≥5000, and ≥ 10,000 as cut-off values for positivity, the prevalence of class I or II anti-HLA antibodies ranged from 4.6% to 20.2% in all cases. When the MFI cut-off value was ≥500 for positivity, multivariate analysis indicated that platelet transfusion, underlying disease, and pregnancy were the most important risk factors for the presence of anti-HLA antibodies for the total patients. Subgroup analysis according to age, gender, and underlying disease showed that pregnancy was the most important risk factor for the presence of anti-HLA antibodies. For all patients (n = 3805), when anti-HLA antibody positivity was defined according to different MFI cut-off values, including ≥1000, ≥1500, ≥2000, ≥5000, and ≥ 10,000, an association of platelet transfusion and pregnancy with anti-HLA antibodies was also demonstrated. Our results suggest that pregnancy and platelet transfusion are the main risk factors for the prevalence of anti-HLA antibodies in haploid allograft candidates, providing evidence for guiding the evaluation of anti-HLA antibodies and helping donor selection for HLA-mismatched transplant candidates.

13.
Environ Int ; 165: 107297, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35709580

RESUMO

BACKGROUND: Emerging evidence suggests that early-life (in-utero and first-year since birth) exposure to ambient PM2.5 is a risk factor for asthma onset and exacerbation among children, while the hazards caused by PM2.5 compositions remain largely unknown. OBJECTIVE: To examine potential associations of early-life exposures to PM2.5 mass and its major chemical constituents with childhood asthma and wheezing. METHODS: By conducting the Phase II of the China, Children, Homes, Health study, we investigated 30,325 preschool children aged 3-6 years during 2019-2020 in mainland China. Early-life exposure to PM2.5 mass and its constituents (i.e., black carbon [BC], organic matter [OM], nitrate, ammonium, sulfate) were calculated based on monthly estimates at a 1 km × 1 km resolution from satellite-based models. We adopted a novel quantile-based g-computation approach to assess the effect of a mixture of PM2.5 constituents on childhood asthma/wheezing. RESULTS: The average PM2.5 concentrations during in-utero and the first year since birth were 64.7 ± 10.6 and 61.8 ± 10.5 µg/m3, respectively. Early-life exposures to a mixture of major PM2.5 constituents were significantly associated with increased risks of asthma and wheezing, while no evident compositions-wheezing associations were found in the first year. Each quintile increases in all five PM2.5 components exposures in utero was accordingly associated with an odds ratio of 1.18 [95% confidence interval: 1.07-1.29] for asthma and 1.08 [1.01-1.16] for wheezing. BC, OM and SO42- contributed more to risks of asthma and wheezing than the other PM2.5 constituents during early life, wherein the effects of BC were only observed during pregnancy. Sex subgroup analyses suggested stronger associations among girls of first-year exposures to PM2.5 components with childhood asthma. CONCLUSION: Early-life exposures to ambient PM2.5, particularly compositions of BC, OM and SO42-, are associated with an increased risk of childhood asthma.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Asma , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Asma/induzido quimicamente , Asma/etiologia , Pré-Escolar , China/epidemiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Feminino , Humanos , Material Particulado/análise , Gravidez , Sons Respiratórios/etiologia
14.
J Immunother Cancer ; 10(6)2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35728870

RESUMO

BACKGROUND: The repression or downregulation of programmed death-ligand 1 (PD-L1) can release its inhibition of T cells and activate antitumor immune responses. Although PD-1 and PD-L1 antibodies are promising treatments for diverse tumor types, their inherent disadvantages and immune-related adverse events remain significant issues. The development of small molecule inhibitors targeting the interaction surface of PD-1 and PD-L1 has been reviving, yet many challenges remain. To address these issues, we aimed to find small molecules with durable efficacy and favorable biosafety that alter PD-L1 surface expression and can be developed into a promising alternative and complementary therapy for existing anti-PD-1/PD-L1 therapies. METHODS: Cell-based screen of 200 metabolic molecules using a high-throughput flow cytometry assay of PD-L1 surface expression was conducted, and L-5-hydroxytryptophan (L-5-HTP) was found to suppress PD-L1 expression induced by interferon gamma (IFN-γ). Inhibition of PD-L1 induction and antitumor effect of L-5-HTP were evaluated in two syngeneic mouse tumor models. Flow cytometry was performed to investigate the change in the tumor microenvironment caused by L-5-HTP treatment. RESULTS: We discovered that L-5-HTP suppressed IFN-γ-induced PD-L1 expression in tumor cells transcriptionally, and this effect was directly due to itself. Mechanistically, L-5-HTP inhibited IFN-γ-induced expression of RTK ligands and thus suppressed phosphorylation-mediated activation of RTK receptors and the downstream MEK/ERK/c-JUN signaling cascade, leading to decreased PD-L1 induction. In syngeneic mouse tumor models, treatment with 100 mg/kg L-5-HTP (intraperitoneal) inhibited PD-L1 expression and exhibited antitumor effect. L-5-HTP upregulated the ratio of granzyme B+ CD8+ activated cytotoxic T cells. An intact immune system and PD-L1 expression was critical for L-5-HTP to exert its antitumor effects. Furthermore, L-5-HTP acted synergistically with PD-1 antibody to improve anticancer effect. CONCLUSION: Our study illustrated L-5-HTP's inhibitory effect on PD-L1 induction stimulated by IFN-γ in tumor cells and also provided insight into repurposing L-5-HTP for use in tumor immunotherapy.

15.
Front Plant Sci ; 13: 910228, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720574

RESUMO

Plant trichomes, protrusions formed from specialized aboveground epidermal cells, provide protection against various biotic and abiotic stresses. Trichomes can be unicellular, bicellular or multicellular, with multiple branches or no branches at all. Unicellular trichomes are generally not secretory, whereas multicellular trichomes include both secretory and non-secretory hairs. The secretory trichomes release secondary metabolites such as artemisinin, which is valuable as an antimalarial agent. Cotton trichomes, also known as cotton fibers, are an important natural product for the textile industry. In recent years, much progress has been made in unraveling the molecular mechanisms of trichome formation in Arabidopsis thaliana, Gossypium hirsutum, Oryza sativa, Cucumis sativus, Solanum lycopersicum, Nicotiana tabacum, and Artemisia annua. Here, we review current knowledge of the molecular mechanisms underlying fate determination and initiation, elongation, and maturation of unicellular, bicellular and multicellular trichomes in several representative plants. We emphasize the regulatory roles of plant hormones, transcription factors, the cell cycle and epigenetic modifications in different stages of trichome development. Finally, we identify the obstacles and key points for future research on plant trichome development, and speculated the development relationship between the salt glands of halophytes and the trichomes of non-halophytes, which provides a reference for future studying the development of plant epidermal cells.

16.
Exp Ther Med ; 24(1): 451, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35720631

RESUMO

Epithelial tumors that originate from the kidney are uncommon. The majority of cases reported in the literature are malignant, with <1% of adenocarcinomas. Adenomas are even rarer. A case of mucinous cystadenoma of the kidney was diagnosed and treated in Cangzhou Hospital of Integrated TCM-WM•HEBEI. The clinical feature of this disease was atypical. The principal symptom of mucinous cystadenoma of the kidney was a lump in the upper abdomen with intermittent pain in the abdomen. The tumor size ranged from 5-12 cm. The patient was clinically diagnosed with multiple renal cysts with thickened walls and hemorrhage. The patient was admitted to the hospital five days later, and a left nephrectomy was performed. The tumor capsule was integrated and did not adhere to the adjacent tissue. One or multiple smooth-walled dilated cystic areas were found on the cut section, some of which were filled with grey opaque gelatinous clots. Under light microscopy, the epithelial lining was characterized by a single layer of columnar with papillary proliferation and almost had no mitosis. Immunohistochemistry showed that the cyst was positive for carcinoembryonic antigen (CEA) and proliferating cell nuclear antigen (PCNA). Following nephrectomy, the patient was followed up for 8 years and no recurrence and metastasis were found. A total of five articles were retrieved, including six cases with mucinous cystadenoma of the kidney. The clinical feature of this disease was atypical, making clinical diagnosis difficult. Histopathological examination revealed that the cyst consisted of mucinous epithelium with supporting fibrous tissue and immunohistochemistry showed that the cyst was positive for CEA and PCNA. Patients with all resection of the affected kidney had an improved prognosis.

17.
BMC Genomics ; 23(1): 449, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35715739

RESUMO

BACKGROUND: Affinity prediction between molecule and protein is an important step of virtual screening, which is usually called drug-target affinity (DTA) prediction. Its accuracy directly influences the progress of drug development. Sequence-based drug-target affinity prediction can predict the affinity according to protein sequence, which is fast and can be applied to large datasets. However, due to the lack of protein structure information, the accuracy needs to be improved. RESULTS: The proposed model which is called WGNN-DTA can be competent in drug-target affinity (DTA) and compound-protein interaction (CPI) prediction tasks. Various experiments are designed to verify the performance of the proposed method in different scenarios, which proves that WGNN-DTA has the advantages of simplicity and high accuracy. Moreover, because it does not need complex steps such as multiple sequence alignment (MSA), it has fast execution speed, and can be suitable for the screening of large databases. CONCLUSION: We construct protein and molecular graphs through sequence and SMILES that can effectively reflect their structures. To utilize the detail contact information of protein, graph neural network is used to extract features and predict the binding affinity based on the graphs, which is called weighted graph neural networks drug-target affinity predictor (WGNN-DTA). The proposed method has the advantages of simplicity and high accuracy.


Assuntos
Redes Neurais de Computação , Proteínas , Sequência de Aminoácidos , Desenvolvimento de Medicamentos , Proteínas/química , Alinhamento de Sequência
18.
Pediatr Blood Cancer ; : e29845, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35731841

RESUMO

Haploidentical hematopoietic stem cell transplant (haplo-HSCT) provides an important alternative for children and adolescents with acquired severe aplastic anemia (SAA) lacking of matched donors. To test whether pre-transplant serum ferritin (SF) represents a candidate predictor for survival and a potential biomarker for graft-versus-host disease (GvHD) in pediatric haplo-HSCT, we retrospectively evaluated 147 eligible patients with SAA who underwent haplo-HSCT. The patients were divided into the low-SF group (< 1000 ng/ml) and the high-SF group (≥ 1000 ng/ml). We found that SF ≥1000 ng/ml independently increased the risk of grade II-IV aGvHD (HR = 2.596, 95% CI 1.304-5.167, p = .007) and grade III-IV aGvHD (HR = 3.350, 95% CI 1.162-9.658, p = .025). Similar probabilities of transplant-related mortality at 100 days were observed in the two groups (6.19 ± 2.45% vs 8.00 ± 3.84%, p = .168). The 2-year overall survival (85.29 ± 3.89% vs 92.00 ±3.84%, p = .746) and failure-free survival (83.23% ± 4.08% vs 83.37 ± 6.27%, p = .915) were comparable. GvHD-/failure-free survival were 60.06 ± 5.10% and 75.56 ± 6.87%, respectively (p = .056). In conclusion, the elevated pre-transplant SF level is associated with higher incidences of grade II-IV aGvHD and grade III-IV aGvHD. However, it is not associated with worse survival after haplo-HSCT for children and adolescent patients with SAA. This article is protected by copyright. All rights reserved.

19.
Biosci Rep ; 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35712981

RESUMO

Hepatocellular carcinoma (HCC) is a common malignant tumour with high rates of morbidity and mortality worldwide. Therefore, it is of great significance to find new molecular markers for HCC diagnosis and treatment. G6PD is known to be dysregulated in a variety of tumours. In addition, the ceRNA network plays a crucial role in the occurrence and development of HCC. However, the mechanism by which the ceRNA network regulates G6PD in HCC remains unclear. We used TCGA-LIHC data to analyse the possibility of using G6PD as an independent prognostic marker. UCR, MCR, and ROC analysis were used to analyse the influence of G6PD overexpression on the prognosis of HCC patients. We also analysed the biological function of G6PD, its effect on the immune microenvironment, and drug sensitivity. Finally, we constructed a ceRNA network of lncRNAs/miR-22-5p/G6PD to explore the regulatory mechanism of G6PD. G6PD was highly expressed in HCC, was related to pathological stage and poor prognosis, and could be used as an independent prognostic indicator of HCC. The expression of G6PD was closely related to the immune microenvironment of HCC. In addition, the expression of G6PD in HCC could be regulated by the ceRNA network. Therefore, G6PD can be used as an immunotherapy target to improve the survival and prognosis of HCC patients, and the ceRNA regulatory network of G6PD has potential diagnostic and therapeutic value for HCC.

20.
Front Immunol ; 13: 915657, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720284

RESUMO

To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp (Cyprinus carpio), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3, claudin-7, ZO-1, and MLCK were significantly up-regulated in the LP+0.4% AKG group, and the relative expression levels of the pro-inflammatory factors IL-1ß and IL-6α were significantly lower with the addition of 0.4%, 0.8%, and 1.2% AKG. Moreover, the abundance of Proteobacteria in the LP+0.4% AKG group was lower than that in the LP group, and the abundance of Firmicutes and Fusobacteria was higher at the phylum level. The abundance of Citrobacter in the LP+0.4% AKG group was decreased compared to the LP group, while the abundance of Aeromonas was increased at the genus level. In short, the effects of AKG on the intestinal health of the common carp were systematically and comprehensively evaluated from the perspectives of intestinal physical barrier, chemical barrier, biological barrier, and immune barrier. We found that an LP diet supplemented with 0.4% AKG was beneficial to the growth performance and intestinal health of common carp.


Assuntos
Carpas , Ração Animal/análise , Animais , Dieta com Restrição de Proteínas , Suplementos Nutricionais , Imunidade Inata , Ácidos Cetoglutáricos/farmacologia
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