This study aims to explore the relationship between the Dietary Index for Gut Microbiota (DI-GM) and diabetes. In recent years, there has been increasing attention to the role of the gut microbiome in regulating host metabolism. However, the relationship between DI-GM and the risk of diabetes has not been sufficiently studied. This study utilized relevant data from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Multiple logistic regression analysis was conducted to explore the relationship between DI-GM and the risk of diabetes. The dose-response relationship between DI-GM and the risk of diabetes was observed using restricted cubic splines (RCS). Threshold effect analysis was performed based on RCS results. Subgroup analyses were used to conduct a sensitivity analysis of the relationship between DI-GM and the risk of diabetes. The results from multiple logistic regression analysis indicated a significant negative correlation between DI-GM and the risk of diabetes (OR, 0.954, 95%CI, 0.918-0.991). RCS results also showed a significant nonlinear negative relationship between DI-GM and the risk of diabetes (P < 0.001, P for nonlinear = 0.010). The threshold effect analysis revealed that when DI-GM was below 6.191, there was a significant negative correlation between DI-GM and the risk of diabetes (OR, 0.921, 95% CI, 0.876-0.969). However, when DI-GM exceeded 6.191, the relationship between DI-GM and the risk of diabetes was no longer significant. Subgroup analysis revealed that the negative correlation between DI-GM and the risk of diabetes remained significant in Whites, participants with a poverty-income ratio > 3.5, body mass index > 24, current drinkers, never or current smokers, and those without chronic kidney disease (P < 0.05). This study demonstrates a nonlinear negative correlation between DI-GM and the risk of diabetes. Maintaining DI-GM above 6.191 may help prevent diabetes.
Notch signaling pathway is involved in the regulation of cell fate, differentiation, proliferation and apoptosis. Previous studies indicate that Notch1 activates myofibroblast differentiation, a key feature of lung fibrosis. However, the in vivo importance of Notch1 mediated myofibroblast differentiation is not clear. In this study, the effects of mesenchymal‐specific deletion of Notch1 on pulmonary fibrosis were examined. Crossing of mice with the floxed notch1 gene with α2(I) collagen enhancer‐CreER(T)‐bearing mice successfully generated progeny with a conditional knockout (CKO) of notch1 in collagen I‐expressing (“mesenchymal”) cells only upon treatment with tamoxifen (notch1 CKO). When treated with endotracheal bleomycin injection, Notch1 CKO mice showed significant attenuation of pulmonary fibrosis relative to control mice as examined by collagen deposition, myofibroblast differentiation and histopathological analyses. No significant differences in inflammatory/immune cell influx were observed in the mutant mice relative to the control mice as showed by flow cytometry analysis. These findings confirmed an essential role for Notch1 mediated myofibroblast differentiation in the pathogenesis of pulmonary fibrosis. Grant Funding Source : Supported by National Institute of Health grants (HL52285, HL91775, HL112880 and DK020572)
Abstract Introduction: Angiotensin-converting enzyme 2 (ACE2) is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effects of SARS-CoV-2 on normal pituitary glands function or pituitary neuroendocrine tumors (PitNETs) have not yet been elucidated. Thus, the present study aimed to investigate the potential risks of SARS-CoV-2 infection on the impairment of pituitary glands and the development of PitNETs. Methods: PitNETs tissues were obtained from 114 patients, and normal pituitary gland tissues were obtained from the autopsy. The mRNA levels of ACE2 and angiotensin II receptor type 1 (AGTR1) were examined by quantitative real-time PCR. Immunohistochemical staining was performed for ACE2 in 69 PitNETs and 3 normal pituitary glands. The primary tumor cells and pituitary cell lines (MMQ, GH3 and AtT-20/D16v-F2) were treated with diminazene aceturate (DIZE), an ACE2 agonist, with various dose regimens. The pituitary hormones between 43 patients with SARS-CoV-2 infection were compared with 45 healthy controls. Results: Pituitary glands and the majority of PitNET tissues showed low/negative ACE2 expression at both the mRNA and protein levels, while AGTR1 showed high expression in normal pituitary and corticotroph adenomas. ACE2 agonist increased the secretion of ACTH in AtT-20/D16v-F2 cells through downregulating AGTR1. The level of serum adrenocorticotropic hormone (ACTH) was significantly increased in COVID-19 patients as compared to normal controls (p<0.001), but was dramatically decreased in critical cases as compared to non-critical patients (p=0.003). Conclusion: This study revealed a potential impact of SARS-CoV-2 infection on corticotroph cells and adenomas.
Dentin hypersensitivity has been widely recognized to be caused by patent dentinal tubules (DTs). A polyaspartic acid-calcium and magnesium (PAsp-Ca&Mg) complex process has been demonstrated to induce biomimetic mineralization of collagen fibrils. This study investigated the in vitro and in vivo occlusion of the DTs by a PAsp-Ca&Mg complex process. Dentin disks were treated by citric acid to open the DTs and randomly divided into 4 groups. Two experimental groups (n = 18) were applied with PAsp-Ca&Mg suspension and phosphate solution or phosphate-fluoride solution in sequence for 10 min. Two positive control groups (n = 18) were treated with Gluma or Duraphat. All the dentin disks were incubated in artificial saliva for 24 h. DT occlusion was characterized by scanning electron microscopy, and dentin permeability measurement was conducted regardless of being subject to abrasive or ultrasonic and acidic challenge. The incisors of 3 New Zealand rabbits were used to verify the in vivo occlusion of the DTs. In vitro and in vivo results demonstrated in-depth occlusion of the DTs to ~100 μm by the PAsp-Ca&Mg complex process. When compared with control groups, the PAsp-Ca&Mg complex process could significantly reduce dentin permeability (P < 0.05) irrespective of abrasive or ultrasonic and acidic challenge. The PAsp-Ca&Mg complex process not only deeply occluded patent DTs but also significantly decreased dentin permeability and provided a paradigm for ion-doped DT occlusion. This provides a promising strategy for managing dentin hypersensitivity.
The CCAAT/enhancer-binding protein β (C/EBPβ) regulates a variety of factors and cellular responses associated with pulmonary fibrosis. To distinguish its role in the mesenchyme from that in other compartments, the effects of mesenchymal-specific deletion of C/EBPβ on pulmonary fibrosis was examined. Crossing of mice with the floxed C/EBPβ gene with α2(I) collagen enhancer-CreER(T)-bearing mice successfully generated progeny with a conditional knockout (CKO) of C/EBPβ in collagen I-expressing ("mesenchymal") cells only on treatment with tamoxifen (C/EBPβ CKO). When treated with an endotracheal bleomycin injection, C/EBPβ CKO mice showed significant attenuation of pulmonary fibrosis relative to control C/EBPβ-intact mice. C/EBPβ CKO mice also had reduced myofibroblasts in the lung. However, no significant differences in inflammatory/immune cell influx were noted in the mutant mice relative to the control mice. DNA microarray and real-time PCR analyses identified a series of myofibroblast differentiation regulators as novel target genes of C/EBPβ. Interestingly, C/EBPβ deficiency caused a marked induction of matrix metalloproteinase 12 expression, suggesting its potential role as a repressor, which could account for the noted reduction in fibrosis in the C/EBPβ-deficient mice. Thus, these findings indicate an essential role for C/EBPβ in the mesenchymal compartment in pulmonary fibrosis that is independent of its effects on inflammation or immune cell infiltration.
Background: Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion. Methods: To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated in vitro and in vivo. Results: Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization via the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion via the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs. Conclusion: This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion via M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.
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