Diosgenin inhibits cell proliferation of primary human thyrocytes via downregulation of PI3K/Akt signaling pathway

Purpose: To determine the potential influence of diosgenin on proliferation of human thyrocytes and its possible mechanism.Methods: Primary human thyrocytes were cultured and treated with diosgenin at various time intervals. Anti-proliferative activity was determined by MTT assay. Cell proliferation was evaluated by EdU assay while cell cycle was analyzed using fluorescence-activated cell sorting (FACS) method. Protein expression of p21 (CIP1), p27 (KIP1), cyclins, protein kinase B (Akt), phosphatidylinositol 3 kinase (PI3K) and p-Akt was determined by the western blot.Results: Diosgenin inhibited proliferation of primary human thyrocytes and caused G0/G1 arrest in a concentration-dependent manner. It also downregulated cyclin D1 and phosphorylation of PI3K and Akt, but upregulated p21 and p27.Conclusion: Inhibition of proliferation of primary human thyrocytes by diosgenin occurs viadownregulation of PI3K/Akt signaling pathway. Therefore, diosgenin can be developed as a potential drug for the treatment of thyroid disease.Keywords: Diosgenin, Proliferation, Primary human thyrocytes, PI3K/Akt signaling pathwa

Machine learning-based multimodal MRI texture analysis for assessing renal function and fibrosis in diabetic nephropathy: a retrospective study

IntroductionDiabetic nephropathy (DN) has become a major public health burden in China. A more stable method is needed to reflect the different stages of renal function impairment. We aimed to determine the possible practicability of machine learning (ML)-based multimodal MRI texture analysis (mMRI-TA) for assessing renal function in DN.MethodsFor this retrospective study, 70 patients (between 1 January 2013 and 1 January 2020) were included and randomly assigned to the training cohort (n1 = 49) and the testing cohort (n2 = 21). According to the estimated glomerular filtration rate (eGFR), patients were assigned into the normal renal function (normal-RF) group, the non-severe renal function impairment (non-sRI) group, and the severe renal function impairment (sRI) group. Based on the largest coronal image of T2WI, the speeded up robust features (SURF) algorithm was used for texture feature extraction. Analysis of variance (ANOVA) and relief and recursive feature elimination (RFE) were applied to select the important features and then support vector machine (SVM), logistic regression (LR), and random forest (RF) algorithms were used for the model construction. The values of area under the curve (AUC) on receiver operating characteristic (ROC) curve analysis were used to assess their performance. The robust T2WI model was selected to construct a multimodal MRI model by combining the measured BOLD (blood oxygenation level-dependent) and diffusion-weighted imaging (DWI) values.ResultsThe mMRI-TA model achieved robust and excellent performance in classifying the sRI group, non-sRI group, and normal-RF group, with an AUC of 0.978 (95% confidence interval [CI]: 0.963, 0.993), 0.852 (95% CI: 0.798, 0.902), and 0.972 (95% CI: 0.995, 1.000), respectively, in the training cohort and 0.961 (95% CI: 0.853, 1.000), 0.809 (95% CI: 0.600, 0.980), and 0.850 (95% CI: 0.638, 0.988), respectively, in the testing cohort.DiscussionThe model built from multimodal MRI on DN outperformed other models in assessing renal function and fibrosis. Compared to the single T2WI sequence, mMRI-TA can improve the performance in assessing renal function

Infection-Associated Nuclear Degeneration in the Rice Blast Fungus Magnaporthe oryzae Requires Non-Selective Macro-Autophagy

addresses: School of Biosciences, University of Exeter, Exeter, Devon, United Kingdom.notes: PMCID: PMC3308974Freely-available open access article.The rice blast fungus Magnaporthe oryzae elaborates a specialized infection structure called an appressorium to breach the rice leaf surface and gain access to plant tissue. Appressorium development is controlled by cell cycle progression, and a single round of nuclear division occurs prior to appressorium formation. Mitosis is always followed by programmed cell death of the spore from which the appressorium develops. Nuclear degeneration in the spore is known to be essential for plant infection, but the precise mechanism by which it occurs is not known

Biophysical Property and Broad Anti-HIV Activity of Albuvirtide, a 3-Maleimimidopropionic Acid-Modified Peptide Fusion Inhibitor

Albuvirtide (ABT) is a 3-maleimimidopropionic acid (MPA)-modified peptide HIV fusion inhibitor that can irreversibly conjugate to serum albumin. Previous studies demonstrated its in vivo long half-life and potent anti-HIV activity. Here, we focused to characterize its biophysical properties and evaluate its antiviral spectrum. In contrast to T20 (Enfuvirtide, Fuzeon), ABT was able to form a stable α-helical conformation with the target sequence and block the fusion-active six-helix bundle (6-HB) formation in a dominant-negative manner. It efficiently inhibited HIV-1 Env-mediated cell membrane fusion and virus entry. A large panel of 42 HIV-1 pseudoviruses with different genotypes were constructed and used for the antiviral evaluation. The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B′, CRF07_BC and CRF01_AE recombinants that are currently circulating in China. Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20. Taken together, our data indicate that the chemically modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor

Genome Sequencing and Comparative Transcriptomics of the Model Entomopathogenic Fungi Metarhizium anisopliae and M. acridum

Metarhizium spp. are being used as environmentally friendly alternatives to chemical insecticides, as model systems for studying insect-fungus interactions, and as a resource of genes for biotechnology. We present a comparative analysis of the genome sequences of the broad-spectrum insect pathogen Metarhizium anisopliae and the acridid-specific M. acridum. Whole-genome analyses indicate that the genome structures of these two species are highly syntenic and suggest that the genus Metarhizium evolved from plant endophytes or pathogens. Both M. anisopliae and M. acridum have a strikingly larger proportion of genes encoding secreted proteins than other fungi, while ∼30% of these have no functionally characterized homologs, suggesting hitherto unsuspected interactions between fungal pathogens and insects. The analysis of transposase genes provided evidence of repeat-induced point mutations occurring in M. acridum but not in M. anisopliae. With the help of pathogen-host interaction gene database, ∼16% of Metarhizium genes were identified that are similar to experimentally verified genes involved in pathogenicity in other fungi, particularly plant pathogens. However, relative to M. acridum, M. anisopliae has evolved with many expanded gene families of proteases, chitinases, cytochrome P450s, polyketide synthases, and nonribosomal peptide synthetases for cuticle-degradation, detoxification, and toxin biosynthesis that may facilitate its ability to adapt to heterogenous environments. Transcriptional analysis of both fungi during early infection processes provided further insights into the genes and pathways involved in infectivity and specificity. Of particular note, M. acridum transcribed distinct G-protein coupled receptors on cuticles from locusts (the natural hosts) and cockroaches, whereas M. anisopliae transcribed the same receptor on both hosts. This study will facilitate the identification of virulence genes and the development of improved biocontrol strains with customized properties

The influence of Zusanli and nonmeridian acupuncture points on the survival rate and intestinal tissue features after fatal hemorrhagic shock in rats,” Evidence-Based Complementary and Alternative Medicine, vol

Sixty Sprague-Dawley rats were divided into 5 groups: (a) control group (HS); (b) Immediate rehydration group (IFR); (c) ST36 electroacupuncture (EA) delay rehydration group (EA/DFR): EA at ST36 immediately after blood loss with infusion 3 h later; (d) EA nonmeridian rehydration group (SEA/DFR): EA at nonacupuncture sites with rehydration similar to EA/DFR; (e) ST36 EA group (EA): EA at ST36 immediately after blood loss with no rehydration. Forty-five percent of the entire blood volume was taken out to make lethal hemorrhagic shock models. We recorded the survival rate, intestinal tissue DAO content, and microcirculation. The survival rate of the EA/DFR group and the IFR group was significantly higher than that of the other three groups ( ). Twelve hours after blood loss, intestinal tissue DAO content of the EA/DFR group and the IFR group was significantly higher than that of the SEA/DFR group, EA group, and HS group ( and ). The mucosal blood flow of the EA/DFR group and the IFR group was significantly higher than the other groups ( each). We conclude that EA improves the blood pressure and raises the early survival rate of hemorrhagic shock rats, maintains the intestinal barrier function, and improves the degree of intestinal ischemia

N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion

A recently approved peptidic human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, T-20 (Fuzeon; Trimeris Inc.), has shown significant promise in clinical application for treating HIV-1-infected individuals who have failed to respond to the currently available antiretroviral drugs. However, T-20 must be injected twice daily and is too expensive. Therefore, it is essential to develop orally available small molecule HIV-1 fusion inhibitors. By screening a chemical library consisting of “drug-like” compounds, we identified two N-substituted pyrroles, designated NB-2 and NB-64, that inhibited HIV-1 replication at a low micromolar range. The absence of the COOH group in NB-2 and NB-64 resulted in a loss of anti-HIV-1 activity, suggesting that this acid group plays an important role in mediating the antiviral activity. NB-2 and NB-64 inhibited HIV-1 fusion and entry by interfering with the gp41 six-helix bundle formation and disrupting the α-helical conformation. They blocked a d-peptide binding to the hydrophobic pocket on surface of the gp41 internal trimeric coiled-coil domain. Computer-aided molecular docking analysis has shown that they fit inside the hydrophobic pocket and that their COOH group interacts with a positively charged residue (K574) around the pocket to form a salt bridge. These results suggest that NB-2 and NB-64 may bind to the gp41 hydrophobic pocket through hydrophobic and ionic interactions and block the formation of the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry. Therefore, NB-2 and NB-64 can be used as lead compounds toward designing and developing more potent small molecule HIV-1 fusion inhibitors targeting gp41