Helical sulfonyl-γ-AApeptides modulating Aß oligomerization and cytotoxicity by recognizing Aß helix.

In contrast to prevalent strategies which make use of ß-sheet mimetics to block Aß fibrillar growth, in this study, we designed a series of sulfonyl-γ-AApeptide helices that targeted the crucial α-helix domain of Aß13-26 and stabilized Aß conformation to avoid forming the neurotoxic Aß oligomeric ß-sheets. Biophysical assays such as amyloid kinetics and TEM demonstrated that the Aß oligomerization and fibrillation could be greatly prevented and even reversed in the presence of sulfonyl-γ-AApeptides in a sequence-specific and dose-dependent manner. The studies based on circular dichroism, Two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) spectra unambiguously suggested that the sulfonyl-γ-AApeptide Ab-6 could bind to the central region of Aß42 and induce α-helix conformation in Aß. Additionally, Electrospray ionisation-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) was employed to rule out a colloidal mechanism of inhibitor and clearly supported the capability of Ab-6 for inhibiting the formation of Aß aggregated forms. Furthermore, Ab-6 could rescue neuroblastoma cells by eradicating Aß-mediated cytotoxicity even in the presence of pre-formed Aß aggregates. The confocal microscopy demonstrated that Ab-6 could still specifically bind Aß42 and colocalize into mitochondria in the cellular environment, suggesting the rescue of cell viability might be due to the protection of mitochondrial function otherwise impaired by Aß42 aggregation. Taken together, our studies indicated that sulfonyl-γ-AApeptides as helical peptidomimetics could direct Aß into the off-pathway helical secondary structure, thereby preventing the formation of Aß oligomerization, fibrillation and rescuing Aß induced cell cytotoxicity.

CottonMD: a multi-omics database for cotton biological study.

Cotton is an important economic crop, and many loci for important traits have been identified, but it remains challenging and time-consuming to identify candidate or causal genes/variants and clarify their roles in phenotype formation and regulation. Here, we first collected and integrated the multi-omics datasets including 25 genomes, transcriptomes in 76 tissue samples, epigenome data of five species and metabolome data of 768 metabolites from four tissues, and genetic variation, trait and transcriptome datasets from 4180 cotton accessions. Then, a cotton multi-omics database (CottonMD, http://yanglab.hzau.edu.cn/CottonMD/) was constructed. In CottonMD, multiple statistical methods were applied to identify the associations between variations and phenotypes, and many easy-to-use analysis tools were provided to help researchers quickly acquire the related omics information and perform multi-omics data analysis. Two case studies demonstrated the power of CottonMD for identifying and analyzing the candidate genes, as well as the great potential of integrating multi-omics data for cotton genetic breeding and functional genomics research.

Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

Ammonium addition reduces phosphorus leaching in a long-term mineral or organic fertilized calcareous soil during flooding conditions.

Organic amendment substitutes mineral fertilizers has been proven to increase the organic matter content of soils, which in turn may induce phosphorus (P) mobilization by triggering the redox reaction. However, under flooded conditions according to local agricultural practices, as one of the factors restricting the decomposition of organic matter, the role ammonium plays in P transformation and leaching from soils with different organic matter remains unclear. To address the knowledge gap, the calcareous soils were collected from a long-term field trial (>13 years) containing two treatments with equal P inputs: a long-term mineral fertilization and a long-term organic amendment. Both long-term mineral fertilized soil and long-term organic amended soil were split into ammonium applications or no ammonium applications. A series of column devices were deployed to create flooded conditions and monitor the P leaching from the collected soils. The K-edge X-ray absorption near-edge structure and sequential extraction method were employed jointly to detect soil P fractions and speciation, and the P sorption/desorption characteristics of soil were evaluated by Langmuir fitting. The results showed a reduction of cumulative leached P from soils by 33.2%-43.3% after ammonium addition, regardless of previous long-term mineral fertilization or organic amendment history. A significant enhancement of soil labile P pool (indicated by the H2O-P fraction and NaHCO3-P fraction) after ammonium addition results in the reduction in soil P leaching. The reduced P sorption capacity coupled with the transformation from hydroxyapatite to ß-tricalcium phosphate indicated that the phosphate retention is attributed to the precipitation formation rather than phosphate sorption by soil. The present study highlights that the ammonium addition could affect the phosphate precipitation transformation. This may be attributed to the effect of ammonium addition on the calcium and magnesium ion content and molar ratio in this soil, thereby regulating the form of soil phosphate precipitation. The mechanisms revealed in this study can support developing optimized agricultural management practices to alleviate soil P loss.

Fed-batch fermentation strategy for efficient welan gum production by Sphingomonas sp. FM01.

BACKGROUND: As a novel type of extracellular polysaccharide produced by Sphingomonas sp., welan gum has been widely applied in various fields because of its excellent properties. The study has improved the fermentation process. RESULTS: The initial sucrose concentration, temperature and stirring speed were set to 20 g L-1, 33 °C and 400 rpm, respectively, and 13.3 g L-1 sucrose was added at 24, 40 and 56 h. The temperature and stirring speed were then set at 28 °C and 600 rpm from 24 to 48 h and 28 °C and 600 rpm from 48 to 72 h, respectively. As a result, welan gum production, dry cell weight, sucrose conversion rate and viscosity were correspondingly increased to 38.60 g L-1, 5.47 g L-1, 0.64 g g-1 and 3779 mPa·s, respectively. In addition, the mechanism by which fermentation strategy promotes welan gum synthesis was investigated by transcriptome analysis. CONCLUSION: Improving respiration and ATP supply, reducing unnecessary protein synthesis, and alleviating competition between cell growth and welan gum synthesis contribute to promoting the fermentation performance of Sphingomonas sp., thus providing a practical strategy for efficient welan gum production. © 2024 Society of Chemical Industry.

Impact of Illness Severity Tools on Adolescent Psychiatric Managed Care in California.

Youth with mental illness struggle to receive essential behavioral health care. One obstacle is denial of coverage by insurance. In California, managed care consumers may apply for independent medical review (IMR) which potentially overturns an insurance denial through the California Department of Managed Healthcare (CDMHC). The authors aim to analyze IMR appeals for psychiatric treatment among adolescents and elucidate factors associated with obtaining coverage of care. We performed an analysis to identify factors that are associated with depression and substance use disorder (SUD) treatment claim denials in 11-20-year-olds from 2001 to 2022 using CDMHC data. Logistic regression modeling was used to identify specific factors related to claim characteristics and medical society instruments that are significantly associated with overturning a denial by IMR. Behavioral health IMRs are overturned at a higher rate than non-behavioral health claims. 54.5% of those with depression and 36.3% of those with SUD initially denied care coverage were overturned by IMR. For those seeking depression treatment, we found a significantly greater odds of overturn by IMR if there was a reference of CALOCUS [1.64, 95%CI (1.06-2.5)]. The odds of a SUD treatment denial being overturned was significantly greater if referencing CALOCUS [3.85 (1.54-9.62)] or ASAM [2.47, [4.3 (1.77-10.47)]. After the standardized implementation of illness severity tools in IMRs, the odds of a medically necessary claim being overturned was 2.5 times higher than before the standards. With a high percentage of claims being overturned after IMR, the findings suggest that health plans inappropriately deny medically necessary behavioral health treatment. The use of medical society instruments was associated with higher odds of overturning a denial. The recent decision of CDMHC to implement standard use of CALOCUS and similar illness severity criteria is supported by our findings and may facilitate more equitable care.

Pathogenicity characterization of PRRSV-1 181187-2 isolated in China.

PRRSV-1 has caused more clinical infections in pigs in Chinese swine herds in recent years, however, the pathogenicity of PRRSV-1 in China is unclear. In order to study the pathogenicity of PRRSV-1, in this study, a PRRSV-1 strain, 181187-2, was isolated in primary alveolar macrophage (PAM) cells from a farm where abortions had been reported in China. The complete genome of 181187-2 was 14932 bp excluding Poly A, with 54-amino acid continuous deletion in the Nsp2 gene and 1 amino deletion in ORF3 gene compared with LV. Additionally, the piglets inoculated with strain 181187-2 by intranasal and intranasal plus intramuscular injection, animal experiments showed clinical symptoms including transient fever and depression, with no death. The obvious histopathological lesions including interstitial pneumonia and lymph node hemorrhage, and there were no significant differences in clinical symptoms and histopathological lesions with different challenge ways. Our results indicated that PRRSV -1 181187-2 was a moderately pathogenic strain in piglets.

Calling large indels in 1047 Arabidopsis with IndelEnsembler.

Large indels greatly impact the observable phenotypes in different organisms including plants and human. Hence, extracting large indels with high precision and sensitivity is important. Here, we developed IndelEnsembler to detect large indels in 1047 Arabidopsis whole-genome sequencing data. IndelEnsembler identified 34 093 deletions, 12 913 tandem duplications and 9773 insertions. Our large indel dataset was more comprehensive and accurate compared with the previous dataset of AthCNV (1). We captured nearly twice of the ground truth deletions and on average 27% more ground truth duplications compared with AthCNV, though our dataset has less number of large indels compared with AthCNV. Our large indels were positively correlated with transposon elements across the Arabidopsis genome. The non-homologous recombination events were the major formation mechanism of deletions in Arabidopsis genome. The Neighbor joining (NJ) tree constructed based on IndelEnsembler's deletions clearly divided the geographic subgroups of 1047 Arabidopsis. More importantly, our large indels represent a previously unassessed source of genetic variation. Approximately 49% of the deletions have low linkage disequilibrium (LD) with surrounding single nucleotide polymorphisms. Some of them could affect trait performance. For instance, using deletion-based genome-wide association study (DEL-GWAS), the accessions containing a 182-bp deletion in AT1G11520 had delayed flowering time and all accessions in north Sweden had the 182-bp deletion. We also found the accessions with 65-bp deletion in the first exon of AT4G00650 (FRI) flowered earlier than those without it. These two deletions cannot be detected in AthCNV and, interestingly, they do not co-occur in any Arabidopsis thaliana accession. By SNP-GWAS, surrounding SNPs of these two deletions do not correlate with flowering time. This example demonstrated that existing large indel datasets miss phenotypic variations and our large indel dataset filled in the gap.

27-gauge microincision vitrectomy surgery compared with 25-gauge microincision vitrectomy surgery on wound closure and need for wound suture and other postoperative parameters in the treatment of vitreoretinal disease: A meta-analysis.

We performed a meta-analysis to evaluate the effect of 27-gauge microincision vitrectomy surgery compared with 25-gauge microincision vitrectomy surgery on wound closure and the need for wound suture and other postoperative parameters in the treatment of vitreoretinal disease. A systematic literature search up to June 2022 was performed and 1264 subjects with the vitreoretinal disease at the baseline of the studies; 562 of them were using the 27-gauge microincision vitrectomy surgery, and 722 were using 25-gauge microincision vitrectomy surgery. Odds ratio (OR), and mean difference (MD) with 95% confidence intervals (CIs) were calculated to assess the effect of 27-gauge microincision vitrectomy surgery compared with 25-gauge microincision vitrectomy surgery on wound closure and the need for wound suture and other postoperative parameters in the treatment of vitreoretinal disease using the dichotomous, and contentious methods with a random or fixed-effect model. The 27-gauge microincision vitrectomy surgery subjects had a significantly lower intraoperative and postoperative wound complication (OR, 6.66; 95% CI, 0.46-0.95, P = .02), and wound suture number (OR, 0.38; 95% CI, 0.20-0.71, P = .002), and best corrected visual acuity (MD, -0.03; 95% CI, -0.05 to -0.001, P = .02) compared with 25-gauge microincision vitrectomy surgery in subjects with vitreoretinal disease. However, 27-gauge microincision vitrectomy surgery subjects had no significant difference in the wound closure time (MD, -8.45; 95% CI, -23.44 to 6.55, P = .27), operation time (MD, 0.85; 95% CI, -1.17 to 2.86, P = .41), intraocular pressure at postoperative day 1 (MD, 0.42; 95% CI, -1.45-2.28, P = .66), primary anatomical success rate (OR, 0.83; 95% CI, 0.42-1.63, P = .58), and central macular thickness (MD, 1.81; 95% CI, -21.76 to 25.37, P = .88) compared to 25-gauge microincision vitrectomy surgery in subjects with vitreoretinal disease. The 27-gauge microincision vitrectomy surgery subjects had a significantly lower intraoperative and postoperative wound complication, wound suture number, and best corrected visual acuity, and no significant difference in the wound closure time, operation time, intraocular pressure at postoperative day 1, primary anatomical success rate, and central macular thickness compared to 25-gauge microincision vitrectomy surgery in subjects with vitreoretinal disease. The analysis of outcomes should be with caution because of the low sample size of 12 out of 15 studies in the meta-analysis and a low number of studies in certain comparisons.

Modulating Angiogenesis by Proteomimetics of Vascular Endothelial Growth Factor.

Angiogenesis, formation of new blood vessels from the existing vascular network, is a hallmark of cancer cells that leads to tumor vascular proliferation and metastasis. This process is mediated through the binding interaction of VEGF-A with VEGF receptors. However, the balance between pro-angiogenic and anti-angiogenic effect after ligand binding yet remains elusive and is therefore challenging to manipulate. To interrogate this interaction, herein we designed a few sulfono-γ-AA peptide based helical peptidomimetics that could effectively mimic a key binding interface on VEGF (helix-α1) for VEGFR recognition. Intriguingly, although both sulfono-γ-AA peptide sequences V2 and V3 bound to VEGF receptors tightly, in vitro angiogenesis assays demonstrated that V3 potently inhibited angiogenesis, whereas V2 activated angiogenesis effectively instead. Our findings suggested that this distinct modulation of angiogenesis might be due to the result of selective binding of V2 to VEGFR-1 and V3 to VEGFR-2, respectively. These molecules thus provide us a key to switch the angiogenic signaling, a biological process that balances the effects of pro-angiogenic and anti-angiogenic factors, where imbalances lead to several diseases including cancer. In addition, both V2 and V3 exhibited remarkable stability toward proteolytic hydrolysis, suggesting that V2 and V3 are promising therapeutic agents for the intervention of disease conditions arising due to angiogenic imbalances and could also be used as novel molecular switching probes to interrogate the mechanism of VEGFR signaling. The findings also further demonstrated the potential of sulfono-γ-AA peptides to mimic the α-helical domain for protein recognition and modulation of protein-protein interactions.

Protective effect of α7 nicotinic acetylcholine receptor activation on experimental colitis and its mechanism.

BACKGROUND: Inflammatory bowel disease (IBD) is a common chronic remitting disease with no satisfactory treatment. The aim of this study was to investigate the protective effect of α7 nicotinic acetylcholine receptor (α7nAChR), and to determine the underlying mechanism of its activity. METHODS: The expression and distribution of α7nAChR in the intestinal tissue of patients with ulcerative colitis and Crohn's disease were analyzed. The effects of vagal excitation on murine experimental colitis were investigated. The colitis model was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). The therapeutic group received treatment with the α7nAChR agonist PNU-282987 by intraperitoneal injection. RESULTS: Our results showed that there was significantly increased expression of α7nAChR in colitis and Crohn's disease intestinal tissue, and its expression was mainly located in macrophages and neutrophils, which were extensively infiltrated in the disease status. Treatment with an α7nAChR agonist potently ameliorated the DSS-induced illness state, including weight loss, stool consistency, bleeding, colon shortening, and colon histological injury. α7nAChR agonist exerted anti-inflammatory effects in DSS colitis mice by suppressing the secretion of multiple types of proinflammatory factors, such as IL6, TNFα, and IL1ß, and it also inhibited the colonic infiltration of inflammatory cells by blocking the DSS-induced overactivation of the NF-κB and MAPK signaling pathways. Mechanistically, activation of α7nAChR decreased the number of infiltrated M1 macrophages in the colitis intestine and inhibited the phagocytosis ability of macrophages, which were activated in response to LPS stimulation. CONCLUSION: Thus, an α7nAChR agonist ameliorated colonic pathology and inflammation in DSS-induced colitis mice by blocking the activation of inflammatory M1 macrophages.

Abnormal expression profile of plasma-derived exosomal microRNAs in patients with treatment-resistant depression.

Whether microRNAs (miRNAs) from plasma exosomes might be dysregulated in patients with depression, especially treatment-resistant depression (TRD), remains unclear, based on study of which novel biomarkers and therapeutic targets could be discovered. To this end, a small sample study was performed by isolation of plasma exosomes from patients with TRD diagnosed by Hamilton scale. In this study, 4 peripheral plasma samples from patients with TRD and 4 healthy controls were collected for extraction of plasma exosomes. Exosomal miRNAs were analyzed by miRNA sequencing, followed by image collection, expression difference analysis, target gene GO enrichment analysis, and KEGG pathway enrichment analysis. Compared with the healthy controls, 2 miRNAs in the plasma exosomes of patients with TRD showed significant differences in expression, among which has-miR-335-5p were significantly upregulated and has-miR-1292-3p were significantly downregulated. Go and KEGG analysis showed that dysregulated miRNAs affect postsynaptic density and axonogenesis as well as the signaling pathway of axon formation and cell growths. The identification of these miRNAs and their target genes may provide novel biomarkers for improving diagnosis accuracy and treatment effectiveness of TRD.

Platinum prodrug nanoparticles inhibiting tumor recurrence and metastasis by concurrent chemoradiotherapy.

BACKGROUND: Although concurrent chemoradiotherapy (CRT), as one of the most effective antineoplastic therapies in clinic, can successfully inhibit the growth of tumor cells, a risk of developing secondary tumor is still an insurmountable barrier in clinical practice. RESULTS: Herein, a new platinum prodrug composed of tannic acid (TA) and Pt2+ (TA-Pt) complex film was synthesized on the surface of Fe2O3 nanoparticles (NPs) with excellent stability and biocompatibility for enhanced CRT. In this system, TA-Pt complex could respond to the tumor acidic microenvironment and damage the DNA of tumor cells. Moreover, the internal iron core not only improved the effect of subsequent radiotherapy (RT), but also disrupted the iron balance in cells, inducing intracellular ferroptosis and eliminating apoptosis-resistant cells. In vitro and vivo experimental results indicated that more than 90% of tumor cells were depleted and more than 75% of the cured tumor-bearing mice evinced no recurrence or metastasis. CONCLUSIONS: This work offered a new idea for combining the effective chemotherapy, RT and ferroptosis therapy to enhance the curative effect of CRT and inhibit tumor recurrence and metastasis.

A meta-analysis of arable soil phosphorus pools response to manure application as influenced by manure types, soil properties, and climate.

Manure amendments to agricultural soils is an excellent opportunity for sustainable utilization of agricultural waste while providing multiple benefits to improve soil quality and increase the availability of nutrients to plants, including phosphorus (P). In this study, a meta-analysis of published data from 411 independent observations based on 133 peer-reviewed papers was performed for an in depth understanding of various factors affecting the transformation of soil P pools with manure application. Manure application increased all soil inorganic P (Pi) by 58.0%-282% and organic P (Po) by 65.0%-105%, while decreasing Po/total P (TP), compared to those in unamended soils. Manure types, soil TP, and manure application rates were the important factors that influenced soil P fractions. Elevation of soil labile Pi was more pronounced with compost application, while poultry and pig manure were more beneficial for promoting soil Pi fractions and stable Po contents compared with other manure types. The manure application rate had pronounced effect on increasing the stable Po fractions. The effects of manure application on increasing soil P fractions were greater in soils with lower TP contents as compared to that in high TP soils. Manure effects on enhancing soil labile Pi and moderately labile Pi were greater in acidic soil than that in neutral and alkaline soils. In addition, soil P fractions showed significant correlation with latitude and mean annual precipitation (MAP). By integrating the impacts of manure types, soil properties, and climate, this meta-analysis would help to develop the management of manure application in a specific region of agriculture as well as promote the interpretation of the interfering factors on the soil P fractions changes in the manure-amended soils.

Radiation exposure in fluoroscopy-guided anterior total hip arthroplasty: a systematic review.

PURPOSE: To investigate the average fluoroscopy time, as well as the patient and surgical staff average radiation exposure in the context of intraoperative fluoroscopy use during anterior total hip arthroplasty (THA). METHODS: PubMed, Cochrane, Embase, Web of Science and Scopus were systematically searched for studies pertaining to intraoperative anterior THA fluoroscopy (PROSPERO ID 258049). The comprehensive literary search was conducted using "THA," "fluoroscopy" and "radiation exposure" as the search criteria, which resulted in 187 total papers. Of these 187 papers, 11 studies were included in this systematic review as they involved anterior THA and specifically contained data regarding radiation exposure dose and/or time. RESULTS: Eleven studies were included, enrolling 1839 patients. The average fluoroscopy time was 21.4 (95% confidence interval [CI] 16.6-26.1) seconds, whereas the average patient radiation dose was 1.8 × 10-3 (95% CI 7.4 × 10-4-2.9 × 10-3) Gy. CONCLUSIONS: Although several studies fail to report fluoroscopy time and radiation dose in THA patients, fluoroscopy-guided THA has emerged as a safe procedure. Additional studies may analyze if radiation exposure during the surgeon's THA learning curve is significantly higher, as well as what protocols may potentially reduce radiation exposure even further.

Comparative transcriptomic analysis of THP-1-derived macrophages infected with Mycobacterium tuberculosis H37Rv, H37Ra and BCG.

Tuberculosis (TB) remains a worldwide healthcare concern, and the exploration of the host-pathogen interaction is essential to develop therapeutic modalities and strategies to control Mycobacterium tuberculosis (M.tb). In this study, RNA sequencing (transcriptome sequencing) was employed to investigate the global transcriptome changes in the macrophages during the different strains of M.tb infection. THP-1 cells derived from macrophages were exposed to the virulent M.tb strain H37Rv (Rv) or the avirulent M.tb strain H37Ra (Ra), and the M.tb BCG vaccine strain was used as a control. The cDNA libraries were prepared from M.tb-infected macrophages and then sequenced. To assess the transcriptional differences between the expressed genes, the bioinformatics analysis was performed using a standard pipeline of quality control, reference mapping, differential expression analysis, protein-protein interaction (PPI) networks, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Q-PCR and Western blot assays were also performed to validate the data. Our findings indicated that, when compared to BCG or M.tb H37Ra infection, the transcriptome analysis identified 66 differentially expressed genes in the M.tb H37Rv-infected macrophages, out of which 36 genes were up-regulated, and 30 genes were down-regulated. The up-regulated genes were associated with immune response regulation, chemokine secretion, and leucocyte chemotaxis. In contrast, the down-regulated genes were associated with amino acid biosynthetic and energy metabolism, connective tissue development and extracellular matrix organization. The Q-PCR and Western blot assays confirmed increased expression of pro-inflammatory factors, altered energy metabolic processes, enhanced activation of pro-inflammatory signalling pathways and increased pyroptosis in H37Rv-infected macrophage. Overall, our RNA sequencing-based transcriptome study successfully identified a comprehensive, in-depth gene expression/regulation profile in M.tb-infected macrophages. The results demonstrated that virulent M.tb strain H37Rv infection triggers a more severe inflammatory immune response associated with increased tissue damage, which helps in understanding the host-pathogen interaction dynamics and pathogenesis features in different strains of M.tb infection.

The Sustainability of Energy Conversion Inhibition for Tumor Ferroptosis Therapy and Chemotherapy.

The hyperactive energy metabolism mostly contributes the tumor cells growth and proliferation. Herein, the intelligent nanoparticles (P-B-D NPs) obtained by loading BAY-876 and doxorubicin (Dox)-Duplex into nanoparticles composed of disulfide bond (SS) containing polymer are reported, which provide an efficient resistance of tumor cells energy metabolism and tumor growth to conquer malignant tumor. In response to the reducing microenvironment of tumor tissue, the SS bond can be disintegrated by intracellular glutathione to block the synthesis of lipid repair enzyme-glutathione peroxidase 4 for ferroptosis therapy. More importantly, the released BAY-876 can inhibit the functionality of glucose transporter 1, restricting the glucose uptake of tumor cells to a low energy metabolism status. Meanwhile, Dox-Duplex can interact with ATP to reduce intracellular ATP content and release Dox to kill tumor cells. Collectively, this work offers a new idea for restricting tumor cells energy metabolism to inhibit their proliferation.

CSN6 promotes the cell migration of breast cancer cells by positively regulating Snail1 stability.

Background: CSN6, a subunit of the highly conserved constitutive photomorphogenesis 9 (COP9) signalosome (CSN), has been reported to be implicated in tumor progression in various kinds of malignant tumors. However, the mechanism underlying CSN6 in the tumor development of breast cancer has not yet been fully elucidated. Methods: CSN6 staining in breast cancer tissues and paracancerous tissues was measured by tissue microarray (TMA) technology. The metastatic effect of CSN6 was measured by cell migration assay. Co-immunoprecipitation study was used to show the interaction between the protein CSN6 and Snail1. Ubiquitination assay was performed to validate whether ubiquitination is involved in the upregulation of Snail1 by CSN6. The impact of CSN6 on tumor metastasis in vivo was analyzed using xenotransplantation experiments in BALB/c mice. Results: Here, we demonstrated that CSN6 expression was dramatically increased in breast cancer tissues compared with paired adjacent cancerous tissues. CSN6 promoted the cell migration and wound healing abilities in breast cancer cell lines. Also we showed that CSN6 associates with Snail1 and enhances Snail1 protein level by inhibiting the ubiquitin-mediated degradation of Snail1. Thus, CSN6 is involved in positively regulating the stability of Snail1. We further proved that CSN6 protein level was positively correlated with the Snail1 expression in xenograft model. Conclusion: These findings provide new insight into applicability of using the CSN6-Snail1 axis as a potential therapeutic target in breast cancer.

Combinatorial effect of blueberry extracts and oxaliplatin in human colon cancer cells.

The use of natural compounds to potentiate the effect of drugs and lower their adverse effects is an active area of research. The objective is to determine the effect of combined blueberry extracts (BE) and oxaliplatin (OX) in colon cancer cells. The results demonstrated that treatments of BE/OX showed inhibitory effects on HCT-116 cell and nontoxic effect on CCD-18Co normal colon cells. Flow cytometry analysis indicated that treatment with the BE, OX or in combination could induce G0/G1 cell cycle arrest, apoptosis, increase of reactive oxygen species, and induce loss of mitochondrial membrane potential in HCT-116 cells. Furthermore, after treatments, the expression of inflammatory cytokines was decreased, cyclin D1 and CDK4 were decreased; caspases-3 and 9 were activated; the Akt/Bad/Bcl-2 pathway was modulated. Moreover, the combination treatment had a considerably higher growth inhibitory effect on human colon cancer HCT-116 cells than that of BE or oxaliplatin alone. Our results showed that BE increased the anticolon cancer effect of OX making it an attractive strategy as adjuvant therapy to potentially reduce the adverse side effects associated with chemotherapeutic drugs.

γ-AApeptides: Design, Structure, and Applications.

The development of sequence-specific peptidomimetics has led to a variety of fascinating discoveries in chemical biology. Many peptidomimetics can mimic primary, secondary, and even tertiary structure of peptides and proteins, and because of their unnatural backbones, they also possess significantly enhanced resistance to enzymatic hydrolysis, improved bioavailability, and chemodiversity. It is known that peptide nucleic acids (PNAs) are peptidic sequences developed for the mimicry of nucleic acids; however, their unique backbone as the molecular scaffold of peptidomimetics to mimic structure and function of bioactive peptides has not been investigated systematically. As such, we recently developed a new class of peptidomimetics, "γ-AApeptides", based on the chiral γ-PNA backbone. They are termed γ-AApeptides because they are the oligomers of γ-substituted-N-acylated-N-aminoethyl amino acids. Similar to other classes of peptidomimetics, γ-AApeptides are also resistant to proteolytic degradation and possess the potential to enhance chemodiversity. Moreover, in our scientific journey on the exploration of this class of peptidomimetics, we have discovered some intriguing structures and functions of γ-AApeptides. In this Account, we summarize the current development and application of γ-AApeptides with biological potential. Briefly, both linear and cyclic (either through head-to-tail or head-to-side-chain cyclization) γ-AApeptides with diverse functional groups can be synthesized easily on the solid phase using the synthetic protocol we developed. γ-AApeptides could mimic the primary structure of peptides, as they project the same number of side chains as peptides of the same lengths. For instance, they could mimic the Tat peptide to permeate cell membranes and bind to HIV RNA with high specificity and affinity. Certain γ-AApeptides show similar activity to the RGD peptide and target integrin specifically on the cell surface. γ-AApeptides with function akin to fMLF peptides are also identified. More importantly, we found that γ-AApeptides can fold into discrete secondary structures, such as helical and ß-turn-like structures. Therefore, they could be rationally designed for a range of biological applications. For instance, γ-AApeptides can mimic host-defense peptides and display potent and broad-spectrum activity toward a panel of drug-resistant bacterial pathogens. Meanwhile, because of their stability against proteolysis and their chemodiversity, γ-AApeptides are also amenable for combinatorial screening. We demonstrate that, through combinatorial selection, certain γ-AApeptides are identified to inhibit Aß40 peptide aggregation, suggesting their potential use as a molecular probe to intervene in Alzheimer's disease. In addition, a few γ-AApeptides identified from the γ-AApeptide library have been shown to bind to the DNA-binding domain of STAT3 and antagonize STAT3/DNA interactions. Our studies suggest that, with further studies and exploration on both structures and functions, γ-AApeptides may emerge to be a new class of peptidomimetics that play an important role in chemical biology and biomedical sciences.