-
International Journal of Biological... Jun 2024The development of novel therapeutic approaches to facilitate endometrial repair and regeneration while preventing adhesion recurrence is a crucial research objective...
The development of novel therapeutic approaches to facilitate endometrial repair and regeneration while preventing adhesion recurrence is a crucial research objective aimed at enhancing clinical outcomes for women with intrauterine adhesions (IUA). In this study, we introduced an injectable Alg-GMA/PTSB zwitterionic hydrogel, characterized by excellent biocompatibility, anti-protein adsorption properties, and biodegradability. In a rat model, the hydrogel significantly promoted the regeneration and angiogenesis of damaged endometrial tissue, leading to improved recovery of epithelial cells, glands, proliferation, and vascularization. Furthermore, it exhibited the ability to suppress cellular apoptosis and collagen deposition, thereby mitigating fibrosis. Additionally, the hydrogel restored the expression of estrogen/progesterone receptors and endometrial receptivity markers, contributing to enhanced embryo implantation and fertility. These findings underscore the potential of the hydrogel as a promising therapeutic strategy for addressing endometrial injury, reducing fibrosis, restoring fertility, and ultimately improving outcomes for women with IUA.
PubMed: 38945326
DOI: 10.1016/j.ijbiomac.2024.133458 -
International Journal of Biological... Jun 2024Cancer poses a significant threat to human health, and monotherapy frequently fails to achieve optimal therapeutic outcomes. Based on this premise, porphyran (PHP), a...
Cancer poses a significant threat to human health, and monotherapy frequently fails to achieve optimal therapeutic outcomes. Based on this premise, porphyran (PHP), a marine polysaccharide with immunomodulatory function, was used as a framework to coat gold nanorods and construct a novel nanomedicine (PHP-MPBA-GNRs) combining photothermal therapy and immunotherapy. In this design, PHP not only maintained the dispersion stability and photothermal stability of gold nanorods but also could be released under weakly acidic conditions to activate anti-tumor immunity. In vivo studies have shown that PHP-MPBA-GNRs can effectively inhibit tumor cell proliferation and reduce metastasis under near-infrared (NIR) light irradiation. Preliminary mechanistic investigation revealed that PHP-MPBA-GNRs could increase reactive oxygen species (ROS) and induce apoptosis in cancer cells. The PHP in PHP-MPBA-GNRs can also activate dendritic cells and up-regulate the expression of co-stimulatory molecules and antigen-presenting complexes. All biological experiments, including in vivo tests, demonstrated that PHP-MPBA-GNRs achieved a combination of photothermal therapy and immunotherapy for tumors.
PubMed: 38945321
DOI: 10.1016/j.ijbiomac.2024.133460 -
Gene Jun 2024Breast cancer (BCa) is a prevalent form of cancer in women, exhibiting varying rates and distribution across different ethnic groups. Among these groups, African...
Breast cancer (BCa) is a prevalent form of cancer in women, exhibiting varying rates and distribution across different ethnic groups. Among these groups, African American (AA) women have the highest incidence of BCa and the lowest levels of Vitamin D (VD). Numerous studies have explored the connection between variations in the VDR gene and BCa risk, particularly in different populations, but research on the AA population remains limited. Epigenetic modifications, including specific microRNAs (miRNAs), can influence gene expression without altering the genetic code and have been implicated in cancer initiation and progression. Our hypothesis suggests that VDR gene variations may increase BCa risk in AA women and that changes in miRNA expression profiles could contribute to BCa development. Using data from the 1000 Genome Project, we identified five VDR gene variants with significant frequency differences between AA and European-American (EA) populations. We genotyped 404 African American BCa cases and controls for five variants using TaqMan® assays. SNPstats assessed their association with BCa risk. The rs1544410 variant's recessive model (A/A) showed a decreased BCa risk in AA (odds ratio 0.33, 95% CI: 0.15-0.73, p-value 0.0041). Conversely, the rs2853563 variant's recessive model (A/A) was linked to an increased BCa risk (odds ratio 4.04, 95% CI: 1.49-10.95, p-value 0.0022). We investigated miRNA expression influenced by VD in HCC1806 Triple-Negative Breast Cancer (TNBC) cell lines with the A/A allele for rs2853563. nCounter® Nanostring technology assessed miRNA profiles after calcitriol treatment. Our results indicated that calcitriol treatment led to reduced expression of six miRNAs, four of which are associated with tumor suppression in the presence of the AA genotype in TNBC cell lines. These findings suggest that specific VDR genotypes could have a potential effect on the miRNAs expression which could potentially serve as markers for cell proliferation in TNBC.
PubMed: 38945313
DOI: 10.1016/j.gene.2024.148695 -
Biochemical Pharmacology Jun 2024The peptide hormone relaxin plays a critical role in tissue remodeling in a variety of tissues through activation of its cognate receptor, RXFP1. Relaxin's ability to...
The peptide hormone relaxin plays a critical role in tissue remodeling in a variety of tissues through activation of its cognate receptor, RXFP1. Relaxin's ability to modify extracellular matrices has provided a strong rationale for treating fibrosis in a variety of tissues. Treatment with recombinant relaxin peptides in clinical studies of heart failure has not yet proven useful, likely due to the short half-life of infused peptide. To circumvent this particular pharmacokinetic pitfall we have used a Protein-in-Protein (PiP) antibody technology described previously, to insert a single-chain human relaxin construct into the complementarity-determining region (CDR) of an immunoglobulin G (IgG) backbone, creating a relaxin molecule with a half-life of ∼4-5 days in mice. Relaxin-PiP biologics displaced Europium-labeled human relaxin in RXFP1-expressing cells and demonstrated full agonist activity on both human and mouse RXFP1 receptors. Relaxin-PiPs did not show signal transduction bias, as they activated cAMP in THP-1 cells, and cGMP and pERK signaling in primary human cardiac fibroblasts. In an induced carbon tetrachloride mouse model of liver fibrosis one relaxin-PiP, R2-PiP, caused reduction of liver lesions, ameliorated collagen accumulation in the liver with the corresponding reduction of Collagen1a1 gene expression, and increased cell proliferation in hepatic parenchyma. These relaxin biologics represent a novel approach to the design of a long-acting RXFP1 agonist to probe the clinical utility of relaxin/RXFP1 signaling to treat a variety of human fibrotic diseases.
PubMed: 38945278
DOI: 10.1016/j.bcp.2024.116401 -
Biochemical Pharmacology Jun 2024GBM is the most threatening form of brain tumor. The advancement of GBM is propelled by the growth, infiltration, and movement of cancer cells. Understanding the...
GBM is the most threatening form of brain tumor. The advancement of GBM is propelled by the growth, infiltration, and movement of cancer cells. Understanding the underlying mechanisms and identifying new therapeutic agents are crucial for effective GBM treatment. Our research focused on examining the withhold influence of Enhydrin on the destructive activity of GBM cells, both in laboratory settings and within living organisms. By employing network pharmacology and bioinformatics analysis, we have determined that Jun serves as the gene of interest, and EMT as the critical signaling pathway. Mechanistically, Enhydrin inhibits the activity of the target gene Jun to increase the expression of Smad7, which is infinitively regulated by the transcription factor Jun, and as the inhibitory transcription factor, Smad7 can down-regulate TGF-β1 and the subsequent Smad2/3 signaling pathway. Consequently, this whole process greatly hinders the EMT mechanism of GBM, leading to the notable decline in cell proliferation, invasion, and migration. In summary, our research shows that Enhydrin hinders EMT by focusing on the Jun/Smad7/TGF-β1 signaling pathway, presenting a promising target for treating GBM. Moreover, Enhydrin demonstrates encouraging prospects as a new medication for GBM treatment.
PubMed: 38945276
DOI: 10.1016/j.bcp.2024.116380 -
Chemosphere Jun 2024Chlorpyrifos (CPF) is a widely used pesticide inducing adverse neurodevelopmental and reproductive effects. However, knowledge of the underlying mechanisms is limited,...
Chlorpyrifos (CPF) is a widely used pesticide inducing adverse neurodevelopmental and reproductive effects. However, knowledge of the underlying mechanisms is limited, particularly in the hypothalamus. We investigated the mode of action of CPF at human relevant concentrations (1 nM - 100 nM) in immortalized mouse hypothalamic GnRH neurons (GT1-7), an elective model for studying disruption of the hypothalamus-pituitary-gonads (HPG) axis. We firstly examined cell vitality, proliferation, and apoptosis/necrosis. At not-cytotoxic concentrations, we evaluated neuron functionality, gene expression, Transmission Electron Microscopy (TEM) and proteomics profiles, validating results by immunofluorescence and western blotting (WB). CPF decreased cell vitality with a dose-response but did not affect cell proliferation. At 100 nM, CPF inhibited gene expression and secretion of GnRH; in addition, CPF reduced the immunoreactivity of the neuronal marker Map2 in a dose-dependent manner. The gene expression of Estrogen Receptor α and β (Erα, Erβ), Androgen Receptor (Ar), aromatase and oxytocin receptor was induced by CPF with different trends. Functional analysis of differentially expressed proteins identified Autophagy, mTOR signaling and Neutrophil extracellular traps (NETs) formation as significant pathways affected at all concentrations. This finding was phenotypically supported by the TEM analysis, showing marked autophagy and damage of mitochondria, as well as by protein analysis demonstrating a dose-dependent decrease of mTOR and its direct target pULK1 (Ser 757). The bioinformatics network analysis identified a core module of interacting proteins, including Erα, Ar, mTOR and Sirt1, whose down-regulation was confirmed by WB analysis. Overall, our results demonstrate that CPF is an inhibitor of the mTOR pathway leading to autophagy in GnRH neurons; a possible involvement of the Erα/Ar signaling is also suggested. The evidence for adverse effects of CPF in the hypothalamus in the nanomolar range, as occurs in human exposure, increases concern on potential adverse outcomes induced by this pesticide on the HPG axis.
PubMed: 38945228
DOI: 10.1016/j.chemosphere.2024.142723 -
Cancer Letters Jun 2024Recent therapeutic strategies for the treatment of triple-negative breast cancer (TNBC) have shifted the focus from vascular growth factors to endothelial cell...
Electroacupuncture Facilitates Vascular Normalization by Inhibiting Glyoxalase1 in Endothelial Cells to Attenuate Glycolysis and Angiogenesis in Triple-Negative Breast Cancer.
Recent therapeutic strategies for the treatment of triple-negative breast cancer (TNBC) have shifted the focus from vascular growth factors to endothelial cell metabolism. This study highlights the underexplored therapeutic potential of peri-tumoral electroacupuncture, a globally accepted non-pharmacological intervention for TNBC, and molecular mechanisms. Our study showed that peri-tumoral electroacupuncture effectively reduced the density of microvasculature and enhanced vascular functionality in 4T1 breast cancer xenografts, with optimal effects on day 3 post-acupuncture. The timely integration of peri-tumoral electroacupuncture amplified the anti-tumor efficacy of paclitaxel. Multi-omics analysis revealed Glyoxalase 1 (Glo1) and the associated methylglyoxal-glycolytic pathway as key mediators of electroacupuncture-induced vascular normalization. Peri-tumoral electroacupuncture notably reduced Glo1 expression in the endothelial cells of 4T1 xenografts. Using an in vivo matrigel plug angiogenesis assay, we demonstrated that either Glo1 knockdown or electroacupuncture inhibited angiogenesis. In contrast, Glo1 overexpression increased blood vessel formation. In vitro pharmacological inhibition and genetic knockdown of Glo1 in human umbilical vein endothelial cells inhibited proliferation and promoted apoptosis via downregulating the methylglyoxal-glycolytic pathway. The study using the Glo1-silenced zebrafish model further supported the role of Glo1 in vascular development. This study underscores the pivotal role of Glo1 in peri-tumoral electroacupuncture, spotlighting a promising avenue for enhancing vascular normalization and improving TNBC treatment outcomes.
PubMed: 38945204
DOI: 10.1016/j.canlet.2024.217094 -
Cancer Letters Jun 2024The causal link between long terminal repeat (LTR) retrotransposon-derived lncRNAs and hepatocellular carcinoma (HCC) remains elusive and whether these cancer-exclusive...
The causal link between long terminal repeat (LTR) retrotransposon-derived lncRNAs and hepatocellular carcinoma (HCC) remains elusive and whether these cancer-exclusive lncRNAs contribute to the effectiveness of current HCC therapies is yet to explore. Here, we investigated the activation of LTR retrotransposon-derived lncRNAs in a broad range of liver diseases. We found that LTR retrotransposon-derived lncRNAs are mainly activated in HCC and is correlated with the proliferation status of HCC. Furthermore, we discovered that an LTR retrotransposon-derived lncRNA, LINC01446, exhibits specific expression in HCC. HCC patients with higher LINC01446 expression had shorter overall survival times. In vitro and in vivo assays showed that LINC01446 promoted HCC growth and angiogenesis. Mechanistically, LINC01446 bound to serine/arginine protein kinase 2 (SRPK2) and activated its downstream target, serine/arginine splicing factor 1 (SRSF1). Furthermore, activation of the SRPK2-SRSF1 axis increased the splicing and expression of VEGF isoform A (VEGFA). Notably, inhibiting LINC01446 expression dramatically impaired tumor growth in vivo and resulted in better therapeutic outcomes when combined with antiangiogenic agents. In addition, we found that the transcription factor MESI2 bound to the cryptic MLT2B3 LTR promoter and drove LINC01446 transcription in HCC cells. Taken together, our findings demonstrate that LTR retrotransposon-derived LINC01446 promotes the progression of HCC by activating the SRPK2/SRSF1/VEGFA axis and highlight targeting LINC01446 as a potential therapeutic strategy for HCC patients.
PubMed: 38945203
DOI: 10.1016/j.canlet.2024.217088 -
Toxicology Jun 2024Ochratoxin A (OTA) is a rat renal carcinogen that induces karyomegaly and micronuclei in proximal tubular epithelial cells (PTECs). We previously performed comprehensive...
Involvement of multiple epigenetic mechanisms by altered DNA methylation from the early stage of renal carcinogenesis before proliferative lesion formation upon repeated administration of ochratoxin A.
Ochratoxin A (OTA) is a rat renal carcinogen that induces karyomegaly and micronuclei in proximal tubular epithelial cells (PTECs). We previously performed comprehensive gene profiling of alterations in promoter-region methylation and gene expression in PTECs of rats treated with OTA for 13 weeks. The OTA-specific gene profile was obtained by excluding genes showing expression changes similar to those upon treatment with 3-chloro-1,2-propanediol, a renal carcinogen not inducing karyomegaly. In this study, we validated the candidate genes using methylated DNA enrichment PCR and real-time RT-PCR, and identified Gen1, Anxa3, Cdkn1a, and Osm as genes showing OTA-specific epigenetic changes. These genes and related molecules were subjected to gene expression and immunohistochemical analyses in the PTECs of rats treated with OTA, other renal carcinogens, or non-carcinogenic renal toxicants for 4 or 13 weeks. Cdkn1a upregulation and increase of p21 karyomegalic PTECs were observed with OTA, matching the findings associated with micronucleus-inducing carcinogens. This suggested that the increase of p21 karyomegalic PTECs is linked to micronucleus formation, which in turn accelerates chromosomal instability. The upregulation of Cdkn1a-related genes with OTA suggests the acquisition of a senescence-associated secretory phenotype, which promotes the establishment of a carcinogenic environment. Meanwhile, OTA specifically caused a decrease of GEN1 PTECs reflecting Gen1 downregulation and an increase of ANXA3 PTECs reflecting Anxa3 upregulation, as well as Osm upregulation. OTA may efficiently disrupt pathways for repairing the DNA double-strand breaks that it itself causes, via Gen1 downregulation, and enhance cell proliferation through the upregulation of Anxa3 and Osm. This may exacerbate the chromosomal instability from the early stage of OTA-induced renal carcinogenesis before proliferative lesions form. OTA may cause renal carcinogenesis involving multiple epigenetic mechanisms.
PubMed: 38945198
DOI: 10.1016/j.tox.2024.153875 -
International Journal of Antimicrobial... Jun 2024The proliferation of metallo-beta-lactamase-producing Pseudomonas aeruginosa represents a significant public health threat. P. aeruginosa can undergo significant...
OBJECTIVES
The proliferation of metallo-beta-lactamase-producing Pseudomonas aeruginosa represents a significant public health threat. P. aeruginosa can undergo significant phenotypic changes that can drastically impair antibiotic efficacy. This study's objectives were (1) to quantify the time-course of killing of VIM-2-producing P. aeruginosa in response to aztreonam-based therapies (including avibactam for coverage of AmpC), and (2) to document the capacity of P. aeruginosa to undergo morphological transformations that facilitate persistence.
METHODS
A well-characterized, clinical VIM-2-producing P. aeruginosa was studied in the Hollow Fiber Infection Model (HFIM) over 9 days (7 days of active antibiotic therapy, 2 days treatment withdrawal) at a 10 CFU/mL starting inoculum. HFIM treatment arms included: growth control, aztreonam, ceftazidime/avibactam, aztreonam/ceftazidime/avibactam, polymyxin B, and aztreonam/ceftazidime/avibactam/polymyxin B. In addition, real-time imaging studies were conducted under static conditions to determine the time-course of the reversion of persister cells.
RESULTS
A pronounced discrepancy was observed between OD and bacterial counts obtained from plating methods (hereafter referred to as 'OD-count discrepancy'). For aztreonam monotherapy, observed counts were 0 CFU/mL by 120 h. Despite this, there was a significant OD-count discrepancy as compared to the pre-treatment 0h. Between therapy withdrawal at 168h and 216h, all arms with suppressed counts had re-grown to the system carrying capacity. Real-time imaging of the P. aeruginosa filaments after drug removal showed rapid reversion from a long, filamentous phenotype to many individual rods within 2 h.
CONCLUSION
Managing MBL-producing P. aeruginosa will require a multi-faceted approach, focused on maximizing killing and minimizing proliferation of resistant and persistent subpopulations, which will involve eliminating drug-induced phenotypic transformers.
PubMed: 38945177
DOI: 10.1016/j.ijantimicag.2024.107260