EGF-driven EGFR/miR-27b-3p/FOXO1 promotes rat FSH synthesis and secretion.

The adenopituitary secretes follicle-stimulating hormone (FSH), which plays a crucial role in regulating the growth, development, and reproductive functions of organisms. Investigating the process of FSH synthesis and secretion can offer valuable insights into potential areas of focus for reproductive research. Epidermal growth factor (EGF) is a significant paracrine/autocrine factor within the body, and studies have demonstrated its ability to stimulate FSH secretion in animals. However, the precise mechanisms that regulate this action are still poorly understood. In this research, in vivo and in vitro experiments showed that the activation of epidermal growth factor receptor (EGFR) by EGF induces the upregulation of miR-27b-3p and that miR-27b-3p targets and inhibits Foxo1 mRNA expression, resulting in increased FSH synthesis and secretion. In summary, this study elucidates the precise molecular mechanism through which EGF governs the synthesis and secretion of FSH via the EGFR/miR-27b-3p/FOXO1 pathway.

GnRH-driven FTO-mediated RNA m6A modification promotes gonadotropin synthesis and secretion.

BACKGROUND: Gonadotropin precisely controls mammalian reproductive activities. Systematic analysis of the mechanisms by which epigenetic modifications regulate the synthesis and secretion of gonadotropin can be useful for more precise regulation of the animal reproductive process. Previous studies have identified many differential m6A modifications in the GnRH-treated adenohypophysis. However, the molecular mechanism by which m6A modification regulates gonadotropin synthesis and secretion remains unclear. RESULTS: Herein, it was found that GnRH can promote gonadotropin synthesis and secretion by promoting the expression of FTO. Highly expressed FTO binds to Foxp2 mRNA in the nucleus, exerting a demethylation function and reducing m6A modification. After Foxp2 mRNA exits the nucleus, the lack of m6A modification prevents YTHDF3 from binding to it, resulting in increased stability and upregulation of Foxp2 mRNA expression, which activates the cAMP/PKA signaling pathway to promote gonadotropin synthesis and secretion. CONCLUSIONS: Overall, the study reveals the molecular mechanism of GnRH regulating the gonadotropin synthesis and secretion through FTO-mediated m6A modification. The results of this study allow systematic interpretation of the regulatory mechanism of gonadotropin synthesis and secretion in the pituitary at the epigenetic level and provide a theoretical basis for the application of reproductive hormones in the regulation of animal artificial reproduction.

Quantifying Structural Polarization by Continuous Regulation of Lone-Pair Electron Expression in Molecular Crystals.

Rational design of structural polarization is vital for modern technologies, as it allows the physical properties of functional materials to be tailored. An effective approach for governing polarization involves the utilization of stereochemical lone-pair electrons (LPEs). However, despite the recognized significance of LPEs in controlling structural polarization, there remains a lack of understanding regarding the quantitative relationship between their expression and the extent of structural polarization. Here, by using pressure to continuously tune the LPE expression, we achieve the precise control and quantification of structural polarization, which brings enhanced second harmonic generation (SHG) of the molecular crystal SbI3·3S8. We introduce the I-Sb-I angle (α̅) that describes the degree of LPE expression and establishes a quantitative relationship between α̅ and structural polarization. That is, decreasing α̅ shapes LPE expression from delocalization to localization, which repels the bonding pairs of electrons and thus enhances the structural polarization. In addition, we extend this quantified relationship to a series of molecular crystals and demonstrate its applicability to the design of structural polarization by tailoring LPE expression.

Breaking Down Barriers in Drug Delivery by Stromal Remodeling Approaches in Pancreatic Cancer.

Pancreatic cancer remains a formidable challenge in oncology due to its aggressive nature and limited treatment options. The dense stroma surrounding pancreatic tumors not only provides structural support but also presents a formidable barrier to effective therapy, hindering drug penetration and immune cell infiltration. This review delves into the intricate interplay between stromal components and cancer cells, highlighting their impact on treatment resistance and prognosis. Strategies for stromal remodeling, including modulation of cancer-associated fibroblasts (CAFs), pancreatic stellate cells (PSCs) activation states, and targeting extracellular matrix (ECM) components, are examined for their potential to enhance drug penetration and improve therapeutic efficacy. Integration of stromal remodeling with conventional therapies, such as chemotherapy and immunotherapy, is discussed along with the emerging field of intelligent nanosystems for targeted drug delivery. This comprehensive overview underscores the importance of stromal remodeling in pancreatic cancer treatment and offers insights into promising avenues for future research and clinical translation.

Repolarizing neutrophils via MnO2 nanoparticle-activated STING pathway enhances Salmonella-mediated tumor immunotherapy.

Engineered Salmonella has emerged as a promising microbial immunotherapy against tumors; however, its clinical effectiveness has encountered limitations. In our investigation, we unveil a non-dose-dependent type of behavior regarding Salmonella's therapeutic impact and reveal the regulatory role of neutrophils in diminishing the efficacy of this. While Salmonella colonization within tumors recruits a substantial neutrophil population, these neutrophils predominantly polarize into the pro-tumor N2 phenotype, elevating PD-L1 expression and fostering an immunosuppressive milieu within the tumor microenvironment. In order to bypass this challenge, we introduce MnO2 nanoparticles engineered to activate the STING pathway. Harnessing the STING pathway to stimulate IFN-ß secretion prompts a shift in neutrophil polarization from the N2 to the N1 phenotype. This strategic repolarization remodels the tumor immune microenvironment, making the infiltration and activation of CD8+ T cells possible. Through these orchestrated mechanisms, the combined employment of Salmonella and MnO2 attains the synergistic enhancement of anti-tumor efficacy, achieving the complete inhibition of tumor growth within 20 days and an impressive 80% survival rate within 40 days, with no discernible signs of significant adverse effects. Our study not only unveils the crucial in vivo constraints obstructing microbial immune therapy but also sets out an innovative strategy to augment its efficacy. These findings pave the way for advancements in cell-based immunotherapy centered on leveraging the potential of neutrophils.

CDMS Analysis of Intact 19S, 20S, 26S, and 30S Proteasomes: Evidence for Higher-Order 20S Assemblies at a Low pH†.

Charge detection mass spectrometry (CDMS) was examined as a means of studying proteasomes. To this end, the following masses of the 20S, 19S, 26S, and 30S proteasomes from Saccharomyces cerevisiae (budding yeast) were measured: m(20S) = 738.8 ± 2.9 kDa, m(19S) = 926.2 ± 4.8 kDa, m(26S) = 1,637.0 ± 7.6 kDa, and m(30S) = 2,534.2 ± 10.8 kDa. Under some conditions, larger (20S)x (where x = 1 to ∼13) assemblies are observed; the 19S regulatory particle also oligomerizes, but to a lesser extent, forming (19S)x complexes (where x = 1 to 4, favoring the x = 3 trimer). The (20S)x oligomers are favored in vitro, as the pH of the solution is lowered (from 7.0 to 5.4, in a 20 mM ammonium acetate solution) and may be related to in vivo proteasome storage granules that are observed under carbon starvation. From measurements of m(20S)x (x = 1 to ∼13) species, it appears that each multimer retains all 28 proteins of the 20S complex subunit. Several types of structures that might explain the formation of (20S)x assemblies are considered. We stress that each structural type [hypothetical planar, raft-like geometries (where individual proteasomes associate through side-by-side interactions); elongated, rodlike geometries (where subunits are bound end-to-end); and geometries that are roughly spherical (arising from aggregation through nonspecific subunit interactions)] is highly speculative but still interesting to consider, and a short discussion is provided. The utility of CDMS for characterizing proteasomes and related oligomers is discussed.

Integrative Proteomics and Phosphoproteomics Analysis of the Rat Adenohypophysis after GnRH Treatment.

The regulation of mammalian reproductive activity is tightly dependent on the HPG axis crosstalk, in which several reproductive hormones play important roles. Among them, the physiological functions of gonadotropins are gradually being uncovered. However, the mechanisms by which GnRH regulates FSH synthesis and secretion still need to be more extensively and deeply explored. With the gradual completion of the human genome project, proteomes have become extremely important in the fields of human disease and biological process research. To explore the changes of protein and protein phosphorylation modifications in the adenohypophysis after GnRH stimulation, proteomics and phosphoproteomics analyses of rat adenohypophysis after GnRH treatment were performed by using TMT markers, HPLC classification, LC/MS, and bioinformatics analysis in this study. A total of 6762 proteins and 15,379 phosphorylation sites contained quantitative information. Twenty-eight upregulated proteins and fifty-three downregulated proteins were obtained in the rat adenohypophysis after GnRH treatment. The 323 upregulated phosphorylation sites and 677 downregulated phosphorylation sites found in the phosphoproteomics implied that a large number of phosphorylation modifications were regulated by GnRH and were involved in FSH synthesis and secretion. These data constitute a protein-protein phosphorylation map in the regulatory mechanism of "GnRH-FSH," which provides a basis for future studies on the complex molecular mechanisms of FSH synthesis and secretion. The results will be helpful for understanding the role of GnRH in the development and reproduction regulated by the pituitary proteome in mammals.

Salidroside Alleviates Chronic Constriction Injury-Induced Neuropathic Pain and Inhibits of TXNIP/NLRP3 Pathway.

Neuropathic pain is one of the most common conditions requiring treatment worldwide. Salidroside (SAL), a phenylpropanoid glucoside extracted from Rhodiola, has been suggested to produce an analgesic effect in chronic pain. However, whether SAL could alleviate pain hypersensitivity after peripheral nerve injury and its mode of action remains unclear. Several studies suggest that activation of the spinal NOD-like receptor protein 3 (NLRP3) inflammasome and its related proteins contribute to neuropathic pain's pathogenesis. This study investigates the time course of activation of spinal NLRP3 inflammasome axis in the development of neuropathic pain and also whether SAL could be an effective treatment for this type of pain by modulating NLRP3 inflammasome. In the chronic constriction injury (CCI) mice model, spinal NLRP3 inflammasome-related proteins and TXNIP, the mediator of NLRP3, were upregulated from the 14th to the 28th day after injury. The TXNIP and NLRP3 inflammasome-related proteins were mainly present in neurons and microglial cells in the spinal dorsal horn after CCI. Intraperitoneal injection of SAL at 200 mg/kg for 14 consecutive days starting from the 7th day of CCI injury could ameliorate mechanical and thermal hypersensitivity in the CCI model. Moreover, SAL inhibited the activation of the TXNIP/NLRP3 inflammasome axis and mitigated the neuronal loss of spinal dorsal horn induced by nerve injury. These results indicate that SAL could produce analgesic and neuroprotective effects in the CCI model of neuropathic pain.

Reversal of Right Ventricular Hypertrophy and Dysfunction by Prostacyclin in a Rat Model of Severe Pulmonary Arterial Hypertension.

Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has not been adequately tested. To further identify underlying responses to prostacyclin, a prostacyclin analogue, treprostinil, was used in a preclinical rat Sugen-chronic hypoxia (SuCH) model of severe PAH that closely resembles the human disease. Male Sprague-Dawley rats were implanted with osmotic pumps containing vehicle or treprostinil, injected concurrently with a bolus of Sugen (SU5416) and exposed to 3-week hypoxia followed by 3-week normoxia. RV function was assessed using pressure-volume loops and hypertrophy by weight assessed. To identify altered mechanisms within the RV, tissue samples were used to perform a custom RNA array analysis, histological staining, and protein and transcript level confirmatory analyses. Treprostinil significantly reduced SuCH-associated RV hypertrophy and decreased the rise in RV systolic pressure, mean pulmonary arterial (mPAP), and right atrial (RAP) pressure. Prostacyclin treatment was associated with improvements in RV stroke work, maximum rate of ventricular pressure change (max dP/dt) and the contractile index, and almost a complete reversal of SuCH-associated increase in RV end-systolic elastance, suggesting the involvement of load-independent improvements in intrinsic RV systolic contractility by prostacyclin treatment. An analysis of the RV tissues showed no changes in cardiac mitochondrial respiration and ATP generation. However, custom RNA array analysis revealed amelioration of SuCH-associated increases in newly identified TBX20 as well as the fibrotic markers collagen1α1 and collagen 3α1 upon treprostinil treatment. Taken together, our data support decreased afterload and load-independent improvements in RV function following prostacyclin administration in severe PAH, and these changes appear to associate with improvements in RV fibrotic responses.

Spatial Distribution of Multi-Fractal Scaling Behaviours of Atmospheric XCO2 Concentration Time Series during 2010-2018 over China.

Exploring the spatial distribution of the multi-fractal scaling behaviours in atmospheric CO2 concentration time series is useful for understanding the dynamic mechanisms of carbon emission and absorption. In this work, we utilise a well-established multi-fractal detrended fluctuation analysis to examine the multi-fractal scaling behaviour of a column-averaged dry-air mole fraction of carbon dioxide (XCO2) concentration time series over China, and portray the spatial distribution of the multi-fractal scaling behaviour. As XCO2 data values from the Greenhouse Gases Observing Satellite (GOSAT) are insufficient, a spatio-temporal thin plate spline interpolation method is applied. The results show that XCO2 concentration records over almost all of China exhibit a multi-fractal nature. Two types of multi-fractal sources are detected. One is long-range correlations, and the other is both long-range correlations and a broad probability density function; these are mainly distributed in southern and northern China, respectively. The atmospheric temperature and carbon emission/absorption are two possible external factors influencing the multi-fractality of the atmospheric XCO2 concentration. Highlight: (1) An XCO2 concentration interpolation is conducted using a spatio-temporal thin plate spline method. (2) The spatial distribution of the multi-fractality of XCO2 concentration over China is shown. (3) Multi-fractal sources and two external factors affecting multi-fractality are analysed.

First demonstration of a C + L band CDC-ROADM with a simple node configuration using multiband switching devices.

While ultrahigh-baud-rate optical signals are effective for extending the transmission distance of large capacity signals, they also reduce the number of wavelengths that can be arranged in a band because of their wider bandwidth. This reduces the flexibility of optical path configuration in reconfigurable optical add/drop multiplexing (ROADM) networks. Particularly in colorless, directionless and contentionless (CDC)-ROADM, the effect reduces the add/drop ratio at a node. Multiband ROADM systems are an effective countermeasure for overcoming this issue, but they make the node configuration more complicated and its operation more difficult. In this paper, we analyze the challenges of C + L band CDC-ROADM and show that optical switch devices that operate over multiple bands are effective in meeting them. For this purpose, we built a C + L band CDC-ROADM node based on C + L band wavelength-selective switches and multicast switches and confirmed its effectiveness experimentally. In particular, to simplify the node configuration, we propose a reduction in the number of optical amplifiers used for node loss compensation and experimentally verify its feasibility.

Aqueous Solutions of Peptides and Trialkylamines Lead to Unexpected Peptide Modification.

When trialkylamines are added to buffered solutions of peptides, unexpected adducts can be formed. These adducts correspond to Schiff base products. The source of the reaction is the unexpected presence of aldehydes in amines. The aldehydes can be detected in a few ways. Most importantly, they can lead to unanticipated results in proteomics experiments. Their undesirable effects can be minimized through the addition of other amines.

Demonstration of digital fronthaul over self-seeded WDM-PON in commercial LTE environment.

CPRI between BBU and RRU equipment is carried by self-seeded WDM-PON prototype system within commercial LTE end-to-end environment. Delay and jitter meets CPRI requirements while services demonstrated show the same performance as bare fiber.

Experimental demonstration of iterative post-equalization algorithm for 37.5-Gbaud PM-16QAM quad-carrier Terabit superchannel.

We experimentally demonstrate a quad-carrier 1-Tb/s solution with 37.5-GBaud PM-16QAM signal over 37.5-GHz optical grid at 6.7 b/s/Hz net spectral efficiency. Digital Nyquist pulse shaping at the transmitter and post-equalization at the receiver are employed to mitigate the impairments of joint inter-symbol-interference (ISI) and inter-channel-interference (ICI) symbol degradation. The post-equalization algorithms consist of one sample/symbol based decision-directed least mean square (DD-LMS) adaptive filter, digital post filter and maximum likelihood sequence estimation (MLSE), and a positive iterative process among them. By combining these algorithms, the improvement as much as 4-dB OSNR (0.1nm) at SD-FEC limit (Q(2) = 6.25 corresponding to BER = 2.0e-2) is obtained when compared to no such post-equalization process, and transmission over 820-km EDFA-only standard single-mode fiber (SSMF) link is achieved for two 1.2-Tb/s signals with the averaged Q(2) factor larger than 6.5 dB for all sub-channels. Additionally, 50-GBaud 16QAM operating at 1.28 samples/symbol in a DAC is also investigated and successful transmission over 410-km SSMF link is achieved at 62.5-GHz optical grid.

Co-administration with cell penetrating peptide enhances the oral bioavailability of docetaxel-loaded nanoparticles.

This study proposes a novel docetaxel (DTX) cyclodextrin inclusion-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (D-CNPs) system with cell penetrating peptide (CPP), and evaluates its potential for oral administration of DTX. Heptaarginine (R7) was used as the CPP. D-CNPs were prepared by the double-emulsification method. The mean particle size and zeta potential of the resulting D-CNPs were 198.7 ± 12.56 nm and -27.25 ± 4.62 mV, respectively, and their mean encapsulation efficiency and drug loading were 80.35 ± 6.37% and 1.02 ± 0.15%, respectively. The morphology of the D-CNPs was observed by scanning electron microscope (SEM) and transmission electron microscope (TEM). The release behavior of the D-CNPs was studied by using the dialysis method. The relative bioavailability of D-CNPs and D-CNPs co-administered with R7 was enhanced about 5.57- and 9.43-fold, respectively, compared with the free DTX suspension. Furthermore, D-CNPs with R7 displayed maximum cytotoxicity against MCF-7 cells in MTT assay. D-CNPs co-administered with R7 showed markedly higher fluorescence intensity than D-CNPs without CPP. The results suggest that the D-CNPs co-administered with R7 could be a potential delivery system with excellent therapeutic efficacy for targeting the drugs to cancer cells.

Association between Toll-like receptor 3 polymorphisms and cancer risk: a meta-analysis.

Toll-like receptors (TLRs) are well known as molecular sensors of pathogen-associated molecular patterns. They control activation of the innate immune response and subsequently shape the adaptive immune response. Polymorphisms in TLR3 gene associated with cancer have been studied extensively. However, the results remain controversial. A literature search was performed among PubMed, Embase, Web of Science, Science Direct, Wanfang, and Chinese National Knowledge Infrastructure databases to identify eligible studies on the association between TLR3 polymorphisms and cancer risk. A total of 12 studies in 11 articles were included in the meta-analysis including 5,861 cases and 6,339 controls. Significant associations with cancer risk were observed for single nucleotide polymorphisms (SNPs) rs3775291 (allele model: odds ratio (OR) = 1.12, 95 % confidence interval (95 % CI) = 1.00-1.25, P = 0.04), rs3775290 (allele model: OR = 1.12, 95 % CI = 1.00-1.25, P = 0.04; dominant model: OR = 1.30, 95 % CI = 1.05-1.60, P = 0.01; homozygous comparison: OR = 1.68, 95 % CI = 1.06-2.68, P = 0.03; heterozygous comparison: OR = 1.25, 95 % CI = 1.01-1.55, P = 0.04), rs5743305 (allele model: OR = 1.07, 95 % CI = 1.01-1.15, P = 0.03; dominant model: OR = 1.11, 95 % CI = 1.01-1.22, P = 0.03), and rs5743312 (allele model: OR = 1.13, 95 % CI = 1.01-1.27, P = 0.03; recessive model: OR = 1.86, 95 % CI = 1.31-2.63, P < 0.01; homozygous comparison: OR = 1.88, 95 % CI = 1.33-2.67, P < 0.01), respectively. Meanwhile, we did not find any significant association with cancer risk for rs7657186 and rs7668666. In conclusion, this meta-analysis indicates a significant association of four TLR3 gene polymorphisms with cancer risk. However, because the study size was limited, further studies are essential to confirm our results.

Cellular and Molecular Roles of Immune Cells in the Gut-Brain Axis in Migraine.

Migraine is a complex and multi-system dysfunction. The realization of its pathophysiology and diagnosis is developing rapidly. Migraine has been linked to gastrointestinal disorders such as irritable bowel syndrome and celiac disease. There is also direct and indirect evidence for a relationship between migraine and the gut-brain axis, but the exact mechanism is not yet explained. Studies have shown that this interaction appears to be influenced by a variety of factors, such as inflammatory mediators, gut microbiota, neuropeptides, and serotonin pathways. Recent studies suggest that immune cells can be the potential tertiary structure between migraine and gut-brain axis. As the hot interdisciplinary subject, the relationship between immunology and gastrointestinal tract is now gradually clear. Inflammatory signals are involved in cellular and molecular responses that link central and peripheral systems. The gastrointestinal symptoms associated with migraine and experiments associated with antibiotics have shown that the intestinal microbiota is abnormal during the attacks. In this review, we focus on the mechanism of migraine and gut-brain axis, and summarize the tertiary structure between immune cells, neural network, and gastrointestinal tract.

An iron-containing nanomedicine for inducing deep tumor penetration and synergistic ferroptosis in enhanced pancreatic cancer therapy.

Pancreatic cancer is an aggressive and challenging malignancy with limited treatment options, largely attributed to the dense tumor stroma and intrinsic drug resistance. Here, we introduce a novel iron-containing nanoparticle formulation termed PTFE, loaded with the ferroptosis inducer Erastin, to overcome these obstacles and enhance pancreatic cancer therapy. The PTFE nanoparticles were prepared through a one-step assembly process, consisting of an Erastin-loaded PLGA core stabilized by a MOF shell formed by coordination between Fe3+ and tannic acid. PTFE demonstrated a unique capability to repolarize tumor-associated macrophages (TAMs) into the M1 phenotype, leading to the regulation of dense tumor stroma by modulating the activation of tumor-associated fibroblasts (TAFs) and reducing collagen deposition. This resulted in enhanced nanoparticle accumulation and deep penetration, as confirmed by in vitro multicellular tumor spheroids and in vivo mesenchymal-rich subcutaneous pancreatic tumor models. Moreover, PTFE effectively combated tumor resistance by synergistically employing the Fe3+-induced Fenton reaction and Erastin-induced ferroptosis, thereby disrupting the redox balance. As a result, significant tumor growth inhibition was achieved in mice-bearing tumor model. Comprehensive safety evaluations demonstrated PTFE's favorable biocompatibility, highlighting its potential as a promising therapeutic platform to effectively address the formidable challenges in pancreatic cancer treatment.

Positive association between Interleukin-8 -251A > T polymorphism and susceptibility to gastric carcinogenesis: a meta-analysis.

BACKGROUNDS: The associations between the polymorphisms of interleukin-8 (IL-8) gene and gastric carcinogenesis have been extensively investigated in recent years. However, the results remain conflicting rather than conclusive. METHODS: A meta-analysis of 18 eligible studies was performed to evaluate the association of IL-8 -251A > T polymorphism with risk of gastric carcinogenesis. A systematic literature search of MEDLINE, Embase, and Web of Science, CNKI databases was conducted. Statistical analysis was performed by using the Revman 5.1 software and the Stata 12.0 software. RESULTS: Of the 293 unique studies identified using our search criteria, 18 studies fulfilled our inclusion criteria and were included in the meta-analysis. These studies cumulatively reported 5,321 cases and 6,465 controls. The combined results based on all studies showed that the IL-8 -251A > T polymorphism was associated with the risk of gastric carciongenesis (A vs. T OR: 1.14 [1.02, 1.26], P = 0.02), especially gastric cancer (A vs. T OR: 1.15 [1.03, 1.29], P = 0.02), but not associated with the risk of precancerous lesion (A vs. T OR: 1.09 [0.99, 1.20], P = 0.08). Analysis stratified by ethnicity may seem that IL-8 -251A > T polymorphism was susceptible to gastric cancer in Asian population, but not in Caucasian population. CONCLUSIONS: Our meta-analysis results provide evidence that IL-8 -251A > T polymorphism is significantly associated with increased risk of gastric carcinogenesis in Asian population, particularly in gastric cancer. Further large and well-designed studies are required to confirm this conclusion.