Crosstalk and plasticity driving between cancer-associated fibroblasts and tumor microenvironment: significance of breast cancer metastasis.

Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell population in breast tumors. A functionally diverse population of CAFs increases the dynamic complexity of the tumor microenvironment (TME). The intertwined network of the TME facilitates the interaction between activated CAFs and breast cancer cells, which can lead to the proliferation and invasion of breast cells. Considering the special transmission function of CAFs, the aim of this review is to summarize and highlight the crosstalk between CAFs and breast cancer cells in the TME as well as the relationship between CAFs and extracellular matrix (ECM), soluble cytokines, and other stromal cells in the metastatic state. The crosstalk between cancer-associated fibroblasts and tumor microenvironment also provides a plastic therapeutic target for breast cancer metastasis. In the course of the study, the inhibitory effects of different natural compounds on targeting CAFs and the advantages of different drug combinations were summarized. CAFs are also widely used in the diagnosis and treatment of breast cancer. The cumulative research on this phenomenon supports the establishment of a targeted immune microenvironment as a possible breakthrough in the prevention of invasive metastasis of breast cancer.

Research progress of natural products for the treatment of ischemic stroke.

Stroke is a leading cause of death and disability world-widely. The incidence rate of stroke has been increasing due to the aging population and lifestyle changes. At present, the only drug approved by the US Food and Drug Administration (FDA) for the treatment of ischemic stroke is tissue plasminogen activator (t-PA), but its clinical application is greatly limited because of its narrow time window and bleeding risk. Natural products have a long history of being used in traditional medicine with good safety, making them an important resource for the development of new drugs. Indeed, some natural products can target a variety of pathophysiological processes related to stroke, including oxidative stress, inflammation and neuronal apoptosis. Therefore, the development of high-efficiency, low-toxicity, safe and cheap active substances from natural products is of great significance for improving the treatment alternatives of patients with stroke. This article reviews the neuroprotective effects of 33 natural compounds by searching recent related literature. Among them, puerarin, pinocembrin, quercetin, epigallocatechin-3-gallate (EGCG), and resveratrol have great potential in the clinical treatment of ischemic stroke. This review will provide a powerful reference for screening natural compounds with potential clinical application value in ischemic stroke or synthesizing new neuroprotective agents with natural compounds as lead compounds.

Development of a risk scoring system for evaluating the prognosis of patients with Her2-positive breast cancer.

BACKGROUND: As one of the many breast cancer subtypes, human epidermal growth factor receptor 2 (Her2)-positive breast cancer has higher invasiveness and poor prognosis, although the advent of anti-Her2 drugs has brought good news to patients. However, the emergence of drug resistance still limits its clinical efficacy, so there is an urgent need to explore new targets and develop a risk scoring system to improve treatments and evaluate patient prognosis. METHODS: Differentially expressed mRNAs associated with Her2-positive breast cancer were screened from a TCGA cohort. The prognostic risk scoring system was constructed according to univariate and Lasso Cox regression model analyses and combined with clinical factors (such as age and TNM) for univariate and multivariate analyses to verify the specificity and sensitivity of the risk scoring system. Finally, based on correlation and CNV mutation analyses, we explored the research value of the mRNAs involved in the system as key genes of the model. RESULTS: In this study, six mRNAs were screened and identified to construct a prognostic risk scoring system, including four up-regulated mRNA (RDH16, SPC25, SPC24, and SCUBE3) and two down-regulated mRNA (DGAT2 and CCDC69). The risk scoring system can divide Her2-positive breast cancer samples into high-risk and low-risk groups to evaluate patient prognosis. In addition, whether through the time-dependent receiver operating characteristics curve or compared with clinical factors, the risk scoring system showed high predictive sensitivity and specificity. Moreover, some CNV mutations in mRNA increase patient risk by influencing expression levels. CONCLUSION: The risk scoring system constructed in this study is helpful to improve the screening of high-risk patients with Her2-positive breast cancer and is beneficial for implementing early diagnosis and personalized treatment. It is suggested that these mRNAs may play an important role in the progression of Her2-positive breast cancer.

Profiling Proteins in the Hypothalamus and Hippocampus of a Rat Model of Premenstrual Syndrome Irritability.

Premenstrual syndrome (PMS) refers to several physical and mental symptoms (such as irritability) commonly encountered in clinical gynaecology. The incidence of PMS has been increasing, attracting greater attention from medical fields. However, PMS pathogenesis remains unclear. This study employed two-dimensional gel electrophoresis (2DE) for proteomic map analysis of the hypothalamus and hippocampus of rat models of premenstrual syndrome (PMS) irritability. Matrix-assisted laser desorption/ionisation time of flight mass spectroscopy (MALDI-TOF-MS) was used to identify proteins possibly related with PMS irritability. Baixiangdan, a traditional Chinese medicine effective against PMS irritability, was used in the rat model to study putative target proteins of this medicine. The hypothalamus and hippocampus of each group modelling PMS displayed the following features: decreased expression of Ulip2, tubulin beta chain 15, α actin, and interleukin 1 receptor accessory protein; increased expression of kappa-B motif-binding phosphoprotein; decreased expression of hydrolase at the end of ubiquitin carboxy, albumin, and aldolase protein; and increased expression of M2 pyruvate kinase, panthenol-cytochrome C reductase core protein I, and calcium-binding protein. Contrasting with previous studies, the current study identified new proteins related to PMS irritability. Our findings contribute to understanding the pathogenesis of PMS irritability and could provide a reference point for further studies.

Anger Emotional Stress Influences VEGF/VEGFR2 and Its Induced PI3K/AKT/mTOR Signaling Pathway.

Objective. We discuss the influence of anger emotional stress upon VEGF/VEGFR2 and its induced PI3K/AKT/mTOR signal pathway. Methods. We created a rat model of induced anger (anger-out and anger-in) emotional response using social isolation and resident-intruder paradigms and assessed changes in hippocampus' VEGF content, neuroplasticity, and the PI3K/AKT/mTOR signaling pathway. Results. The resident-intruder method successfully generated anger-out and anger-in models that differed significantly in composite aggression score, aggression incubation, open field behavior, sucrose preference, and weight gain. Anger emotional stress decreased synaptic connections and VEGFR2 expression. Anger emotional stress led to abnormal expression of VEGF/VEGFR2 mRNA and protein and disorderly expression of key factors in the PI3K/AKT/mTOR signal pathway. Fluoxetine administration ameliorated behavioral abnormalities and damage to hippocampal neurons caused by anger emotional stress, as well as abnormal expression of some proteins in VEGF/VEGFR2 and its induced PI3K/AKT/mTOR signal pathway. Conclusion. This research provides a detailed classification of anger emotion and verifies its influence upon VEGF and the VEGF-induced signaling pathway, thus providing circumstantial evidence of mechanisms by which anger emotion damages neurogenesis. As VEGFR2 can promote neurogenesis and vasculogenesis in the hippocampus and frontal lobe, these results suggest that anger emotional stress can result in decreased neurogenesis.

[Efficacy of Hebi Formula Combined Methotrexate on Early Rheumatoid Arthritis Patients with Dis- harmony of Gan and Pi Syndrome and Its Effects on Serum MMP-3 and RANK/RANKL/OPG Expressions].

Objective To observe the efficacy of Hebi Formula (HF) combined Methotrexate (MTX) on early rheumatoid arthritis (RA) patients with disharmony of Gan and Pi syndrome (DGPS) and its effects on matrix metalloproteinase-3 (MMP-3) activator of nuclear factor-KB/receptor activator of nu- clear factor-KB/osteoprotegerin (RANK/RANKL/OPG). Methods Totally 72 early RA patients with DGPS were assigned to the treatment group and the control group according to random digit table, 36 in each group. Patients in the control group took MTX, while those in the treatment group additionally took HF. MTX dose was increased from 7. 5 mg to 12. 5 mg gradually, once per week, and the course of treatment was 24 weeks. Efficacy for Chinese medicine (CM) syndromes, ACR20 improvement rate, laboratory re- lated indices [ rheumatoid factor ( RF ) , erythrocyte sedimentation rate ( ESR ) , C-reactive protein (CRP) , anti-cyclic citrullinated peptide antibody (CCP)], serum levels of MMP-3, OPG, RANKL, and adverse reactions were observed. Results The standard arriving rate of ACR20 was 82. 86% (2935) in the treatment group, higher than that in the control group [51. 52% (173) ;P <0. 05). The effective rate of CM syndrome was 85. 7% (30f35) in the treatment group, higher than that in the control group [63. 6% (21/33) ;P <0. 05). Compared with before treatment in the same group, levels of RF,ESR,CRP,MMP-3, and RANKL decreased, the OPG level increased in the two groups after treatment (P <0. 05, P <0. 01). Compared with the control group, levels of RF, ESR, CRP, and RANKL all decreased with statistical difference (P <0. 01 , P <0. 05). Liver dysfunction occurred in 1 case of the treatment group. Leucopenia occurred in 1 case and liver dysfunction occurred in 2 cases of the control group. Conclusion HF com- bined MTX could improve symptoms of early RA patients with DGPS, and regulate bone destruction in- duced by RANK/RANKL/OPG systems.

[In vitro anti-tumor effect of human dendritic cells vaccine induced by astragalus polysacharin: an experimental study].

OBJECTIVE: To explore the in vitro anti-tumor effect and mechanism of dendritic cell (DC) tumor vaccine induced by astragalus polysacharin (APS). METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from human peripheral blood. DCs obtained from human peripheral blood were cultivated and added with culture solution for in vitro inducing them to immature DCs. On the 5th day of culture, 100 microg/mL (as the final concentration) APS was added to cells in the APS group. DCs were induced to mature in the cytokine groups by adding 20 ng/mL rhTNF-alpha (as the final concentration). Changes of morphology and phenotype of DCs were observed. Mature DCs were sensitized with tumor antigen SGC-7901 and co-cultured with allogeneic T cells. The proliferative function of T lymphocytes was detected by MTT assay. Levels of IL-12 and IFN-gamma in co-cultured supernatant were detected by ELISA. Cytotoxic lymphocytes (CTL) activated by DC were co-cultured with tumor cell SGC-7901. The specific killing capacity of CTL to target cells was detected by LDH release assay. RESULTS: The morphological observation and phenotypic identification of APS induced DCs were in accordance with the characteristics of mature DCs. APS induced mature DCs could stimulate the proliferation of allogeneic T lymphocytes. The proliferation index of T cells increased with increased ratio of stimulator cells to effector cells (P < 0.05). Levels of IL-12 and IFN-gamma in co-culture supernatant significantly increased in a time-dependent manner (P < 0.05). CTL cells activated by sensitization of DCs could significantly kill tumor cells, and the killing effect increased along with increased effector-to-target ratio. CONCLUSION: APS could in vitro induce DCs to mature, promote its antigen-presenting capacity, effectively activate CTLs, and enhance anti-tumor function of the organism.

Reprogramming of Lipid Metabolism Mediates Crosstalk, Remodeling, and Intervention of Microenvironment Components in Breast Cancer.

Due to the unique characteristics of breast cancer initiation sites and significant alterations in tumor metabolism, breast cancer cells rely on lipid metabolic reprogramming to effectively regulate metabolic programs during the disease progression cascade. This adaptation enables them to meet the energy demands required for proliferation, invasion, metastasis, and responses to signaling molecules in the breast cancer microenvironment. In this review, we comprehensively examined the distinctive features of lipid metabolic reprogramming in breast cancer and elucidated the underlying mechanisms driving aberrant behavior of tumor cells. Additionally, we emphasize the potential role and adaptive changes in lipid metabolism within the breast cancer microenvironment, while summarizing recent preclinical studies. Overall, precise control over lipid metabolism rewiring and understanding of plasticity within the breast cancer microenvironment hold promising implications for developing targeted treatment strategies against this disease. Therefore, interventions targeting the lipid metabolism in breast cancer may facilitate innovative advancements in clinical applications.

From synergy to resistance: Navigating the complex relationship between sorafenib and ferroptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a major global health burden, and sorafenib, a multi-kinase inhibitor, has shown effectiveness in the treatment of HCC and is considered as the first-line therapy for advanced HCC. However, the response to sorafenib varies among patients, and the development of drug resistance poses a prevalent obstacle. Ferroptosis, a newly characterized form of cell death featured by iron-dependent lipid peroxidation, has emerged as a critical player in the reaction to sorafenib therapy in HCC. The induction of ferroptosis has been shown to augment the anticancer benefits of sorafenib. However, it has also been observed to contribute to sorafenib resistance. This review presents a comprehensive and thorough analysis that elucidates the intricate relationship between ferroptosis and sorafenib over recent years, aiming to formulate effective therapeutic approaches for liver cancer. Based on this exploration, we propose innovative strategies intended to overcome sorafenib resistance via targeted modulation of ferroptosis.

Analysis of the Potential Angiogenic Mechanisms of BuShenHuoXue Decoction against Osteonecrosis of the Femoral Head Based on Network Pharmacology and Experimental Validation.

OBJECTIVE: Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease with a high disability rate. The clinical effect of BuShenHuoXue decoction (BSHX) for ONFH is satisfactory. We aimed to elucidate the potential angiogenic mechanisms of BSHX in a rat femoral osteonecrosis model and bone marrow mesenchymal stem cells (BMSCs). METHODS: With in vivo experiments, we established the steroid-induced osteonecrosis of the femoral head (SONFH) model using Sprague-Dawley (SD) rats (8-week-old). The rats were randomly divided into five group of 12 rats each and given the corresponding interventions: control, model (gavaged with 0.9% saline), BSHX low-, medium- and high-dose groups (0.132 3, 0.264 6, and 0.529 2 g/mL BSHX solution by gavage). After 12 weeks, haematoxylin and eosin (H&E) staining was preformed to evaluate rat osteonecrosis. the expression of angiogenic factors (CD31, VEGFA, KDR, VWF) in rat femoral head was detected by immunohistochemistry, qPCR and western blotting. In cell experiment, BMSCs were isolated and cultured in the femoral bone marrow cavity of 4-week-old SD rats. BMSCs were randomly divided into eight groups and intervened with different doses of BSHX-containing serum and glucocorticoids: control group (CG); BSHX low-, medium-, and high-dose groups (CG + 0.661 5, 1.323, and 2.646 g/kg BSHX gavage rat serum); dexamethasone (Dex) group; and Dex + BSHX low-, medium-, and high-dose groups (Dex + 0.661 5, 1.323, and 2.646 g/kg BSHX gavaged rat serum), the effects of BSHX-containing serum on the angiogenic capacity of BMSCs were examined by qPCR and Western blotting. A co-culture system of rat aortic endothelial cells (RAOECs) and BMSCs was then established. Migration and angiogenesis of RAOECs were observed using angiogenesis and transwell assay. Identification of potential targets of BSHX against ONFH was obtained using network pharmacology. RESULTS: BSHX upregulated the expression of CD31, VEGFA, KDR, and VWF in rat femoral head samples and BMSCs (p < 0.05, vs. control group or model group). Different concentrations of BSHX-containing serum significantly ameliorated the inhibition of CD31, VEGFA, KDR and VWF expression by high concentrations of Dex. BSHX-containing serum-induced BMSCs promoted the migration and angiogenesis of RAOECs, reversed to some extent the adverse effect of Dex on microangiogenesis in RAOECs, and increased the number of microangiogenic vessels. Furthermore, we identified VEGFA, COL1A1, COL3A1, and SPP1 as important targets of BSHX against ONFH. CONCLUSION: BSHX upregulated the expression of angiogenic factors in the femoral head tissue of ONFH model rats and promoted the angiogenic capacity of rat RAOECs and BMSCs. This study provides an important basis for the use of BSHX for ONFH prevention and treatment.

Looking for a Beam of Light to Heal Chronic Pain.

Chronic pain (CP) is a leading cause of disability and a potential factor that affects biological processes, family relationships, and self-esteem of patients. However, the need for treatment of CP is presently unmet. Current methods of pain management involve the use of drugs, but there are different degrees of concerning side effects. At present, the potential mechanisms underlying CP are not completely clear. As research progresses and novel therapeutic approaches are developed, the shortcomings of current pain treatment methods may be overcome. In this review, we discuss the retinal photoreceptors and brain regions associated with photoanalgesia, as well as the targets involved in photoanalgesia, shedding light on its potential underlying mechanisms. Our aim is to provide a foundation to understand the mechanisms underlying CP and develop light as a novel analgesic treatment has its biological regulation principle for CP. This approach may provide an opportunity to drive the field towards future translational, clinical studies and support pain drug development.

Jingfang granules protects against intracerebral hemorrhage by inhibiting neuroinflammation and protecting blood-brain barrier damage.

Intracerebral hemorrhage (ICH) can induce intensive oxidative stress, neuroinflammation, and brain cell apoptosis. However, conventional methods for ICH treatment have many disadvantages. There is an urgent need for alternative, effective therapies with minimal side effects. Pharmacodynamics experiment, molecular docking, network pharmacology, and metabolomics were adopted to investigate the treatment and its mechanism of Jingfang Granules (JFG) in ICH. In this study, we investigated the therapeutic effects of JFG on ICH using behavioral, brain water content and Magnetic resonance imaging experiments. However, the key active component and targets of JFG remain unknown. Here we verified that JFG was beneficial to improve brain injury after ICH. A network pharmacology analysis revealed that the anti-inflammatory effect of JFG is predominantly mediated by its activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway through Luteolin, (+)-Anomalin and Phaseol and their targeting of AKT1, tumor necrosis factorα (TNF-α), and interleukin-1ß (IL-1ß). Molecular docking analyses revealed an average affinity of -8.633 kcal/mol, indicating a binding strength of less than -5 kcal/mol. Metabolomic analysis showed that JFG exerted its therapeutic effect on ICH by regulating metabolic pathways, such as the metabolism of taurine and hypotaurine, biosynthesis of valine, leucine, and isoleucine. In conclusion, we demonstrated that JFG attenuated neuroinflammation and BBB injury subsequent to ICH by activating the PI3K/Akt signaling pathway.

Bufalin inhibits epithelial-mesenchymal transition and increases radiosensitivity of non-small cell lung cancer via inhibition of the Src signaling.

Background: Epithelial-mesenchymal transition (EMT) is a biological process involved in tumor migration, invasion, and radiotherapy resistance. Bufalin can affect the proliferation, apoptosis and invasion of tumor cells by regulating multiple signaling pathways. Whether bufalin can increase radiosensitivity through EMT deserves further investigation. Methods: In this study, we investigated the effect of bufalin on the EMT and radiosensitivity of non-small cell lung cancer (NSCLC) and the underlying molecular mechanism. NSCLC cells were treated with bufalin (at a dose of 0-100 nM) or irradiated with 6 MV X-rays (4 Gy/min). The effects of bufalin on cell survival, cell cycle, radiosensitivity, cell migration, and invasion were detected. Western blot was used to analyze the gene expression changes of Src signaling in NSCLC cell induced by Bufalin. Results: Bufalin significantly inhibited cell survival, migration, and invasion and induced G2/M arrest and apoptosis. Cells co-treated with bufalin and radiation manifested a higher inhibitory effect compared to those treated with radiation or bufalin alone. Furthermore, the levels of p-Src and p-STAT3 were considerably reduced following bufalin treatment. Interestingly, elevated p-Src and p-STAT3 were observed in cells treated with radiation. Bufalin inhibited radiation-induced p-Src and p-STAT3, whereas the knockdown of Src abrogated the effects of bufalin on cell migration, invasion, EMT, and radiosensitivity. Conclusions: Bufalin inhibits EMT and enhances radiosensitivity through targeting Src signaling in NSCLC.

Exosomal ncRNAs facilitate interactive 'dialogue' between tumor cells and tumor-associated macrophages.

As a biological carrier, exosomes participate in the communication between various kinds of cells, and can mediate the interactive 'dialogue' between tumor cells and tumor-associated macrophages (TAMs). TAMs are the most abundant cell population in the tumor stroma and are an important part of the tumor immune microenvironment. Various stimulating factors in the tumor microenvironment influence the polarization of TAMs into multiple phenotypes, such as M1 and M2. It plays a dual role in tumor immunity by both promoting and inhibiting tumor growth. Exosome-encapsulated non-coding RNAs (ncRNAs) participate in the interactive 'dialogue' between exosome-mediated TAMs and tumor cells. Tumor-derived exosomal ncRNAs can promote macrophage polarization, whereas exosomal ncRNAs derived from TAMs can affect tumor proliferation, metastasis, angiogenesis, and chemotherapy resistance. The present review summarizes the dual effects of exosomal ncRNAs on tumor cells and TAMs, and discusses the application of exosomal ncRNAs as a potential diagnostic or prognostic marker and drug delivery system, to provide a new perspective and potential therapeutic drugs on targeting exosomes and macrophages in the treatment of tumors.

Preparation and Evaluation of Auxiliary Permeable Microneedle Patch Composed of Polyvinyl Alcohol and Eudragit NM30D Aqueous Dispersion.

Poor transdermal permeability limits the possibility of most drug delivery through the skin. Auxiliary permeable microneedles (AP-MNs) with a three-dimensional network structure can effectively break the skin stratum corneum barrier and assist in the transdermal delivery of active ingredients. Herein, we propose a simple method for preparing AP-MNs using polyvinyl alcohol and Eudragit NM30D for the first time. To optimize the formulation of microneedles, the characteristics of swelling properties, skin insertion, solution viscosity, and needle integrity were systematically examined. Additionally, the morphology, mechanical strength, formation mechanism, skin permeability, swelling performance, biocompatibility, and in vitro transdermal drug delivery of AP-MNs were evaluated. The results indicated that the microneedles exhibited excellent mechanical-strength and hydrogel-forming properties after swelling. Further, it proved that a continuous and unblockable network channel was created based on physical entanglement and encapsulation of two materials. The 24 h cumulative permeation of acidic and alkaline model drugs, azelaic acid and matrine, were 51.73 ± 2.61% and 54.02 ± 2.85%, respectively, significantly enhancing the transdermal permeability of the two drugs. In summary, the novel auxiliary permeable microneedles prepared through a simple blending route of two materials was a promising and valuable way to improve drug permeation efficiency.

Recent advances in regulating lipid metabolism to prevent coronary heart disease.

The pathogenesis of coronary heart disease is a highly complex process, with lipid metabolism disorders being closely linked to its development. Therefore, this paper analyzes the various factors that influence lipid metabolism, including obesity, genes, intestinal microflora, and ferroptosis, through a comprehensive review of basic and clinical studies. Additionally, this paper delves deeply into the pathways and patterns of coronary heart disease. Based on these findings, it proposes various intervention pathways and therapeutic methods, such as the regulation of lipoprotein enzymes, lipid metabolites, and lipoprotein regulatory factors, as well as the modulation of intestinal microflora and the inhibition of ferroptosis. Ultimately, this paper aims to offer new ideas for the prevention and treatment of coronary heart disease.

Anticancer effects and mechanisms of astragaloside­IV (Review).

Astragalus membranaceus Bunge is widely used in Traditional Chinese Medicine to treat various cancers. Astragaloside­IV (AS­IV) is one of the major compounds isolated from A. membranaceus Bunge and has been demonstrated to have antitumor effects by inhibiting cell proliferation, invasion and metastasis in various cancer types. Numerous studies have used in vitro cell culture and in vivo animal models of cancer to explore the antitumor activities of AS­IV. In the present study, the antitumor effects and mechanisms of AS­IV reported in studies recorded in the PubMed database were reviewed. First, the antitumor effects of AS­IV on proliferation, cell cycle, apoptosis, autophagy, invasion, migration, metastasis and epithelial­mesenchymal transition processes in cancer cells and the tumor microenvironment, including angiogenesis, tumor immunity and macrophage­related immune responses to cancer cells, were comprehensively discussed. Subsequently, the molecular mechanisms and related signaling pathways associated with antitumor effects of AS­IV as indicated by in vitro and in vivo studies were summarized, including the Wnt/AKT/GSK-3ß (glycogen synthase kinase­3ß)/ß­catenin, TGF­ß/PI3K/AKT/mTOR, PI3K/MAPK/mTOR, PI3K/AKT/NF­κB, Rac family small GTPase 1/RAS/MAPK/ERK, TNF­α/protein kinase C/ERK1/2­NF­κB and Tregs (T­regulatory cells)/IL­11/STAT3 signaling pathways. Of note, several novel mechanisms of Toll­like receptor 4 (TLR4)/NF­κB/STAT3, pSmad3C/3L, nuclear factor erythroid 2­related factor (NrF2)/heme oxygenase 1, circDLST/microRNA­489­3p/eukaryotic translation initiation factor 4A1 and macrophage­related high­mobility group box 1­TLR4 signaling pathways associated with the anticancer activity of AS­IV were also included. Finally, the limitations of current studies that must be addressed in future studies were pointed out to facilitate the establishment of AS­IV as a potent therapeutic drug in cancer treatment.

Protocatechuic aldehyde increases pericyte coverage and mitigates pericyte damage to enhance the atherosclerotic plaque stability.

Pericyte dysfunction and loss contribute substantially to the destabilization and rupture of atherosclerotic plaques. Protocatechuic aldehyde (PCAD), a natural polyphenol, exerts anti-atherosclerotic effects. However, the effects and mechanisms of this polyphenol on pericyte recruitment, coverage, and pericyte function remain unknown. We here treated apolipoprotein E-deficient mice having high-fat diet-induced atherosclerosis with PCAD. PCAD achieved therapeutic effects similar to rosuvastatin in lowering lipid levels and thus preventing atherosclerosis progression. With PCAD administration, plaque phenotype exhibited higher stability with markedly reduced lesion vulnerability, which is characterized by reduced lipid content and macrophage accumulation, and a consequent increase in collagen deposition. PCAD therapy increased pericyte coverage in the plaques, reduced VEGF-A production, and inhibited intraplaque neovascularization. PCAD promoted pericyte proliferation, adhesion, and migration to mitigate ox-LDL-induced pericyte dysfunction, which thus maintained the capillary network structure and stability. Furthermore, TGFBR1 silencing partially reversed the protective effect exerted by PCAD on human microvascular pericytes. PCAD increased pericyte coverage and impeded ox-LDL-induced damages through TGF-ß1/TGFBR1/Smad2/3 signaling. All these novel findings indicated that PCAD increases pericyte coverage and alleviates pericyte damage to improve the stability of atherosclerotic plaques, which is accomplished by regulating TGF-ß1/TGFBR1/Smad2/3 signaling in pericytes.

ncRNA-mediated ceRNA regulatory network: Transcriptomic insights into breast cancer progression and treatment strategies.

With the rapid development of next-generation sequencing technology, several studies have shown that ncRNAs can act as competitive endogenous RNAs (ceRNAs) and are involved in various biological processes, such as proliferation, differentiation, apoptosis, and migration of breast cancer (BC) cells, and plays an important role in BC progression as a molecular target for its diagnosis, treatment, prognosis, and differentiation of subtypes and age groups of BC patients. Based on the description of ceRNA-related biological functions, this study screened and sorted the sequencing analysis and experimental verification conclusions of BC-related ceRNAs and found that the ncRNAs mediated ceRNA networks can promote the development of BC by promoting the expression of genes related to BC proliferation, drug resistance, and apoptosis, inducing the production of epithelial-mesenchymal transition (EMT) to promote metastasis and activating cancer-related signaling pathways.

The NLRP3 inflammasome is involved in resident intruder paradigm-induced aggressive behaviors in mice.

Background: Aggressive behaviors are one of the most important negative behaviors that seriously endangers human health. Also, the central para-inflammation of microglia triggered by stress can affect neurological function, plasticity, and behavior. NLRP3 integrates stress-related signals and is a key driver of this neural para-inflammation. However, it is unclear whether the NLRP3 inflammasome is implicated in the development of aggressive behaviors. Methods: First, aggressive behavior model mice were established using the resident intruder paradigm. Then, aggressive behaviors were determined with open-field tests (OFT), elevated plus-maze (EPM), and aggressive behavior tests (AT). Moreover, the expression of P2X7R and NLRP3 inflammasome complexes were assessed by immunofluorescence and Western blot. The levels of NLRP3 and inflammatory cytokines were evaluated using enzyme-linked immunosorbent assay (ELISA) kits. Finally, nerve plasticity damage was observed by immunofluorescence, transmission electron microscope, and BrdU staining. Results: Overall, the resident intruder paradigm induced aggressive behaviors, activated the hippocampal P2X7R and NLRP3 inflammasome, and promoted the release of proinflammatory cytokines IL-1ß in mice. Moreover, NLRP3 knockdown, administration of P2X7R antagonist (A804598), and IL-1ß blocker (IL-1Ra) prevented NLRP3 inflammasome-driven inflammatory responses and ameliorated resident intruder paradigm-induced aggressive behaviors. Also, the resident intruder paradigm promoted the activation of mouse microglia, damaging synapses in the hippocampus, and suppressing hippocampal regeneration in mice. Besides, NLRP3 knockdown, administration of A804598, and IL-1Ra inhibited the activation of microglia, improved synaptic damage, and restored hippocampal regeneration. Conclusion: The NLRP3 inflammasome-driven inflammatory response contributed to resident intruder paradigm-induced aggressive behavior, which might be related to neuroplasticity. Therefore, the NLRP3 inflammasome can be a potential target to treat aggressive behavior-related mental illnesses.