Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. METHODS: Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. RESULTS: It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-L1+ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that CXCL1EV-dead enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. CONCLUSIONS: Our results highlight CXCL1EV-dead as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis.

Brain-Targeted Black Phosphorus-Based Nanotherapeutic Platform for Enhanced Hypericin Delivery in Depression.

Depression is a significant global health concern that remains inadequately treated due to the limited effectiveness of conventional drug therapies. One potential therapeutic agent, hypericin (HYP), is identified as an effective natural antidepressant. However, its poor water solubility, low bioavailability, and limited ability to penetrate the brain parenchyma have hindered its clinical application. To address these shortcomings and enhance the therapeutic efficacy of HYP, it is loaded onto black phosphorus nanosheets (BP) modified with the neural cell-targeting peptide RVG29 to synthesize a nanoplatform named BP-RVG29@HYP (BRH). This platform served as a nanocarrier for HYP and integrated the advantages of BP with advanced delivery methods and precise targeting strategies. Under the influence of 808 nm near-infrared irradiation (NIR), BRH effectively traversed an in vitro BBB model. In vivo experiments validated these findings, demonstrating that treatment with BRH significantly alleviated depressive-like behaviors and oxidative stress in mice. Importantly, BRH exhibited an excellent safety profile, causing minimal adverse effects, which highlighted its potential as a promising therapeutic agent. In brief, this novel nanocarrier holds great promise in the development of antidepressant drugs and can create new avenues for the treatment of depression.

Developing liver-targeted naringenin nanoparticles for breast cancer endocrine therapy by promoting estrogen metabolism.

Endocrine therapy is standard for hormone receptor-positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.

Global stability for age-infection-structured human immunodeficiency virus model with heterogeneous transmission.

In this paper, we analyze the global asymptotic behaviors of a mathematical susceptible-infected(SI) age-infection-structured human immunodeficiency virus(HIV) model with heterogeneous transmission. Mathematical analysis shows that the local and global dynamics are completely determined by the basic reproductive number R0. If R0<1, disease-free equilibrium is globally asymptotically stable. If R0>1, it shows that disease-free equilibrium is unstable and the unique endemic equilibrium is globally asymptotically stable. The proofs of global stability utilize Lyapunov functions. Besides, the numerical simulations are illustrated to support these theoretical results and sensitivity analysis of each parameter for R0 is performed by the method of partial rank correlation coefficient(PRCC).

Forecast of peak infection and estimate of excess deaths in COVID-19 transmission and prevalence in Taiyuan City, 2022 to 2023.

In this paper, with the method of epidemic dynamics, we assess the spread and prevalence of COVID-19 after the policy adjustment of prevention and control measure in December 2022 in Taiyuan City in China, and estimate the excess population deaths caused by COVID-19. Based on the transmission mechanism of COVID-19 among individuals, a dynamic model with heterogeneous contacts is established to describe the change of control measures and the population's social behavior in Taiyuan city. The model is verified and simulated by basing on reported case data from November 8th to December 5th, 2022 in Taiyuan city and the statistical data of the questionnaire survey from December 1st to 23rd, 2022 in Neijiang city. Combining with reported numbers of permanent residents and deaths from 2017 to 2021 in Taiyuan city, we apply the dynamic model to estimate theoretical population of 2022 under the assumption that there is no effect of COVID-19. In addition, we carry out sensitivity analysis to determine the propagation character of the Omicron strain and the effect of the control measures. As a result of the study, it is concluded that after adjusting the epidemic policy on December 6th, 2022, three peaks of infection in Taiyuan are estimated to be from December 22nd to 31st, 2022, from May 10th to June 1st, 2023, and from September 5th to October 13th, 2023, and the corresponding daily peaks of new cases can reach 400 000, 44 000 and 22 000, respectively. By the end of 2022, excess deaths can range from 887 to 4887, and excess mortality rate can range from 3.06% to 14.82%. The threshold of the infectivity of the COVID-19 variant is estimated 0.0353, that is if the strain infectivity is above it, the epidemic cannot be control with the previous normalization measures.

Plant-Derived Vesicles: A New Era for Anti-Cancer Drug Delivery and Cancer Treatment.

Lipid-structured vesicles have been applied for drug delivery system for over 50 years. Based on their origin, lipid-structured vesicles are divided into two main categories, namely synthetic lipid vesicles (SLNVEs) and vesicles of mammalian origin (MDVEs). Although SLNVEs can stably transport anti-cancer drugs, their biocompatibility is poor and degradation of exogenous substances is a potential risk. Unlike SLNVEs, MDVEs have excellent biocompatibility but are limited by a lack of stability and a risk of contamination by dangerous pathogens from donor cells. Since the first discovery of plant-derived vesicles (PDVEs) in carrot cell supernatants in 1967, emerging evidence has shown that PDVEs integrate the advantages of both SLNVEs and MDVEs. Notably, 55 years of dedicated research has indicated that PDVEs are an ideal candidate vesicle for drug preparation, transport, and disease treatment. The current review systematically focuses on the role of PDVEs in cancer therapy and in particular compares the properties of PDVEs with those of conventional lipid vesicles, summarizes the preparation methods and quality control of PDVEs, and discusses the application of PDVEs in delivering anti-cancer drugs and their underlying molecular mechanisms for cancer therapy. Finally, the challenges and future perspectives of PDVEs for the development of novel therapeutic strategies against cancer are discussed.

Stability analysis of an HIV/AIDS epidemic model with sexual transmission in a patchy environment.

A multi-patch HIV/AIDS model with heterosexual transmission is formulated to investigate the impact of population migration on the spread of HIV/AIDS. We derive the basic reproduction number R0 and prove that if R0<1, the disease-free equilibrium is globally asymptotically stable. If R0>1 and certain conditions are satisfied, the endemic equilibrium is globally asymptotically stable. We apply the model to two patches and conduct numerical simulations. If HIV/AIDS becomes extinct in each patch when two patches are isolated, the disease remains extinct in two patches when the population migration occurs; if HIV/AIDS spreads in each patch when two patches are isolated, the disease remains persistent in two patches when the population migration occurs; if the disease disappears in one patch and spreads in the other patch when they are isolated, the disease can spread or disappear in two patches if migration rates of individuals are suitably chosen.

CONSTANS interacts with and antagonizes ABF transcription factors during salt stress under long-day conditions.

CONSTANS (CO) is a critical regulator of flowering that combines photoperiodic and circadian signals in Arabidopsis (Arabidopsis thaliana). CO is expressed in multiple tissues, including seedling roots and young leaves. However, the roles and underlying mechanisms of CO in modulating physiological processes outside of flowering remain obscure. Here, we show that the expression of CO responds to salinity treatment. CO negatively mediated salinity tolerance under long-day (LD) conditions. Seedlings from co-mutants were more tolerant to salinity stress, whereas overexpression of CO resulted in plants with reduced tolerance to salinity stress. Further genetic analyses revealed the negative involvement of GIGANTEA (GI) in salinity tolerance requires a functional CO. Mechanistic analysis demonstrated that CO physically interacts with 4 critical basic leucine zipper (bZIP) transcription factors; ABSCISIC ACID-RESPONSIVE ELEMENT BINDING FACTOR1 (ABF1), ABF2, ABF3, and ABF4. Disrupting these ABFs made plants hypersensitive to salinity stress, demonstrating that ABFs enhance salinity tolerance. Moreover, ABF mutations largely rescued the salinity-tolerant phenotype of co-mutants. CO suppresses the expression of several salinity-responsive genes and influences the transcriptional regulation function of ABF3. Collectively, our results show that the LD-induced CO works antagonistically with ABFs to modulate salinity responses, thus revealing how CO negatively regulates plant adaptation to salinity stress.

Chronic psychological stress promotes breast cancer pre-metastatic niche formation by mobilizing splenic MDSCs via TAM/CXCL1 signaling.

BACKGROUND: Emerging studies have identified chronic psychological stress as an independent risk factor influencing breast cancer growth and metastasis. However, the effects of chronic psychological stress on pre-metastatic niche (PMN) formation and the underlying immunological mechanisms remain largely unknown. METHODS: The effects and molecular mechanisms of chronic unpredictable mild stress (CUMS) on modulating tumor-associated macrophages (TAMs) and PMN formation were clarified by multiplex immunofluorescence technique, cytokine array, chromatin immunoprecipitation, the dual-luciferase reporter assay, and breast cancer xenografts. Transwell and CD8+ T cytotoxicity detection were used to analyze the mobilization and function of myeloid-derived suppressor cells (MDSCs). mCherry-labeled tracing strategy and bone marrow transplantation were applied to explore the crucial role of splenic CXCR2+/+ MDSCs facilitating PMN formation under CUMS. RESULTS: CUMS significantly promoted breast cancer growth and metastasis, accompanied by TAMs accumulation in the microenvironment. CXCL1 was identified as a crucial chemokine in TAMs facilitating PMN formation in a glucocorticoid receptor (GR)-dependent manner. Interestingly, the spleen index was significantly reduced under CUMS, and splenic MDSCs were validated as a key factor mediating CXCL1-induced PMN formation. The molecular mechanism study revealed that TAM-derived CXCL1 enhanced the proliferation, migration, and anti-CD8+ T cell functions of MDSCs via CXCR2. Moreover, CXCR2 knockout and CXCR2-/-MDSCs transplantation significantly impaired CUMS-mediated MDSC elevation, PMN formation, and breast cancer metastasis. CONCLUSION: Our findings shed new light on the association between chronic psychological stress and splenic MDSC mobilization, and suggest that stress-related glucocorticoid elevation can enhance TAM/CXCL1 signaling and subsequently recruit splenic MDSCs to promote PMN formation via CXCR2.

PHOSPHATE STARVATION RESPONSE1 (PHR1) interacts with JASMONATE ZIM-DOMAIN (JAZ) and MYC2 to modulate phosphate deficiency-induced jasmonate signaling in Arabidopsis.

Phosphorus (P) is a macronutrient necessary for plant growth and development. Inorganic phosphate (Pi) deficiency modulates the signaling pathway of the phytohormone jasmonate in Arabidopsis thaliana, but the underlying molecular mechanism currently remains elusive. Here, we confirmed that jasmonate signaling was enhanced under low Pi conditions, and the CORONATINE INSENSITIVE1 (COI1)-mediated pathway is critical for this process. A mechanistic investigation revealed that several JASMONATE ZIM-DOMAIN (JAZ) repressors physically interacted with the Pi signaling-related core transcription factors PHOSPHATE STARVATION RESPONSE1 (PHR1), PHR1-LIKE2 (PHL2), and PHL3. Phenotypic analyses showed that PHR1 and its homologs positively regulated jasmonate-induced anthocyanin accumulation and root growth inhibition. PHR1 stimulated the expression of several jasmonate-responsive genes, whereas JAZ proteins interfered with its transcriptional function. Furthermore, PHR1 physically associated with the basic helix-loop-helix (bHLH) transcription factors MYC2, MYC3, and MYC4. Genetic analyses and biochemical assays indicated that PHR1 and MYC2 synergistically increased the transcription of downstream jasmonate-responsive genes and enhanced the responses to jasmonate. Collectively, our study reveals the crucial regulatory roles of PHR1 in modulating jasmonate responses and provides a mechanistic understanding of how PHR1 functions together with JAZ and MYC2 to maintain the appropriate level of jasmonate signaling under conditions of Pi deficiency.

Dynamic analysis of rumor propagation model with media report and time delay on social networks.

When a rumor appears on social networks, the media of relevant departments need reaction time to make an authoritative announcement. Considering the effects of the media report and time delay on a rumor spreading, and the different attitudes of individuals towards media reports. We proposed a susceptible-expose-infective-media-remover (SEIMR) rumor propagation model with media reports and time delay. Firstly, the basic reproduction number of the model is obtained. Secondly, the positivity, boundedness and existence of the solutions of the model are analyzed. Then, the local asymptotic stability of the rumor free equilibrium and the boundary equilibriums is proved, and the global asymptotic stability of the equilibriums is proved by constructing Lyapunov function when the time delay is zero. Besides, the prevention and control effects of the media report on rumor spreading and the effect of time delay are analyzed. The shorter time delay in media report and the greater the impact of the media report, the more effective the suppression of rumors will be. Finally, the accuracy of the theoretical results as well as the effects of different parameters of the model have been verified through numerical simulations, and the effectiveness of the SEIMR model has been verified via comparative experiments.

Naringenin in Si-Ni-San formula inhibits chronic psychological stress-induced breast cancer growth and metastasis by modulating estrogen metabolism through FXR/EST pathway.

INTRODUCTION: Chronic psychological stress is a well-established risk factor for breast cancer development. Si-Ni-San (SNS) is a classical traditional Chinese medicine formula prescribed to psychological disorder patients. However, its action effects, molecular mechanisms, and bioactive phytochemicals against breast cancer are not yet clear. OBJECTIVES: This study aimed to explore the modulatory mechanism and bioactive compound of SNS in regulating estrogen metabolism during breast cancer development induced by chronic psychological stress. METHODS: Mouse breast cancer xenograft was used to determine the effect of SNS on breast cancer growth and metastasis. Metabolomics analysis was conducted to discover the impact of SNS on metabolic profile changes in vivo. Multiple molecular biology experiments and breast cancer xenografts were applied to verify the anti-metastatic potentials of the screened bioactive compound. RESULTS: SNS remarkably inhibited chronic psychological stress-induced breast cancer growth and metastasis in the mouse breast cancer xenograft. Meanwhile, chronic psychological stress increased the level of cholic acid, accompanied by the elevation of estradiol. Mechanistic investigation demonstrated that cholic acid activated farnesoid X receptor (FXR) expression, which inhibited hepatocyte nuclear factor 4α (HNF4α)-mediated estrogen sulfotransferase (EST) transcription in hepatocytes, and finally resulting in estradiol elevation. Notably, SNS inhibited breast cancer growth by suppressing estradiol level via modulating FXR/EST signaling. Furthermore, luciferase-reporting gene assay screened naringenin as the most bioactive compound in SNS for triggering EST activity in hepatocytes. Interestingly, pharmacokinetic study revealed that naringenin had the highest absorption in the liver tissue. Following in vivo and in vitro studies demonstrated that naringenin inhibited stress-induced breast cancer growth and metastasis by promoting estradiol metabolism via FXR/EST signaling. CONCLUSION: This study not only highlights FXR/EST signaling as a crucial target in mediating stress-induced breast cancer development, but also provides naringenin as a potential candidate for breast cancer endocrine therapy via promoting estradiol metabolism.

Development and Validation of a Risk Prediction Model for Breast Cancer Prognosis Based on Depression-Related Genes.

Background: Depression plays a significant role in mediating breast cancer recurrence and metastasis. However, a precise risk model is lacking to evaluate the potential impact of depression on breast cancer prognosis. In this study, we established a depression-related gene (DRG) signature that can predict overall survival (OS) and elucidate its correlation with pathological parameters and sensitivity to therapy in breast cancer. Methods: The model training and validation assays were based on the analyses of 1,096 patients from The Cancer Genome Atlas (TCGA) database and 2,969 patients from GSE96058. A risk signature was established through univariate and multivariate Cox regression analyses. Results: Ten DRGs were determined to construct the risk signature. Multivariate analysis revealed that the signature was an independent prognostic factor for OS. Receiver operating characteristic (ROC) curves indicated good performance of the model in predicting 1-, 3-, and 5-year OS, particularly for patients with triple-negative breast cancer (TNBC). In the high-risk group, the proportion of immunosuppressive cells, including M0 macrophages, M2 macrophages, and neutrophils, was higher than that in the low-risk group. Furthermore, low-risk patients responded better to chemotherapy and endocrine therapy. Finally, a nomogram integrating risk score, age, tumor-node-metastasis (TNM) stage, and molecular subtypes were established, and it showed good agreement between the predicted and observed OS. Conclusion: The 10-gene risk model not only highlights the significance of depression in breast cancer prognosis but also provides a novel gene-testing tool to better prevent the potential adverse impact of depression on breast cancer prognosis.

Corrigendum: Autophagy Blockade by Ai Du Qing Formula Promotes Chemosensitivity of Breast Cancer Stem Cells Via GRP78/ß-Catenin/ABCG2 Axis.

[This corrects the article DOI: 10.3389/fphar.2021.659297.].

The Impact of Quarantine and Medical Resources on the Control of COVID-19 in Wuhan based on a Household Model.

In order to understand how Wuhan curbed the COVID-19 outbreak in 2020, we build a network transmission model of 123 dimensions incorporating the impact of quarantine and medical resources as well as household transmission. Using our new model, the final infection size of Wuhan is predicted to be 50,662 (95%CI: 46,234, 55,493), and the epidemic would last until April 25 (95%CI: April 23, April 29), which are consistent with the actual situation. It is shown that quarantining close contacts greatly reduces the final size and shorten the epidemic duration. The opening of Fangcang shelter hospitals reduces the final size by about 17,000. Had the number of hospital beds been sufficient when the lockdown started, the number of deaths would have been reduced by at least 54.26%. We also investigate the distribution of infectious individuals in unquarantined households of different sizes. The high-risk households are those with size from two to four before the peak time, while the households with only one member have the highest risk after the peak time. Our findings provide a reference for the prevention, mitigation and control of COVID-19 in other cities of the world.

The dynamics of sexually transmitted diseases with men who have sex with men.

In this paper, we give a rather complete analysis for a susceptible-infective sexually transmitted disease (STD) model, where the males are divided into two different groups based on their different sexual orientation. The threshold [Formula: see text] of STD model is obtained. If [Formula: see text], the disease-free equilibrium is globally asymptotically stable. Further, we investigate the existence and stability of the boundary equilibria that characterize the males of the different sexual orientation. We also investigate the existence and stability of the positive equilibrium, which characterizes the possibility of coexistence of male heterosexual and male homosexual. We obtain sufficient and necessary conditions for the existence and global stability of these equilibria. We see that the proportion of heterosexuality in MSM affects the stability of the system. The theoretical results are verified by numerical simulation.

Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation.

Chronic psychological stress is closely correlated with breast cancer growth and metastasis. Sini San (SNS) formula is a classical prescription for relieving depression-related symptoms in traditional Chinese medicine (TCM). Current researches have suggested that chronic psychological stress is closely correlated with cancer stem cells (CSCs) and endoplasmic reticulum (ER) stress. This study aimed to investigate the effects of chronic psychological stress on ER stress-mediated breast cancer stemness and the therapeutic implication of SNS. Chronic psychological stress promoted lung metastasis in 4T1 breast tumor-bearing mice and increased the stem cell-like populations and stemness-related gene expression. Meanwhile, GRP78, a marker of ER stress, was significantly increased in the breast tumors and lung metastases under chronic psychological stress. As a biochemical hallmark of chronic psychological stress, cortisol dramatically enhanced the stem cell-like populations and mammospheres formation by activating GRP78 transcriptionally. However, GRP78 inhibitors or shRNA attenuated the stemness enhancement mediated by cortisol. Similarly, SNS inhibited chronic psychological stress-induced lung metastasis and stemness of breast cancer cells, as well as reversed cortisol-induced stem cell-like populations and mammospheres formation by attenuating GRP78 expression. Co-localization and co-immunoprecipitation experiments showed that SNS interrupted the interaction between GRP78 and LRP5 on the cell surface, thus inhibiting the Wnt/ß-catenin signaling of breast CSCs. Altogether, this study not only uncovers the biological influence and molecular mechanism of chronic psychological stress on breast CSCs but also highlights SNS as a promising strategy for relieving GRP78-induced breast cancer stemness via inhibiting GRP78 activation.

StWRKY13 promotes anthocyanin biosynthesis in potato (Solanum tuberosum) tubers.

Although the role of WRKY transcription factors (TFs) in colour formation has been reported in several species, their function in potato (Solanum tuberosum L.) anthocyanin biosynthesis remains unclear. In this study, the potato WRKY gene StWRKY13 was isolated and characterised. Expression analysis revealed a significantly higher StWRKY13 expression in chromatic tubers than in yellow ones. Transient activation assays showed that StWRKY13 could enhance the role of StAN2 in promoting anthocyanin biosynthesis in tobacco (Nicotiana tabacum L.). Over-expressing the StWRKY13 gene promoted anthocyanin biosynthesis in potato tubers. Further investigations indicated that StWRKY13 could interact with the StCHS, StF3H, StDFR, and StANS gene promoters and significantly enhance their activities. Our findings showed that StWRKY13 could promote anthocyanin biosynthesis by activating StCHS, StF3H, StDFR, and StANS transcription in potato tubers, thereby supporting the theoretical basis for anthocyanins formation in coloured potato tubers.