Dronedarone inhibits the proliferation of esophageal squamous cell carcinoma through the CDK4/CDK6-RB1 axis in vitro and in vivo.

Treatment options for patients with esophageal squamous cell carcinoma (ESCC) often result in poor prognosis and declining health-related quality of life. Screening FDA-approved drugs for cancer chemoprevention is a promising and cost-efficient strategy. Here, we found that dronedarone, an antiarrhythmic drug, could inhibit the proliferation of ESCC cells. Moreover, we conducted phosphorylomics analysis to investigate the mechanism of dronedarone-treated ESCC cells. Through computational docking models and pull-down assays, we demonstrated that dronedarone could directly bind to CDK4 and CDK6 kinases. We also proved that dronedarone effectively inhibited ESCC proliferation by targeting CDK4/CDK6 and blocking the G0/G1 phase through RB1 phosphorylation inhibition by in vitro kinase assays and cell cycle assays. Subsequently, we found that knocking out CDK4 and CDK6 decreased the susceptibility of ESCC cells to dronedarone. Furthermore, dronedarone suppressed the growth of ESCC in patient-derived tumor xenograft models in vivo. Thus, our study demonstrated that dronedarone could be repurposed as a CDK4/6 inhibitor for ESCC chemoprevention.

The use of chitosan as an antioxidant in the feed of cultivated P. vannamei shrimp against oxidative stress induced by exposure to microplastics.

Microplastics (MP) are omnipresent in aquaculture and can induce several toxic effects, mainly oxidative stress. Therefore, alternatives to minimize these effects are welcome. In this study, chitosan (1 and 3 g/kg) was supplemented through the feed of farmed shrimp P. vannamei for 30 days. After this period, the shrimp were exposed to MP (0.5 mg/L) for 7 days. The results showed the presence of MP in hepatopancreas, gills and muscle. Hepatopancreas morphological alterations, as well as lipid peroxidation, a decrease in GSH level, and an increase in SOD activity indicated an oxidative stress that was reversed by chitosan. The muscle was also affected by MP, showing decreased CAT activity and increased SOD activity, though no lipid peroxidation was observed. In muscle, chitosan reversed the SOD increase to basal activity. The results obtained showed that chitosan was more effective against oxidative stress than in preventing accumulation and histological damage.

Comparing approaches for chemoprevention for school-based malaria control in Malawi: an open label, randomized, controlled clinical trial.

Background: School-age children in sub-Saharan Africa suffer an underappreciated burden of malaria which threatens their health and education. To address this problem, we compared the efficacy of two school-based chemoprevention approaches: giving all students intermittent preventive treatment (IPT) or screening and treating only students with detected infections (IST). Methods: In a three-arm, open-label, randomized, controlled trial (NCT05244954) in Malawi, 746 primary school students, aged 5-19 years, were individually randomized within each grade-level to IPT (n = 249), IST with a high-sensitivity rapid diagnostic test (hs-RDT, n = 248), or control (n = 249). At six-week intervals three times within the peak malaria transmission season (February-June 2022) treatment with dihydroartemisinin-piperaquine (DP) was administered to girls <10 years and all boys, and chloroquine to older girls. The primary outcome was Plasmodium falciparum (Pf) infection detected by PCR 6-8 weeks after the final intervention. Secondary outcomes included anaemia, clinical malaria, and scores on tests of attention, literacy, and math. Analysis was by modified intention-to-treat. Findings: Outcomes analyses included 727 (97%) participants. At the end of the study, prevalence of Pf infection was 17% (41/243) in the IPT arm, 24% (58/244) in the IST arm, and 53% (127/240) in the control arm. Compared to controls, IPT and IST reduced the odds of Pf infection (IPT adjusted odds ratio [aOR]: 0.18 (95% CI: 0.11, 0.27); p < 0.0001; IST aOR: 0.27 (95% CI: 0.18, 0.40); p < 0.0001). However, only participants receiving IPT had a lower incidence of clinical malaria (0.19 cases per person per six months (95% CI: 0.14, 0.27) vs 0.56 (95% CI: 0.46, 0.68); incidence rate ratio: 0.38 (95% CI: 0.26, 0.55); p < 0.0001)) and prevalence of anaemia (8% [20/243] vs 15% [36/240]; aOR: 0.49 (95% CI: 0.27, 0.91); p = 0.023) compared to controls. Literacy scores were higher in both intervention arms. No between group differences in tests of attention or math or number of serious adverse events were found. Interpretation: Results support implementation of IST with hs-RDTs or IPT for reduction in the prevalence of infection. Based on reductions in clinical malaria, IPT may provide additional benefits warranting further consideration by school-based malaria chemoprevention programs. Funding: Doris Duke Charitable Foundation Clinical Scientist Development Award 2021191, U.S. NIH K24AI114996 & K23AI135076.

Immunomodulatory and chemopreventive effects of resveratrol on the digestive system cancers.

Resveratrol (RSV), the primary polyphenol found in grapes, has been revealed to have anti-inflammatory properties by reducing the capacity of the peripheral blood mononuclear cells to produce pro-inflammatory cytokines, including IL-1ß, IL-6, IL-1ra and TNFα. Considering the close association between chronic inflammation and cancer development, RSV's immunomodulatory properties are one way by which the polyphenol may inhibit cancer initiation, proliferation, neovascularization, and migration. Resveratrol influences the generation of microtumor environment which is one of the key factors in cancer progress. In addition to immunomodulation, RSV inhibits cancer development by expressing anti-oxidant effects, causing cell cycle arrest, stimulating the function of certain enzymes, and activating cell signaling pathways. The end outcome is one of the various forms of cell death, including apoptosis, pyroptosis, necroptosis, and more, as it has been observed in vitro. RSV has been shown to act against cancer in practically every organ, while its effects on colon cancer have been documented more frequently. It is remarkable that longer-term clinical studies that may have established the potential for this natural substance to serve as a therapeutic adjuvant to traditional anti-cancer medications were not prompted by the encouraging outcomes seen with cancer cells treated with non-toxic doses of resveratrol. The current review aims to assess the recent findings about the immunological and anti-cancer characteristics of RSV, with a particular emphasis on cancers of the digestive tract, as a challenge for future clinical research that may contribute to the better prognosis of cancer.

Effectiveness of malaria chemoprevention in the first two years of life in Cameroon and Côte d'Ivoire compared to standard of care: study protocol for a population-based prospective cohort impact evaluation study.

BACKGROUND: Perennial malaria chemoprevention (PMC) is a chemoprevention strategy endorsed by the World Health Organization (WHO) and is increasingly being adopted by National Malaria Programmes. PMC aims to reduce morbidity and mortality caused by malaria and anaemia in in young children through provision of antimalarial drugs at routine contact points with the local health system. This study aims to evaluate the impact of the programmatically-implemented country-tailored PMC programmes targeting children up to two years of age using sulfadoxine-pyrimethamine (SP) on the incidence of malaria and anaemia in children in Cameroon and Côte d'Ivoire. METHODS: We will assess the impact of PMC using passive and active monitoring of a prospective observational cohort of children up to 36 months of age at recruitment in selected study sites in Cameroon and Côte d'Ivoire. The primary and secondary outcomes include malaria, anaemia and malnutrition incidence. We will also conduct a time-series analysis of passively detected malaria and anaemia cases comparing the periods before and after PMC introduction. This study is powered to detect a 30% and 40% reduction of malaria incidence compared to the standard of care in Cameroon and Côte d'Ivoire, respectively. DISCUSSION: This multi-country study aims to provide evidence of the effectiveness of PMC targeting children in the first two years of life on malaria and anaemia and will provide important information to inform optimal operationalization and evaluation of this strategy. TRIAL REGISTRATION: Cameroon - NCT05889052; Côte d'Ivoire - NCT05856357.

Perceived barriers and opportunities for the introduction of post-discharge malaria chemoprevention (PDMC) in five sub-Saharan countries: a qualitative survey amongst malaria key stakeholders.

BACKGROUND: Post-discharge malaria chemoprevention (PDMC) is an intervention aimed at reducing morbidity and mortality in patients hospitalized with severe anaemia, with its effectiveness established in several clinical trials. The aim of this study was to better understand factors that would influence the scale up of this intervention, and to identify preferences for two delivery mechanisms, facility-based or community-based. METHODS: Forty-six qualitative individual interviews were conducted in five sub-Saharan countries amongst malaria key opinion leaders and national decision makers. Findings were analysed following a thematic inductive approach. RESULTS: Half of participants were familiar with PDMC, with a satisfactory understanding of the intervention. Although PDMC was perceived as beneficial by most respondents, there was some unclarity on the target population. Both delivery approaches were perceived as valuable and potentially complementary. From an adoption perspective, relevant evidence generation, favorable policy environment, and committed funding were identified as key elements for the scale up of PDMC. CONCLUSIONS: The findings suggest that although PDMC was perceived as a relevant tool to prevent malaria, further clarification was needed in terms of the relevant patient population, delivery mechanisms, and more evidence should be generated from implementation research to ensure policy adoption and funding.

Novel lipid nanovesicle-loaded dissolving microarray patches for fenretinide in breast cancer chemoprevention.

The retinoid fenretinide (FENR) is a promising compound for preventing breast cancer recurrence but faces challenges due to poor solubility and low bioavailability. This study explores the development of dissolving microneedles (MNs) containing FENR-loaded ethosomes for minimally invasive breast cancer chemoprevention, aiming to enhance local drug distribution. Ethosomes were formulated using ethanol, propylene glycol, soya lecithin, water, and polysorbate 80 micelles. MNs were created from poly(vinyl alcohol) and poly(vinylpyrrolidone) hydrogels by adding polymer powder directly into ethosomes suspensions, reducing manufacturing time and cost. Two methods were used to load ethosomes into high-density moulds: 1) only in the needle area, and 2) in both the needle area and baseplate. Dynamic light scattering confirmed nanostructures in the hydrogels and MNs. Micelle-based ethosomes dissolved MNs in 15 min, compared to 30 min for other MNs. Skin deposition studies showed greater drug deposition (up to 10 µg/patch) and enhanced skin permeation of FENR (up to 40 µg) with Method 2. In-vivo studies in rats demonstrated that oral administration resulted in plasma FENR levels below 10 ng/g in the first three hours, whereas MN administration delayed delivery, reaching a maximum plasma concentration of 52 ng/g at 48 h. Skin deposition of FENR from MNs decreased from 3 µg/g on day 1 to <0.3 µg/g by the last day. This study indicates that MNs are a potential minimally invasive dosage form for delivering FENR, offering a new approach for breast cancer chemoprevention.

Anticancer Effects of Secoiridoids-A Scoping Review of the Molecular Mechanisms behind the Chemopreventive Effects of the Olive Tree Components Oleocanthal, Oleacein, and Oleuropein.

The olive tree (Olea europaea) and olive oil hold significant cultural and historical importance in Europe. The health benefits associated with olive oil consumption have been well documented. This paper explores the mechanisms of the anti-cancer effects of olive oil and olive leaf, focusing on their key bioactive compounds, namely oleocanthal, oleacein, and oleuropein. The chemopreventive potential of oleocanthal, oleacein, and oleuropein is comprehensively examined through this systematic review. We conducted a systematic literature search to identify eligible articles from Scopus, PubMed, and Web of Science databases published up to 10 October 2023. Among 4037 identified articles, there were 88 eligible articles describing mechanisms of chemopreventive effects of oleocanthal, oleacein, and oleuropein. These compounds have the ability to inhibit cell proliferation, induce cell death (apoptosis, autophagy, and necrosis), inhibit angiogenesis, suppress tumor metastasis, and modulate cancer-associated signalling pathways. Additionally, oleocanthal and oleuropein were also reported to disrupt redox hemostasis. This review provides insights into the chemopreventive mechanisms of O. europaea-derived secoiridoids, shedding light on their role in chemoprevention. The bioactivities summarized in the paper support the epidemiological evidence demonstrating a negative correlation between olive oil consumption and cancer risk. Furthermore, the mapped and summarized secondary signalling pathways may provide information to elucidate new synergies with other chemopreventive agents to complement chemotherapies and develop novel nutrition-based anti-cancer approaches.

Modulation of energetic and lipid pathways by curcumin as a potential chemopreventive strategy in human prostate cancer cells.

In Western industrialized countries, prostate cancer (PCa) is the second most common malignant disease and prevalent cause of death for men. Epidemiological studies have shown that curcumin (CUR) either prevents PCa initiation or delays its progression to a more aggressive and treatment-refractory form, thus reducing related mortality. Our previous studies have proven the anticancer, antioxidant, and anti-inflammatory properties of CUR on PCa cells. However, there are few reports of the effect of CUR on energy and lipid pathways in PCa. Herein, we show that CUR can modulate the two metabolic energy pathways, increasing glycolytic reserve and reducing oxidative phosphorylation. Moreover, through the regulation of key enzymes and proteins, CUR affected the lipid pathway in PC-3 to a greater extent compared to the healthy PNT-2 cells. According to molecular docking investigations, the CUR activity in PCa may be mediated by the direct binding to the pyruvate dehydrogenase (PDHA1) enzyme, which is essential for regulating the appropriate mitochondrial activity. Taken together, our results shed light on the mechanism of action of CUR in the PCa cell metabolism and provide evidence of its potential value as an anticancer metabolic modulator, paving opportunities for novel therapeutic strategies.

The monthly trends of malaria cases in children under 5 years of age in Guinea: comparative analysis between a seasonal malaria chemoprevention (SMC) and a non-SMC health district.

BACKGROUND: The Republic of Guinea, where malaria represents the leading cause of morbidity and mortality among children, the seasonal malaria chemoprevention (SMC) is deployed only in areas with very seasonal modes of transmission. It should target children at the highest risk of serious illness. The objective of the study was to prevent uncomplicated and serious cases of malaria in the target population. This study aimed to analyse the monthly trends in malaria-related morbidity among children under the age of 5 in Guinea. METHODS: This was a quasi-experimental study with routine data from the National Health Information System (SNIS). The two districts Mamou (the SMC intervention site) and Kindia (the control site) were selected to compare the monthly trends in malaria cases among children under the age of 5, from July to October, covering the years from 2015 to 2020. The statistical analysis used interrupted time series to estimate the effects of the SMC. RESULTS: The SMC programme contributed to a significant average reduction in the number of malaria cases of 225 cases per month in the intervention district (95% CI - 362 to - 88; p = 0.002), compared to the control district. However, the study also revealed that the effect of SMC varied between cycles, presenting different monthly malaria cases. CONCLUSION: The SMC contributed to a significant reduction in malaria cases among children under the age of 5 in the health district of Mamou from 2018 to 2020. However, this reduction varied by monthly SMC cycle. This study suggests extending the SMC in other areas with high perennial seasonal transmission respecting the World Health Organization SMC eligibility criteria, as a strategy in the dynamic of reducing malaria cases in children under the age of 5 in Guinea.

Efficacy and safety of a 0.05 % nanoencapsulated imiquimod hydrogel for the treatment of actinic cheilitis: Drug release analysis and clinical study.

Actinic cheilitis (AC) is a lip disorder, with no standard treatment. Imiquimod (IMIQ) is an immunomodulator that treat precancerous lesions; however, its commercial form causes severe adverse effects. This study aimed to assess IMQ release from a chitosan hydrogel containing 0.05 % nanoencapsulated (NANO) imiquimod (IMIQ-0.05 %-NANO) and its efficacy in AC treatment. The hydrogels were prepared by incorporating chitosan into polymeric nanocapsules (NCimiq) loaded with IMQ, produced using the interfacial deposition of preformed polymer method. IMQ release was evaluated using automated Franz Cells. A triple-blind randomized controlled trial (49 subjects) compared the efficacy of: IMIQ-0.05 %-NANO, 5 % free imiquimod (IMIQ-5 %), 0.05 % free imiquimod (IMIQ-0.05 %), and placebo hydrogel. The IMIQ-NANO-0.05 % and IMIQ-5 % groups exhibited significantly higher rates of clinical improvement (p < 0.05); however, the IMIQ-5 % group experienced more adverse effects (92.3 % of subjects) compared to other groups (p < 0.05). In conclusion, in the studied sample, IMIQ-NANO-0.05 % was a safe and effective option to treat AC.

Using the role model approach to optimise caregiver administration of sulfadoxine-pyrimethamine amodiaquine to children aged 3-59 months in Burkina Faso, Chad and Togo: findings from an evaluation.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a World Health Organization-recommended intervention for the prevention of malaria among children at high risk in areas with seasonal transmission. During the coronavirus disease 2019 (COVID-19) pandemic, SMC drug distribution was rapidly adapted to reduce contact and mitigate the risk of transmission between communities and community distributors, with caregivers administering doses. To address the challenges and find local solutions to improve administration and adherence, the role model approach was designed, implemented and evaluated in selected communities of Burkina Faso, Chad and Togo. This paper describes the results of this evaluation. METHODS: Focus group discussions were held with primary caregivers in all three countries to understand their perceptions of the approach's acceptability and feasibility. In Burkina Faso and Togo, household surveys assessed the characteristics of caregivers reached by role model activities. Key indicators on SMC coverage and adherence allowed for an assessment of caregiver engagement outcomes related to participation in activities. Statistical associations between participation in study's activities and caregiver beliefs related to SMC had been tested. RESULTS: The majority of caregivers believed the approach to have a positive effect on drug administration, with most adopting the promoted strategies. Greater involvement of fathers in drug administration and acknowledgement of their joint responsibility was a notable positive outcome. However, several barriers to participation were noted and there was criticism of the group approach. In Burkina Faso and Togo, end-of-round survey results revealed that 98.4% of respondents agreed the approach improved their knowledge and skills in malaria prevention, while 100% expressed a desire to continue practicing the behaviours learned. However, there was a relatively low level of awareness of the approach among communities. Participation was strongly associated with participants' self-reported belief in ease of remembering to administer, and ease of administering, SMC medicines. CONCLUSION: Caregivers perceived the role model approach to be beneficial in aiding drug administration, with other positive impacts also reported. Replication and scale-up should utilize the most popular communication channels and existing community structures to ensure activities are promoted effectively. A mixture of group and one-on-one approaches should be used where appropriate and feasible.

Anticancer potential of hydroxycinnamic acids: mechanisms, bioavailability, and therapeutic applications.

Hydroxycinnamic acids (HCAs) are plant compounds with anticancer potential due to their antioxidant, anti-inflammatory, apoptosis-inducing, and proliferation-inhibiting effects. This review aims to consolidate and analyze current knowledge on the anticancer effects of HCAs, exploring their mechanisms of action, bioavailability challenges, and potential therapeutic applications. A comprehensive literature search on PubMed/MedLine, Scopus, Web of Science, and Google Scholar focused on the anticancer properties, mechanisms, bioavailability, and safety profiles of HCAs. Studies have shown that HCAs, such as caffeic acid, ferulic acid, and sinapic acid, inhibit the growth of cancer cells in vitro and in vivo and sensitize cancer cells to chemotherapy and radiation therapy. These effects are mediated by mechanisms including the inhibition of cell survival pathways, modulation of gene expression, and induction of oxidative stress and DNA damage. Additionally, several studies have demonstrated that HCAs exhibit selective toxicity, with a higher propensity to induce cell death in cancerous cells compared to normal cells. However, the toxicity profile of HCAs can vary depending on the specific compound, dosage, and experimental conditions. The anticancer properties of HCAs suggest potential applications in cancer prevention and treatment. However, it is essential to distinguish between their use as dietary supplements and therapeutic agents, as the dosage and formulation suitable for dietary supplements may be insufficient for therapeutic purposes. The regulatory and practical implications of using HCAs in these different contexts require careful consideration. Further research is needed to determine appropriate dosages, formulations, long-term effects, and regulatory frameworks for HCAs as both dietary supplements and therapeutic agents.

Gastrointestinal Health Benefits of Sorghum Phenolics.

Sorghum is considered a promising food security crop and remarkable rich source of bioactive components including phenolic acids, flavonoids, and tannins. Sorghum phenolics exhibited numerous protective effects against multiple chronic diseases. However, there is no review of the effects of sorghum phenolics on gastrointestinal (GI) health. Specifically, recent studies have highly suggested that sorghum phenolics can maintain gastrointestinal homeostasis and enhance microbial diversity and richness. Furthermore, sorghum phenolics showed GI anticancer effects in both in vitro and in vivo studies against colorectal and esophageal cancers. Treatment of GI related human cancer cell lines stimulated apoptosis and suppressed proliferation. Sorghum intake and extracts treatments reduced intestinal oxidative stress and inflammatory mediators in human and in vivo studies. In addition, understanding the role and mechanisms underlying gastrointestinal health benefits of sorghum phenolics is crucial to determine treatment strategies of different GI diseases.

Comparative Analysis of Polyphenolic Profile and Chemopreventive Potential of Hemp Sprouts, Leaves, and Flowers of the Sofia Variety.

This study investigates the phytochemical composition and biological activities of hemp (Cannabis sativa L.) leaves, flowers' methanolic extracts from the Sofia variety, and its sprouts cultivated under different light conditions (natural light, darkness, blue, and white LED light for 5, 7, and 9 days). Phytochemical analysis using HPLC identified four key polyphenolic compounds in sprouts' extracts: chlorogenic, caffeic, and gallic acids, and myricetin, with a predomination of the chlorogenic acid. In contrast, leaves and flowers' extracts contained cannflavins A and B and chlorogenic, p-coumaric, and ferulic acids, with a significant presence of isochlorogenic acid. Antioxidant capacity, assessed by FRAP method, revealed higher antioxidant potential in leaves compared to flowers and sprouts, with sprouts grown under blue and white LED lights exhibiting the highest activity. Cytotoxic activity was evaluated on human colon cancer cell lines (HT29, HCT116, DLD-1) and normal colon epithelial cells (CCD 841 CoN). Results demonstrated significant and selective cytotoxicity against cancer cell lines, with leaves showing more pronounced effects than flowers, and sprouts only moderate activity. All samples revealed an anti-inflammatory effect in vitro. To conclude, sprouts, leaves, and flowers of the Sofia hemp may be considered promising products for chemoprevention in the future.

Metformin in Chemoprevention of Lung Cancer: A Retrospective Population-Based Cohort Study in Lithuania.

Background and Objectives: This study aimed to evaluate the potential chemopreventive effect of antidiabetic medications, specifically metformin and pioglitazone, on lung cancer in patients with type 2 diabetes mellitus (T2DM). Additionally, the potential dose-response relationship for metformin use was analyzed. Methods: We conducted a retrospective cohort study utilizing comprehensive national health insurance and cancer registry databases to gather a large cohort of T2DM patients. Cox proportional hazards regression models were used to assess the risk of lung cancer across different antidiabetic medication groups, adjusting for potential confounders such as age and gender. A dose-response analysis was conducted for metformin users. Results: Our results indicated that metformin users had a significantly lower lung cancer risk than the reference group (HR = 0.69, 95% CI [0.55-0.86], p = 0.001). The risk reduction increased with higher cumulative metformin doses: a metformin cumulative dose between 1,370,000 and 2,976,000 had an HR of 0.61 (95% CI [0.49-0.75], p < 0.001) vs. cumulative metformin dose >2,976,000 which had an HR of 0.35 (95% CI [0.21-0.59], p < 0.001). No significant association between pioglitazone use and the risk of lung cancer was found (HR = 1.00, 95% CI [0.25-4.02]). Conclusions: This study shows that metformin may have a dose-dependent chemopreventive effect against lung cancer in T2DM, while the impact of pioglitazone remains unclear and requires further investigation.

Natural polyphenols: A protective approach to reduce colorectal cancer.

Background: A form of cancer that affects the rectum or colon (large intestine) is called colorectal cancer (CRC). The main risk factors for CRC include dietary, lifestyle, and environmental variables. Currently natural polyphenols have demonstrated impressive anticarcinogenic capabilities. Objective: The main objective was to provide an updated, thorough assessment of the defensive mechanism of natural polyphenols for the global suppression of colorectal cancer. More precisely, this study aimed to analyze a set of chosen polyphenols with demonstrated safety, effectiveness, and biochemical defense mechanism on colon cancer models in order to facilitate future research. Methods: This review was carried out with purposefully attentive and often updated scientific databases, including PubMed, Scopus, Science Direct, and Web of Science. After selecting approximately 178 potentially relevant papers based just on abstracts, 145 studies were meticulously reviewed and discussed. Results: The outcomes disclosed that anti-CRC mechanisms of natural polyphenols involved the control of several molecular and signaling pathways. Natural polyphenols have also been shown to have the ability to limit the growth and genesis of tumors via altering the gut microbiota and cancer stem cells. However, the biochemical uses of many natural polyphenols have remained restricted because of their truncated water solubility and low bioavailability. In order to attain synergistic properties it is recommended to combine the use of different natural polyphenols because of their low bioavailability and volatility. However, the use of lipid-based nano- and micro-carriers also may be helpful to solve these problems with efficient distribution system to target sites. Conclusion: In conclusion, the use of polyphenols for CRC treatment appears promising. To ascertain their efficacy, more clinical research is anticipated.

Angelica sinensis polysaccharides promote extramedullary stress erythropoiesis via ameliorating splenic glycolysis and EPO/STAT5 signaling-regulated macrophages.

Conventional treatments exhibit various side effects on chronic stress anemia. Extramedullary stress erythropoiesis is a compensatory mechanism, which may effectively counteract anemia. Angelica sinensis polysaccharides (ASP) are the main active ingredient found in Angelica sinensis and exhibit antioxidant and hematopoietic effects. However, the effects of ASP on extramedullary stress erythropoiesis remain to be unclear. Here, we demonstrated the protective effects of ASP on chemotherapeutic drug 5-fluorouracil (5-FU)-induced decline in peripheral blood parameters such as RBC counts, HGB, HCT, and MCH, and the decline of BFU-E colony enumeration in the bone marrow. Meanwhile, ASP promoted extramedullary erythropoiesis, increasing cellular proliferation in the splenic red pulp and cyclin D1 protein expression, abrogating phase G0/G1 arrest of c-kit+ cells in mouse spleen. RT-qPCR and immunohistochemistry further revealed that ASP increased macrophage chemokine Ccl2 genetic expression and the number of F4/80+ macrophages in the spleen. The colony-forming assay showed that ASP significantly increased splenic BFU-E. Furthermore, we found that ASP facilitated glycolytic genes including Hk2, Pgk1, Pkm, Pdk1, and Ldha via PI3K/Akt/HIF2α signaling in the spleen. Subsequently, ASP declined pro-proinflammatory factor IL-1ß, whereas upregulating erythroid proliferation-associated genes Gdf15, Bmp4, Wnt2b, and Wnt8a. Moreover, ASP facilitated EPO/STAT5 signaling in splenic macrophages, thus enhancing erythroid lineage Gata2 genetic expression. Our study indicated that ASP may improve glycolysis, promoting the activity of splenic macrophages, subsequently promoting erythroid progenitor cell expansion. Additionally, ASP facilitates erythroid differentiation via macrophage-mediated EpoR/STAT5 signaling; suggesting it might be a promising strategy for stress anemia treatment.