BRBiomedical Reports2049-94342049-9442D.A. SpandidosBR-17-3-0155810.3892/br.2022.1558ReviewPotential role of β-carotene-modulated autophagy in puerperal breast inflammation (Review)Tinia HasiannaStella1GunadiJulia Windi2RohmawatyEnny3LesmanaRonny4Doctoral Program of Medical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java 45363, IndonesiaDepartment of Physiology, Faculty of Medicine, Universitas Kristen Maranatha, Bandung, West Java 40164, IndonesiaPharmacology Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java 45363, IndonesiaPhysiology Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java 45363, IndonesiaCorrespondence to: Dr Ronny Lesmana, Physiology Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang, KM.21, Hegarmanah, Kec. Jatinangor, Kabupaten Sumedang, West Java 45363, Indonesia ronny@unpad.ac.id
Puerperal breast inflammation is common in the first 6-8 weeks postpartum, and without proper management, may lead to a decrease in breastmilk production and early cessation of breastfeeding. Recent studies showed that carotenoids decrease the severity of puerperal breast inflammation. This article summarizes the significant findings on β-carotene with a potential role as an autophagy modulator in puerperal breast inflammation. Puerperal milk stasis causes an increase in inflammatory cytokines and inflammatory cells, leading to reactive oxygen species (ROS) activation that causes oxidative damage to mammary glands and affects breast milk secretion. β-carotene has an anti-inflammatory effect related to its ROS-scavenging activity and modulates autophagy, thus stimulating the removal of damaged cellular structures and supporting milk gland survival. β-carotene modulates autophagy through phosphorylation of NF-κB, JNK, p38, Akt, and Nrf2, affects the ratio of Microtubule-associated protein 1A/1B-light chain 3 (LC3)-II/LC3-I, and has a role in the regulation of the JAK2/STAT3, PI2K/Akt/mTOR and AMPK pathways. Although the in vitro and in vivo studies showed promising results, further studies on humans are required to better conclude the potential role of β-carotene in managing puerperal breast inflammation.
autophagybreast milkinflammationβ-caroteneROSpuerperalFunding: This study was supported by a WCR grant from the Ministry of Education and Culture (grant no. 1207/UN6.3.1/PT.00/2021) and an internal grant from the Universitas Kristen Maranatha (grant no. 034/SK/ADD/UKM/VI/2021).1. Introduction
In exclusive breastfeeding (EBF), breast milk becomes the only source of nutrition for infants without any other liquids or solids (1). EBF is beneficial for the baby as well as the mother (2-4), and the World Health Organization (WHO) and United Nations Children's Fund (UNICEF) recommend EBF for the first 6 months of an infant's life and should then be continued for 2 years or more (5). However, in 2020, only 44% of babies under 6 months worldwide received exclusive breastfeeding (2). Many factors influence the cessation of breastfeeding, including insufficient milk supply (6-8), self-weaning (9), primiparity (10), mother/infant separation (6), inconvenience/fatigue due to breastfeeding (11), and inflammatory breast diseases such as mastitis (12,13).
Mastitis is inflammation of the breast, with or without infection (14). Worldwide, -20% of women suffer from mastitis whilst breastfeeding (15). The majority of cases occur in the first 6-8 weeks postpartum, and approximately one-third of women experience a recurrent episode (16,17). Up to 3% of cases of mastitis develop into a breast abscess (18). Puerperal breast inflammation starts with insufficient breast emptying (milk stasis) (12). This causes an increase in intraductal pressure and opens milk duct epithelial cells' intercellular junctions. Breast milk further moves into the connective tissue and generates a sterile inflammatory environment, from which a secondary bacterial infection may follow. Without proper treatment, this can progress to a mammary abscess that requires surgical treatment (12). Several studies indicate that puerperal breast inflammation is correlated with the cessation of breastfeeding (12,16).
Milk stasis increases the levels of inflammatory cytokines (TNF-α, IL-1b, IL-6, IL-8), neutrophils, macrophages, lymphocytes, eosinophils, and various epithelial cells of mammary tissue (19). Cytokines further activate reactive oxygen species (ROS), which play a complex role in the inflammatory process (20). The excessive buildup of ROS disrupts cellular homeostasis, causes oxidative stress and mitochondrial dysfunction, and induces autophagy (21). The oxidative damage in breast inflammation can cause mammary gland cell death and affects breast milk secretions (15).
Antioxidant supplementation decreases the incidence, duration, and severity of mastitis (22,23). Antioxidants scavenge free radicals and inhibit the activity of oxidizing enzymes, thus reducing the damage caused by free radicals (23). Some herbal treatments with high antioxidant and anti-inflammatory activities are widely used in mastitis treatment, such as Moringa leaves (24), binahong leaves (Anredera cordifolia) (25), cherry leaf decoction (Muntingia calabura L.) (26), Red Algae Eucheuma Spinosum (27), Macroalgae Extract (28), garlic, manjakani fruit, betel leaf, white turmeric, and eucalyptus leaves (29). Carotenoids are another type of active substance found in plants with high antioxidant contents and anti-inflammatory effects, but have not been as widely explored as treatment or prevention options for mastitis. Previous studies showed that increasing serum retinol concentrations in dairy cows was associated with a decreased risk of clinical mastitis, and low concentrations of vitamin A and β-carotene increased the severity of mastitis (30,31). Carotenoids have a significant impact on maintaining the health of epithelial tissue and the stability of mucosal surface integrity (32).
Carotenoids are yellow-orange pigments that are abundantly present in several plants, marine invertebrates, and microorganisms. There are ~50 carotenoids consumed in a standard human diet, but only 20 have been identified in the human plasma, with β-carotene, α-carotene, lycopene, and cryptoxanthin as the most common (33). Carotenoids have potent antioxidant, anti-inflammatory, and immunomodulatory abilities. (34) β-carotene is the most common carotenoid, which is also known as pro-vitamin A, and is one of the most abundant carotenoids in the human blood with several health-promoting properties (35,36). The anti-inflammatory effects of β-carotene have been demonstrated in multiple systems (37,38).
Previous studies showed that β-carotene and vitamin A reduce the risk of puerperal breast inflammation (39). Low concentrations of plasma vitamin A (<80 µg/100 ml) and β-carotene (<200 µg/100 ml) correlated with the severity of mastitis (23,30). Animal studies in cows showed that mastitic cows, as determined using the California Mastitis Test score, had significantly lower plasma vitamin A and β-carotene concentrations than healthy cows (32). To reduce the risk of mastitis, a dry and lactating cow's diet should contain 110 IU/kg bwt/day of vitamin A (22). Plasma concentrations of β-carotene >3 mg/l promoted udder health in dairy cattle (40). Low concentrations of plasma vitamin A (<0.8 µg/ml) and β-carotene (<2 µg/ml) were linked with the severity of mastitis. However, unfortunately, there is minimal data regarding the optimal dose of β-carotene for postpartum women in correlation to treatment or prevention of puerperal breast inflammation.
As an antioxidant, β-carotene suppresses intracellular ROS production and reduces antioxidative enzyme activity (36,41,42). Β-carotene supplementation exerts a stabilizing effect on polymorphonuclear cells such as neutrophils, eosinophils, and basophils, and optimizes lymphocyte function (23). The inflammatory response in mastitis and the role of β-carotene as an antioxidant is summarized in Fig. 1. However, there is limited study on the role of β-carotene in correlation with autophagy modulation and puerperal breast inflammation. The present review summarizes the major findings on β-carotene as a potential autophagy modulator in puerperal breast inflammation.
2. Autophagy in puerperal breast inflammation
Breast fullness or breast engorgement is a part of lactogenesis in the postpartum period. This fullness manifests ~36 h postpartum and occurs 3-7 days postpartum, with primiparous mothers most commonly affected (43). In breast engorgement, the breast undergoes increased vascularity, congestion, milk accumulation, and oedema (43,44).
In milk stasis, the accumulation of breast milk disrupts vascularisation and causes tissue hypoxia (19). Tissue hypoxia induces the transcription of Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and induction of NIX following HIF1 activation (21). This in turn competes with beclin-1 for the binding of Bcl-2, and the release of beclin-1 is triggered, followed by autophagy (45). PERK, an ER stress sensor, is stimulated and, later in the process, stimulates the expression of Microtubule-associated protein 1A/1B-light chain 3 (LC3) and autophagy gene (ATG)5, both of which are ATGs (46). Oxidative stress triggers FOXO3 and then stimulates the transcription of LC3, BNIP, and NRF2, which induces transcription of p62(21). The process mentioned above positively modulates autophagy. p53 has a role in activating DNA damage-regulated autophagy modulator and sestrins, two autophagy-related genes that positively regulate autophagy (47). TP53-Induced Glycolysis and Apoptosis Regulator negatively regulates autophagy, but while it is a p53 target, it possesses a p53-independent function in autophagy (21). AMPK is also p53-independent, and is activated by sestrins to inhibit mTOR activity and thus induce autophagy (48). ROS constrains ATG4 protease activity and promotes autophagosome formation (21,49).
Milk stasis also results in high oxygen and energy demands and increases ROS production as a result (12). ROS can assist the healing and tissue repair process in moderate concentrations, but in excess, ROS disrupts redox homeostasis and this results in oxidative stress and damage to cell organelles (50). The increase in free radical levels in puerperal breast inflammation is triggered by the increase of neutrophils, macrophages, lymphocytes, eosinophils, and mammary tissue epithelial cells, TNF-α, IL-1b, IL-6, IL-8, and nitric oxide (NO) (51). ROS accumulation triggers endothelial dysfunction and tissue injury in mammary gland tissue, opens inter-endothelial junctions, and stimulates inflammatory cell migration across the endothelial barrier. These cells support the clearance of pathogens, but excessive amounts may also cause tissue injury (52).
ROS is essential in promoting cell autophagy as a critical signalling molecule (53). Autophagy facilitates the degradation of intracellular proteins and organelles via lysosomes. ROS induces autophagy, and autophagy reduces oxidative damage (49). During inflammation, the NRF2 transcription factor enhances p62 expression, and p62, in turn, creates a positive feedback loop for NRF2(49).
Autophagy is involved in inflammatory reactions and barrier repair by degrading cell components via the lysosomal pathway (54). Autophagosomes are formed during autophagy to encapsulate protein aggregates and/or damaged organelles. Hydrolytic enzymes degrade the damaged organelles after autophagosome fusion with a lysosome (55). Autophagy is stimulated by any stressor that causes cellular stress, including hypoxia (56), nutrient deficiency (57), chemical exposure (56), excessive ROS (58), or intracellular pathogens (59). Autophagy is a cellular recycling process that involves potential cell death outcomes and functions to protect cells from apoptosis (60).
Four sub-groups of ATGs regulate autophagy; namely Atg1/unc-51-like kinase (ULK) complex, two ubiquitin-like proteins [Atg12 and Atg8/microtubule-associated protein light chain 3 (LC3)] conjugation systems, the class III phosphatidylinositol 3-kinase (PI3K)/vacuolar protein sorting 34 (Vps34) complex I, and two transmembrane proteins, Atg9/mAtg9 and VMP1(61). ROS induces autophagy through two methods, directly and indirectly. The direct regulation is established through modulation of the involved proteins, such as Atg4, Atg5, and Beclin. Indirect regulation is achieved through autophagy-related signaling pathways, such as the mTOR, mitogen-activated protein kinase (MAPK), p38, ERK, and JNK (62). ROS inhibits mTOR activity and activates AMPK, and initiates autophagy through the increase of Vps34 complex activity (50). Activation of the p53 pathway causes JNK and Sestrin2 activation. JNK and Sestrin2 bind to TSC1/TSC2 and induce autophagy (62). ROS also promotes LC3-II translocation through the inhibition of ATG4, which converts LC3-II into LC3-I (63).
Excessive ROS production triggers cell death extrinsically and intrinsically (52). The extrinsic pathway is mediated via four major cell death receptors; TNF receptor 1, TNF-related apoptosis-inducing ligand receptor (TRAIL-R)1, TRAIL-R2, and the Fas receptor (19). TNFα, Fas ligand, and TRAIL bind to these receptors. TNFα is secreted by activated macrophages and is involved in the increase in inflammatory cytokines (50).
The increase in mitochondrial outer membrane permeability (MOMP) triggers intrinsic pathways of cell death (52). MOMP induces the release of Cytochrome-c (Cyt-c), Smac/Diablo, apoptosis-inducing factor (AIF), and endonuclease G, which play a role in cell death in either a caspase-dependent or -independent manner (64). This increase in MOMP is stimulated by an excessive entry of calcium and a high level of oxidative stress, which causes mitochondrial membrane depolarization (52). An apoptosome is formed as Cyt-c attaches to apoptosis activation factor-1 and this recruits the initiator pro-caspase 9. Caspase-9 functions to trigger caspase-3. (58) Smac/Diablo also plays a role in activating effector caspases by eliminating the blockage of the inhibitor of apoptosis proteins (50). After AIF is activated, DNA condensation and cleavage induction occur (52). The primary determinant of cell death is the mitochondrial release of Cyt-c. BH3 interacting-domain death agonist, a pro-apoptotic member of the Bcl-2 family, cleaves caspase-8 and increases MOMP, followed by oligomerization of pro-apoptotic proteins Bax/Bak which induce Cyt-c release (52).
The release of Cyt-c is triggered by oxidative stress, facilitates electron transport chain uncoupling, and increases mitochondrial ROS production/levels. Cardiolipin (CL) is an anionic phospholipid that aids Cyt-c anchoring to the inner mitochondrial membrane. The affinity binding with Cyt-c is reduced in oxidative stress due to CL oxidation. CL-bound mitochondrial Cyt-c catalyses CL peroxidation, and this phenomenon can occur at a lower H2O2 concentration when bound to CL-containing membranes. Thus, oxidative stress stimulates cell death through the peroxidase activity of Cyt-c and CL peroxidation (52).
3. The role of β-carotene in the modulation of autophagy in puerperal breast inflammation
Mastitis is related to an inadequate intake of vitamin E, selenium, β-carotene, and vitamin A (65). Antioxidants decrease the duration, incidence, and severity of mastitis (23). Β-carotene and vitamin A can protect mammary tissues and milk from the destructive effects of free radicals. Food containing vitamin A and β-carotene contributed to a reduced incidence of mastitis during the early dry period in cows (23).
Carotene exhibits a range of important functions, and the numerous benefits of carotenoids are related to their antioxidant and anti-inflammatory effects. Vitamin A and β-carotene trigger the generation of immune cells and prevent the initiation of the fatty acid peroxidation chain reaction (39). Antioxidants directly scavenge free radicals and inhibit the activity of oxidizing enzymes, thus protecting the body from free radicals (23). β-carotene quenches singlet oxygen and neutralizes lipid peroxyl radicals. It has been previously shown that 800 mg/kg body weight of algae Spirulina fusiformis, containing β-carotene and SOD, reduced the levels of almost all oxidative stress biomarkers measured in the study. Serum lipid hydroperoxide levels were reduced by 45%, and leukocyte MDA levels were reduced by 50% (66). β-carotene has a long system of conjugated double bonds with π-electrons delocalized over the length of the polyene chain, providing it with an effective ability to scavenge ROS (67). Studies have shown that β-carotene significantly inhibited intracellular ROS production (30,32,42).
In a study investigating the effects of β-carotene in corneal endothelial cells, a film scaffold incorporated with an appropriate amount of β-carotene showed enhanced initial cell adhesion, proliferation, proper cell morphology, and gene expression compared with a pristine silk fibroin (SF) scaffold. β-carotene in the SF film scaffold enhanced the function of the ATPase pump of corneal endothelial cells (68). In infected tissues, β-carotene decreases the expression of inflammatory mediators, MAPKs, and redox-sensitive transcription factors (69).
β-carotene is widely available in common foodstuffs with broad affordability for the general community. Using β-carotene for postpartum mothers can reduce the occurrence of severe mastitis and maternal and infant morbidity and mortality (32). Although β-carotene and vitamin A serve essential roles in immunity, the latest recommendation from WHO states that vitamin A supplementation for postpartum mothers is not recommended as a public health intervention to prevent maternal and infant morbidity and mortality. Postpartum mothers must obtain a balanced healthy nutritional intake to obtain an adequate amount of various nutrients needed (70,71). Dietary dosage of carotenoids may promote health, but supplementation with high doses may be associated with adverse effects, especially in smokers or subjects exposed to environmental pollutants (72).
β-carotene is abundantly present in green leafy vegetables, carrots, pumpkins, papaya and red palm oil, milk, liver, and fish oil (71). It has been shown that consuming fruit and vegetable sources of β-carotene increases the vitamin A status of lactating women (73). Vitamin A is recommended at 1,300 mcg retinol activity equivalent (RAE) daily. One mcg RAE is equivalent to 2 mcg supplemental β-carotene or 12 mcg dietary β-carotene (74). However, several factors affect the bioavailability and equivalency of vitamin A, such as food processing techniques and the specific dietary intake of an individual (73).
β-carotene plays an essential role in modulating autophagy. In LPS-induced rat intestinal tissue, β-carotene treatment significantly reduced the LPS-mediated phosphorylation of JAK2/STAT3 and NF-κB (59), and significantly suppressed the LPS-induced phosphorylation of JNK and p38(41) The levels of p-Akt are decreased following LPS treatment, and β-carotene significantly upregulated the phosphorylation of Akt. (41) It also significantly suppressed the ratio of LC3-II/LC3-I, which was upregulated by LPS (41). LC3 consists of LC3-I and LC3-II. LC3-II is positively correlated with the degree of autophagy, and is used as an autophagy marker. LC3-I is present in the cytoplasm where a small segment of the polypeptide is cleaved and is converted into LC3-II (75). β-carotene modulates LPS-induced autophagy and inhibits the activity of the related inflammation pathways (41).
However, another study showed that oral β-carotene supplementation daily for 14 days in male ddY mice (8 wk old) did not alter the ratio of LC3-II to LC3-I in the β-carotene group (76). In H9C2 cell lines, low-dose β-carotene induces autophagy, as shown by a decrease in LC3II and p62 levels. NF-κB protein levels were lowered, and Nrf2 was triggered, but no significant alteration of Nrf1 was observed. A low dose of βcarotene stimulates cell viability by suppressing the apoptotic signals carried by caspase 3 and 9. Furthermore, a low dose of β-carotene increases cell viability through autophagy stimulation, inhibition of pro-inflammatory factors, and suppression of apoptosis (36).
Treatment of SAOs and Caco-2, cell lines derived from a human osteosarcoma and colon adenocarcinoma, respectively, using 200-400 µg/ml carotene extract nanoemulsion (CEN) triggered autophagy, based on the increase of autophagosome formation, increased expression of LC3-II, modulation of autophagic flux, increased phosphorylation, and an increase in the levels of the active form of AMPK kinase pAMPKThr172, which activates AMPK and induces autophagy (33). β-carotene is the major carotenoid in CEN (33). However, treatment with the same dose of β-carotene alone did not show the same effect as when combined in the CEN, indicating a dose-dependent effect or a synergism of different components in CEN (33).
The PI3K/Akt/mTOR signaling pathway is important in cell survival and autophagy (77). Inhibition of this signaling pathway induces autophagy. Consistent with previous studies, β-carotene treatment was also shown to decrease Advanced Glycation End products (AGE)-induced elevation of the LC3II/LC3I ratio and the number of LC3-labeled puncta. The protective effect of β-carotene in AGE-induced H9c2 cells was achieved through the activation of the PI3K/Akt/mTOR signaling pathway (42). Fig. 2 summarizes the pathways affected by β-carotene as an autophagy modulator.
β-carotene shows promising potential as an autophagy modulator in increasing mammary gland cell survival and maintaining breastmilk production. Further research is required to understand the role of β-carotene in puerperal breast inflammation management.
4. Conclusion
Puerperal breast inflammation can cause result in cessation of breastfeeding due to mammary gland damage and a decrease in milk production. Excessive ROS levels in puerperal breast inflammation results in oxidative damage and induces improper autophagy. β-carotene has ROS-scavenging activity and the ability to modulate autophagy through the suppression of JAK2/STAT3, NF-κB, JNK, and p38 phosphorylation, suppressing the ratio of LC3-II/LC3-I and upregulating the phosphorylation of Akt. Further studies are required to conclude the full potential of β-carotene in puerperal breast inflammation.
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Authors' contributions
STH, RL, JWG, and ER performed the literature search and assisted in drafting and revising the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.
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Competing interests
The authors declare that they have no competing interests.
ReferencesSilvaFVDiasFCostaGCamposMDGChamomile reveals to be a potent galactogogue: The unexpected effect3111611820182800051910.1080/14767058.2016.1274300World Health Organization (WHO) and United Nations Children's Fund (UNICEF): Indicators for Assessing Infant and Young Child Feeding Practices. Vol. WHA55 A55/. WHO, Geneva, p122, 2021. http://apps.who.int/iris/bitstream/handle/10665/44306/9789241599290_eng.pdf?sequence=1%0Ahttp://whqlibdoc.who.int/publications/2008/9789241596664_eng.pdf%5Cnhttp://www.unicef.org/programme/breastfeeding/innocenti.htm%5Cnhttp://innocenti15.net/declaration.MoscaFGiannìMLHuman milk: Composition and health benefits3915520172867307610.4081/pmc.2017.155HenrickBMNagKYaoXDDrannikAGAldrovandiGMRosenthalKLMilk matters: Soluble toll-like receptor 2 (sTLR2) in breast milk significantly inhibits HIV-1 infection and inflammation7e4013820122279223010.1371/journal.pone.0040138World Health Organization and United Nations Children's Fund (UNICEF): Baby-friendly hospital initiative: revised, updated and expanded for integrated care. WHO, Geneva, 2009. https://apps.who.int/iris/handle/10665/43593.ChangPCLiSFYangHYWangLCWengCYChenKFChenWFanSYFactors associated with cessation of exclusive breastfeeding at 1 and 2 months postpartum in Taiwan141820193108049310.1186/s13006-019-0213-1GrzeskowiakLEWlodekMEGeddesDTWhat evidence do we have for pharmaceutical galactagogues in the treatment of lactation insufficiency?-a narrative review1197420193103537610.3390/nu11050974LouZZengGHuangLWangYZhouLKavanaghKFMaternal reported indicators and causes of insufficient milk supply30466473quiz 511-220142503102910.1177/0890334414542685BrownCRLDoddsLLeggeABryantonJSemenicSFactors influencing the reasons why mothers stop breastfeeding105e179e18520142516583610.17269/cjph.105.4244GrzeskowiakLEDaltonJAFielderALFactors associated with domperidone use as a galactogogue at an australian tertiary teaching hospital3124925320152535578510.1177/0890334414557175RiordanJBibbDMillerMRawlinsTPredicting breastfeeding duration using the LATCH breastfeeding assessment tool17202320011184784710.1177/089033440101700105WöckelAAbou-DaknMBeggelAArckPInflammatory breast diseases during lactation: Health effects on the newborn-A literature review200829876020081843723210.1155/2008/298760SchwartzKD'ArcyHJGillespieBBoboJLongewayMFoxmanBFactors associated with weaning in the first 3 months postpartum51439444200212019051BondDMMorrisJMNassarNStudy protocol: Evaluation of the probiotic Lactobacillus Fermentum CECT5716 for the prevention of mastitis in breastfeeding women: A randomised controlled trial1714820172852598410.1186/s12884-017-1330-8PevznerMDahanAMastitis while breastfeeding: Prevention, the importance of proper treatment, and potential complications9232820203270783210.3390/jcm9082328ScottJARobertsonMFitzpatrickJKnightCMulhollandSOccurrence of lactational mastitis and medical management: A prospective cohort study in Glasgow32120081872148710.1186/1746-4358-3-21CooklinARAmirLHNguyenCDBuckMLCullinaneMFisherJRWDonathSMCASTLE Study TeamPhysical health, breastfeeding problems and maternal mood in the early postpartum: A prospective cohort study2136537420182926464610.1007/s00737-017-0805-yRoysterEMilk quality and mastitis1332016SordilloLMFactors affecting mammary gland immunity and mastitis susceptibility9889992005LiCSolomonsNWScottMEKoskiKGSubclinical mastitis (SCM) and proinflammatory cytokines are associated with mineral and trace element concentrations in human breast milk46556120182941311110.1016/j.jtemb.2017.11.010LiLTanJMiaoYLeiPZhangQROS and Autophagy: Interactions and molecular regulatory mechanisms3561562120152572213110.1007/s10571-015-0166-xYangFLLiXSRole of antioxidant vitamins and trace elements in mastitis in dairy cows2192015EllahMRRole of Free Radicals and Antioxidants in Mastitis3172013KurniantoDInhibitory power of moringa leaf juice (Moringa oleifera) against Staphylococcus aureus and Escherichia coli growth as the etiology of mastitis in cattle (unpublished PhD thesis). Universitas Brawijaya, 2015.WijayantiDArdigurnitaFThe development of binahong leaf as an antiseptic to overcome mastitis in dairy cows in the Giri Mukti herd, Tasikmalaya41481522019https://publikasi.polije.ac.id/index.php/j-dinamika/article/view/1087.KurniawanISarwiyonoSSurjowardojoPThe effect of teat dipping using cherry leaf decoction (Muntingia calabura L.) on the incidence of mastitis2327312010XiaoHZhaoJFangCCaoQXingMLiXHouJJiASongSAdvances in studies on the pharmacological activities of fucoxanthin1863420203332229610.3390/md18120634PutriSUEffect of Macroalgae extract on bacteria Staphylococcus aureus and methicillin resistant Staphylococcus aureus (unpublished PhD thesis). Alauddin Islamic State University, 2016.TriandiniIGAAHRuqqayahSAstutiNLBIn vitro research on plants as natural antibiotics for breast inflammation (Mastitis)4(3)14172018https://sangkareang.org/index.php/SANGKAREANG/article/view/122.LeblancSJHerdtTHSeymourWMDuffieldTFLeslieKEPeripartum serum vitamin E, retinol, and beta-carotene in dairy cattle and their associations with disease8760961920041520264510.3168/jds.S0022-0302(04)73203-8ChewBPHollenLLHillersJKHerlugsonMLRelationship between vitamin A and β-carotene in blood plasma and milk and mastitis in holsteins65211121181982689139010.3168/jds.S0022-0302(82)82469-7HeinrichsAJCostelloSSJonesCMControl of heifer mastitis by nutrition13417217620091894794310.1016/j.vetmic.2008.09.025RussoMMocciaSBilottoSSpagnuoloCDuranteMLenucciMSMitaGVolpeMGAquinoRPRussoGLA carotenoid extract from a Southern Italian cultivar of pumpkin triggers nonprotective autophagy in malignant cells2017746853820172943028410.1155/2017/7468538ZielińskaMAWesołowskaAPawlusBHamułkaJHealth effects of carotenoids during pregnancy and lactation983820172877735610.3390/nu9080838CrackersNRPerVUSDA National Nutrient Database for Standard Reference3372019https://ods.od.nih.gov/pubs/usdandb/VitA-betaCarotene-Content.pdf.LesmanaRFelia YusufIGoenawanHAchadiyaniAKhairaniAFNur FatimahSSupratmanULow Dose of β-carotene regulates inflammation, reduces caspase signaling, and correlates with autophagy activation in cardiomyoblast cell lines26e92864820203336174410.12659/MSMBR.928648ChengJBalbuenaEMillerBErogluAThe role of β-carotene in colonic inflammation and intestinal barrier integrity872348020213464684910.3389/fnut.2021.723480PalozzaPCan beta-carotene regulate cell growth by a redox mechanism? An answer from cultured cells174021522120051594968910.1016/j.bbadis.2004.12.008JanikIAThe detection and prediction of mastitis in dairy cows by particle analysis (unpublished PhD thesis). Coventry University, 2013.O'RourkeDNutrition and udder health in dairy cows: A review62 (Suppl 4)S15S2020092208234010.1186/2046-0481-62-S4-S15YangYLiRHuiJLiLZhengXβ-Carotene attenuates LPS-induced rat intestinal inflammation via modulating autophagy and regulating the JAK2/STAT3 and JNK/p38 MAPK signaling pathways45e1354420213314765010.1111/jfbc.13544ZhaoGZhangXWangHChenZBeta carotene protects H9c2 cardiomyocytes from advanced glycation end product-induced endoplasmic reticulum stress, apoptosis, and autophagy via the PI3K/Akt/mTOR signaling pathway864720203256658410.21037/atm-20-3768MassSBreast pain: Engorgement, nipple pain and mastitis4767668220041532643010.1097/01.grf.0000135652.49154.75GuoWLiuBYinYKanXGongQLiYCaoYWangJXuDMaHLicochalcone A protects the blood milk barrier integrity and relieves the inflammatory response in LPS-Indued mastitis1028720193085884910.3389/fimmu.2019.00287ZhuYChengJMinZYinTZhangRZhangWHuLCuiZGaoCXuSEffects of fucoxanthin on autophagy and apoptosis in SGC-7901cells and the mechanism1197274728420182976189410.1002/jcb.27022ZengMSangWChenSChenRZhangHXueFLiZLiuYGongYZhangHKongX4-PBA inhibits LPS-induced inflammation through regulating ER stress and autophagy in acute lung injury models271263720172824598510.1016/j.toxlet.2017.02.023WangXSuFYuXGengNLiLWangRZhangMLiuJLiuYHanBRNA-Seq whole transcriptome analysis of bovine mammary epithelial cells in response to intracellular staphylococcus aureus764220203342601110.3389/fvets.2020.00642HouLLGaoCChenLHuGQXieSQEssential role of autophagy in fucoxanthin-induced cytotoxicity to human epithelial cervical cancer HeLa cells341403141020132397451710.1038/aps.2013.90Scherz-ShouvalRElazarZRegulation of autophagy by ROS: Physiology and pathology36303820112072836210.1016/j.tibs.2010.07.007HeLHeTFarrarSJiLLiuTMaXAntioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species4453255320172914519110.1159/000485089AtakisiOOralHAtakisiEMerhanOMetin PancarciSOzcanAMarasliSPolatBColakAKayaSSubclinical mastitis causes alterations in nitric oxide, total oxidant and antioxidant capacity in cow milk89101320102013295610.1016/j.rvsc.2010.01.008MittalMSiddiquiMRTranKReddySPMalikABReactive oxygen species in inflammation and tissue injury201126116720142399188810.1089/ars.2012.5149CaoYWangJTianHFuGHMitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer3911920203257620610.1186/s13046-020-01621-yGuoWLiWSuYLiuSKanXRanXCaoYFuSLiuJGPR109A alleviate mastitis and enhances the blood milk barrier by activating AMPK/Nrf2 and autophagy174271428420213480349710.7150/ijbs.62380QianMFangXWangXAutophagy and inflammation62420172874836010.1186/s40169-017-0154-5SunYHuangYHHuangFYMeiWLLiuQWangCCLinYYHuangCLiYNDaiHFTanGH3'-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/Akt/mTOR axis in lung cancer cells82044206020182955637210.7150/thno.23304JungCHRoSHCaoJOttoNMKimDHMTOR regulation of autophagy5841287129520102008311410.1016/j.febslet.2010.01.017ChangKCLiuPFChangCHLinYCChenYJShuCWThe interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases12120223498027310.1186/s13578-021-00736-9HadadNLevyRThe synergistic anti-inflammatory effects of lycopene, lutein, β-carotene, and carnosic acid combinations via redox-based inhibition of NF-κB signaling531381139120122288959610.1016/j.freeradbiomed.2012.07.078LeeHLimJWKimHEffect of Astaxanthin on Activation of Autophagy and Inhibition of Apoptosis in Helicobacter pylori-Infected Gastric Epithelial Cell Line AGS12175020203254539510.3390/nu12061750JiangGMTanYWangHPengLChenHTMengXJLiLLLiuYLiWFShanHThe relationship between autophagy and the immune system and its applications for tumor immunotherapy181720193067868910.1186/s12943-019-0944-zBolisettySJaimesEAMitochondria and reactive oxygen species: Physiology and pathophysiology146306634420132352885910.3390/ijms14036306MartinezJMalireddiRSLuQCunhaLDPelletierSGingrasSOrchardRGuanJLTanHPengJMolecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2, and autophagy proteins1789390620152609857610.1038/ncb3192ShinJSongMHOhJWKeumYSSainiRKPro-oxidant actions of carotenoids in triggering apoptosis of cancer cells: A review of emerging evidence953220203256047810.3390/antiox9060532FilteauSMRiceALBallJJChakrabortyJStoltzfusRde FranciscoAWillumsenJFBreast milk immune factors in Bangladeshi women supplemented postpartum with retinol or beta-carotene6995395819991023263610.1093/ajcn/69.5.953KasperczykSDobrakowskiMKasperczykJOstałowskaAZalejska-FiolkaJBirknerEBeta-carotene reduces oxidative stress, improves glutathione metabolism and modifies antioxidant defense systems in lead-exposed workers280364120142503831410.1016/j.taap.2014.07.006ZbyradowskiMDudaMWisniewska-BeckerAHeriyanto RajwaWFiedorJCvetkovicDPilchMFiedorLTriplet-driven chemical reactivity of β-carotene and its biological implications13247420223551337410.1038/s41467-022-30095-zKimDKSimBRKimJIKhangGFunctionalized silk fibroin film scaffold using β-Carotene for cornea endothelial cell regeneration16434034620182941361510.1016/j.colsurfb.2017.11.052KangHKimHAstaxanthin and β-carotene in Helicobacter pylori-induced gastric inflammation: A mini-review on action mechanisms22576120172869885810.15430/JCP.2017.22.2.57McGuireSWHO guideline: Vitamin A supplementation in pregnant women. Geneva: WHO, 2011; WHO guideline: Vitamin A supplementation in postpartum women. Geneva: WHO, 2011321521620122251673010.3945/an.111.001701World Health Organization (WHO): Guideline: vitamin A supplementation in postpartum women. WHO, Geneva, 2011. https://apps.who.int/iris/handle/10665/44623.TanakaTShnimizuMMoriwakiHCancer chemoprevention by carotenoids173202324220122241892610.3390/molecules17033202HaskellMJThe challenge to reach nutritional adequacy for vitamin A: β-carotene bioavailability and conversion-evidence in humans961193S1203S20122305356010.3945/ajcn.112.034850National Institutes of Health (NIH): Vitamin A and carotenoids. NIH, Bethesda, MD, pp1-19, 2022. https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/. Accessed June 1, 2022.XuJZhangJMaoQFWuJWangYThe interaction between autophagy and JAK/STAT3 signaling pathway in tumors1388035920223555903710.3389/fgene.2022.880359KitakazeTHaradaNImagitaHYamajiRβ-carotene increases muscle mass and hypertrophy in the soleus muscle in mice6148148720152687549010.3177/jnsv.61.481GengNLiuKLuJXuYWangXWangRLiuJLiuYHanBAutophagy of bovine mammary epithelial cell induced by intracellular Staphylococcus aureus5832032920203210344210.1007/s12275-020-9182-8
Model of the inflammatory response within a lactating breast and the role of β-carotene as an antioxidant and autophagy modulator.
β-carotene scavenges excessive ROS and modulates autophagy through the phosphorylation of several proteins involved in autophagy, affecting JAK/STAT3, PI2K/Akt/mTOR, and the AMPK pathways, β-carotene also affects autophagosome formation and autophagic flux. ROS, reactive oxygen species.