{"id":58800,"date":"2024-06-25T11:10:28","date_gmt":"2024-06-25T11:10:28","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=58800"},"modified":"2024-07-04T10:56:27","modified_gmt":"2024-07-04T10:56:27","slug":"administration-of-nanocurcumin-in-mice-models-of-endometriosis-as-an-effort-to-improve-folliculogenesis","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no2\/administration-of-nanocurcumin-in-mice-models-of-endometriosis-as-an-effort-to-improve-folliculogenesis\/","title":{"rendered":"Administration of Nanocurcumin in Mice Models of Endometriosis as an Effort to Improve Folliculogenesis"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

The existence of endometrial-like tissue outside the uterus is known as endometriosis, which induces chronic inflammation1<\/sup>. In general, the estimated prevalence of endometriosis in females is between 6 and 10%2<\/sup>. One of the complaints that often arise in women with endometriosis is infertility3<\/sup>. The prevalence is 21% in women with infertility complaints, and increases to 82% in women with pelvic pain complaints4<\/sup>.<\/p>\n\n\n\n

The inability to\nconceive following a year of unprotected sex is known as infertility3<\/sup> and decreased fertility\nin women with endometriosis5<\/sup>.\nOne theory that has been published regarding the relationship between\nendometriosis and infertility is the theory regarding changes in the environment\naround the uterus and egg cells caused by endometriosis. Endometriosis can\ncause inflammation and scar tissue formation around the uterus, ovaries, and\nfallopian tubes. These changes can disrupt the normal function of the female\nreproductive organs and reproductive processes6,7,8<\/sup>. One key idea\nabout endometriosis is that it’s characterized by a localized inflammatory\nprocess in the pelvis, oxidative stress from increased Reactive oxygen species (ROS) production, and altered\nimmune system-related cell function in the peritoneal milieu9<\/sup>,<\/sup>10<\/sup>.\nOocytes are shielded from oxidative damage during folliculogenesis by a variety\nof antioxidants that the body produces. However, excessive and persistent ROS production\ncan interfere with folliculogenesis11<\/sup>.<\/p>\n\n\n\n

ROS are generated\nin response to various environmental stimuli, and excessive ROS production can\nlead to lipid peroxidation, which is often monitored by measuring\nmalondialdehyde (MDA). MDA is produced as a byproduct of oxidative\nstress-induced lipid peroxidation12<\/sup>.<\/p>\n\n\n\n

Curcumin (1,7-bis\n(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), derived from the rhizome\nof Curcuma spp., has antioxidant properties1<\/sup>3<\/sup>.\nNanocurcumin is curcumin with nanoparticle size so that it has better\nbioavailability and stability than the original curcumin molecule. The\nadministration of curcumin as a treatment for endometriosis is still\ncontroversial. This may be because there have not been many studies and\npublications on the administration of curcumin as a treatment for\nendometriosis, especially in infertility problems related to endometriosis. In\ntheir article, Swarnakar and Paul state\nthat the benefits of curcumin in various diseases include being an antioxidant.\nBased on this, curcumin is thought to provide benefits as a therapy in endometriosis1<\/sup>4<\/sup>.<\/p>\n\n\n\n

This research aims\nto study the effect of nanocurcumin 10-50 nm on endometriosis as an effort to\nimprove oocyte quality and embryonic development through antioxidant mechanisms\nby improving folliculogenesis. Considering that nanocurcumin has never been\nused in humans for the treatment of endometriosis with infertility and human\nstudies to determine the effect of nanocurcumin are ethically constrained, this\nstudy used mice as models of endometriosis.<\/p>\n\n\n\n

Materials and\nMethods<\/strong> <\/p>\n\n\n\n

This research was\ncarried out through several stages, namely making mice model of endometriosis,\nproviding nanocurcumin 10-50 nm treatment, measuring the MDA of peritoneal\nfluid and folliculogenesis in the ovaries. <\/p>\n\n\n\n

Materials<\/strong><\/p>\n\n\n\n

Curcumin (8.20354-Sigma,\nAldrich); alcohol, betadine, sterile gauze, round\ncotton, silk thread 3-0, catgut, ketamine, xylazine, sodium chloride (NaCl) 0.9% (PT. Widatra Bakti); PMSG (Folligon, Intervet,\nBoxmeer, Holland); hCG (Chorulon, Intervet, Boxmeer, Holland); ketamine\nHCL (Ketamil<\/em>\u00ae, Troy Laboratories PTY\nLimited, Australia); MDA\nELISA Kit (MDA Assay Kit competitive ELISA, Abcam- ab238537); 10%\nNeutraled Buffered Formaldehyde (NBF)\n(HT-501128-Sigma,\nAldrich).<\/p>\n\n\n\n

Ethical\napproval<\/strong><\/p>\n\n\n\n

The ethical permition\ncertificate was obtained from the Faculty of Veterinary Medicine, Universitas\nAirlangga, Surabaya, Indonesia, with number 1.KE.053.05.2022.<\/p>\n\n\n\n

Animal study<\/strong><\/p>\n\n\n\n

The Embryology\nLaboratory and Histology Laboratory, Faculty of Veterinary Medicine,\nUniversitas Airlangga, are the sites of this laboratory experiment study, which\nemploys a completely randomized design (CRD). 24 Mice (Mus musculus<\/em>) were employed in this study, and they were split up into\n4 treatment groups, each with 6 mice. The experimental animals were acclimated\nand provided with enough food and drink for seven days prior to the treatment.<\/p>\n\n\n\n

Preparation and Characterization of Nanocurcumin<\/strong><\/p>\n\n\n\n

This examination is used to ensure that\nthe curcumin used has nano particle size. The mean particle size of the\nnanocurcumin was observed by Dynamic Light Scattering (DLS). In brief, the\nsample was prepared by taking 1 mg of the nanocurcumin powder (Curcumin 8.20354-Sigma, Aldrich) in 10 ml distilled water and\nused in characterization studies. Scanning Electron Microscopy (SEM) (EX-250 System,\nHoriba, Kyoto, Japan) was performed by spreading the\nnanoparticle dispersion over a carbon tape and drying it under a nitrogen\nstream. The sample was then coated in a sputter with a gold layer in a vacuum\ncondition34<\/sup>. <\/sup><\/p>\n\n\n\n

Endometriosis Animal Model<\/strong><\/p>\n\n\n\n

Four groups of\nendometriosis model rats were created, namely the positive control (C+) as mice\nmodel of endometriosis, Treatment 1 (T1) as mice model of endometriosis given\nnanocurcumin 10-50 nm (2.5 mg\/KgBW) PO, Treatment 2 (T2) mice given\nnanocurcumin (5 mg\/KgBW) and Treatment 3 (T3) as mice model of endometriosis\ntreated with nanocurcumin (10 mg\/KgBW) 0.5 ml orally (PO) while C (+) was given a placebo.\nExposure time is carried out every morning\nfor 14 days.<\/p>\n\n\n\n

Sample\nCollection and Histopathology<\/strong><\/p>\n\n\n\n

All mice received injections of PMSG after 14 days of therapy, and 48 hours\nlater, hCG. The Mice were also mated with male mice for ovulation induction. 17 hours later\nthe vaginal plug were evaluated plug and if positive, the\ntermination was done using ketamine HCL (Ketamil<\/em>\u00ae, Troy Laboratories\nPTY Limited, Australia) 100 mg\/kgBW. After the mice was terminated, Using a scalpel, the incision was\ncreated in the ventral midline, and the thorax and abdomen were then prepared\nwith scissors.<\/p>\n\n\n\n

Peritoneal fluid was taken using a 1 cc syringe in the abdominal cavity.\nThe collected fluid was checked for MDA levels by ELISA. After\nbeing removed, the ovaries were put in a sample pot with 10% Neutraled Buffered\nFormaldehyde (NBF) (HT-501128-Sigma, Aldrich) inside\nof them. After that, the organ samples were brought to the Universitas\nAirlangga Faculty of Veterinary Medicine’s Pathology Laboratory for\nhistological preparations.<\/p>\n\n\n\n

MDA Level <\/strong>Estimation<\/strong><\/p>\n\n\n\n

MDA level analysis was done at the Laboratory of\nPhysiology, Faculty of Medicine, Universitas Airlangga using the Colorimetric\nELISA method with a commercial kit (MDA Assay Kit competitive ELISA, Abcam- ab238537). MDA levels are expressed in ng\/ml. Measure the OD value\nat 450 nm<\/em> with a microplate\nreader. Calculate with standard concentration OD value and sample concentration\nwith formula that according to the assay kits used by the laboratory\n(Standard Diagnostic, Inc., Yongin, Korea).<\/p>\n\n\n\n

Folliculogenesis Profile\nExamination<\/strong><\/p>\n\n\n\n

Histological\npreparations of previously prepared ovarian tissue were used to examine the\nfolliculogenesis profile. Ovarian\ntissue fixated with buffer formalin 10%. Then staining process using\nHematoxylin and Eosin. A 400x magnification\nOlympus\u00ae light microscope was used to conduct the inspection and then Graafian\nfollicles, tertiary follicles, primary follicles, secondary follicles, and CL\nnumbers were recorded. Five fields of view are used for the computation, and\nthe results are averaged after that.<\/p>\n\n\n\n

Statistical Analysis<\/strong><\/p>\n\n\n\n

The statistical\nanalysis used\nIBM SPSS 23 application with One-Way ANOVA and post-hoc Duncan to seek for differences between\ngroups of variables in MDA levels, and number\nof CL, primary,\nsecondary, tertiary, and Graafian\nfollicles.<\/p>\n\n\n\n

Results and\nDiscussion<\/strong><\/p>\n\n\n\n

The study was conducted by measuring two parameters, namely folliculogenesis, and MDA levels on mice model of endometriosis given nanocurcumin 10-50 nm. In this study, there were five treatment groups used with each treatment consisting of four replications, namely treatment C+ (positive control) as mice model of endometriosis, T1 (treatment 1) mice model of endometriosis group treated with 2.5 mg\/KgBW dose of nanocurcumin, T2 (treatment 2) mice model of endometriosis group treated with 5 mg\/KgBW dose of nanocurcumin, and T3 (treatment 3) mice model of endometriosis group treated with 10 mg\/KgBW dose of nanocurcumin.<\/p>\n\n\n\n

Effect of treatment on Folliculogenesis<\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Histological <\/strong>figure<\/strong> of the ovaries of endomet<\/strong>r<\/strong>iosis model mice treated with nanocurcumin. <\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Histological picture in fig. 1 shows that the atretic follicle (yellow\narrow) is most abundant in the T1 group. The atretic follicle looks pale. It\nwill continue to shrink, eventually forming a small scar on the side of the\novary. Meanwhile, on average, tertiary follicles (red arrows) appeared a lot in\nthe T1 and T3 groups. Tertiary follicle identifying characteristic is a\nfluid-filled cavity, the antral follicle. The oocyte lies at the edge in a\nmound made of granulosa epithelial cells, the cumulus oophorus. primary\nfollicle (white arrow) which is shown to consist of a central oocyte surrounded\nby a single or double layer of follicular cells. Primary follicles were most visible\nin the T3 group. Meanwhile, de Graaf follicles (green arrow) only appear in the\nT3 group with large follicles. The follicular fluid fills a single space,\ncalled the antrum, which is surrounded by the follicular cells.<\/p>\n\n\n\n

Table 1: The average and deviation from the mean of primary, secondary, tertiary, and De Graaf follicles, as well as corpus luteum counts, were assessed in the ovaries of mice with endometriosis treated with nanocurcumin therapy at different concentrations.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n
\n

Group<\/strong><\/p>\n<\/td>\n

\n

Primary Follicle (Mean\u00b1SD)<\/strong><\/p>\n<\/td>\n

\n

Secondary Follicle (Mean\u00b1SD)<\/strong><\/p>\n<\/td>\n

\n

Tertiary Follicle (Mean\u00b1SD)<\/strong><\/p>\n<\/td>\n

\n

Graafian Follicle (Mean\u00b1SD)<\/strong><\/p>\n<\/td>\n

\n

Corpus Luteum  (Mean\u00b1SD)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C(+)<\/p>\n<\/td>\n

\n

0.71c<\/sup>\u00b10.75<\/p>\n<\/td>\n

\n

1.71b<\/sup>\u00b10.76<\/p>\n<\/td>\n

\n

0.86b<\/sup>\u00b11.06<\/p>\n<\/td>\n

\n

0.00a<\/sup>\u00b10.00<\/p>\n<\/td>\n

\n

2.14a<\/sup>\u00b10.69<\/p>\n<\/td>\n<\/tr>\n

\n

T1<\/p>\n<\/td>\n

\n

1.57cb<\/sup>\u00b10.78<\/p>\n<\/td>\n

\n

3.71b<\/sup>\u00b11.11<\/p>\n<\/td>\n

\n

1.71ab<\/sup>\u00b11.25<\/p>\n<\/td>\n

\n

0.00a<\/sup>\u00b10.00<\/p>\n<\/td>\n

\n

3.57a<\/sup>\u00b10.53<\/p>\n<\/td>\n<\/tr>\n

\n

T2<\/p>\n<\/td>\n

\n

2.29b<\/sup>\u00b11.38<\/p>\n<\/td>\n

\n

3.71b<\/sup>\u00b11.98<\/p>\n<\/td>\n

\n

0.43b<\/sup>\u00b10.53<\/p>\n<\/td>\n

\n

0.00a<\/sup>\u00b10.00<\/p>\n<\/td>\n

\n

2.71a<\/sup>\u00b12.13<\/p>\n<\/td>\n<\/tr>\n

\n

T3<\/p>\n<\/td>\n

\n

6.71a<\/sup>\u00b13.27<\/p>\n<\/td>\n

\n

7.85a<\/sup>\u00b13.76<\/p>\n<\/td>\n

\n

2.14a<\/sup>\u00b11.57<\/p>\n<\/td>\n

\n

0.14a<\/sup>\u00b10.38<\/p>\n<\/td>\n

\n

2.85a<\/sup>\u00b11.24<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Note: Different superscripts (a,b,c) in the same column show significant differences between treatments (p<0.05).<\/p>\n\n\n

The follicle examination results indicated that the T3 group exhibited the highest counts of primary, secondary, tertiary, and Graafian follicles, specifically 6.71\u00b13.27, 7.85\u00b13.76, 2.14\u00b11.57, and 0.14 \u00b1 0.38, respectively. Statistically significant differences (p<0.05) were observed in the counts of primary, secondary, and tertiary follicles compared to the other groups. Although not statistically significant (p>0.05), an increasing trend was noted in the count of Graafian follicles. The number of corpus luteum (CL) in each group did not show statistically significant differences (p>0.05) (Table 1; Figure 1).<\/p>\n\n\n\n

Based the result\nat Table 1,\nin treatment group 3 (T3), the addition of nanocurcumin at a dose of 10 nm\nimproved the follicle development process, which shows the development of\nprimary, secondary, tertiary, and de Graaf follicles.<\/p>\n\n\n\n

In this study,\nthere was an increase in the number of primary follicles in the treatment group\nwith the highest number in the T3 group, which was significantly different from\nthe other groups. Similarly, in calculating the number of secondary follicles,\nit was found that the T3 group with the highest number and significantly\ndifferent from the other groups. This demonstrates that in a mice model of endometriosis,\nthe injection of not italic can increase the number of primary and secondary\nfollicles.<\/p>\n\n\n\n

Antioxidants\nincluding catalase, superoxide dismutase (SOD), glutathione transferase,\nparaoxanase, heat shock protein (HSP) 27, and protein isomerase shield oocytes\nfrom oxidative damage during folliculogenesis. Once generated, ROS have the\nability to interact with other molecules to cause cellular functions and\nvarious organelles to malfunction. ROS overproduction that persists over time\ncan have detrimental effects on a number of signaling pathways that are\nnecessary for folliculogenesis11<\/sup>.<\/p>\n\n\n\n

It is commonly\nknown that in animals, the development of follicles and oocytes starts in the\nwomb. In summary, the primordial germ cells go through mitosis in order to\ngenerate primary oocytes. Following that, meiotic development starts at the\ndiplotene phase of the first meiotic division and ends there2<\/sup>4<\/sup>.\nEntering puberty, meiotic development will continue, the chromosomes relax and\nthe resulting nuclear structure is called the germinal vesicle (GV). After the\nluteinizing hormone (LH) surge, the GV disappears, the chromatin is condensed,\nthe homologous chromosome pairs are separated and the half will be expelled in\nthe first polar body. At this point meiosis stops again (metaphase II – MII). At\nthis time, the oocyte is said to be mature and ready to receive sperm to\nundergo fertilization2<\/sup>5<\/sup>.\nAdditionally, granulosa cells and theca cells generate the peptide hormone\ninhibin during the process of folliculogenesis, as well as the ovarian hormones\nprogesterone (P) and estradiol (E2). These hormones act as a feedback system to\ncontrol the production and release of FSH, LH, and GnRH. At the tiny antral\nfollicle stage, the majority of ovarian follicles go through an apoptotic\nprocess known as atresia instead of ovulation2<\/sup>5<\/sup>.\nThis study succeeded in proving that the administration of nanocurcumin could\nimprove folliculogenesis by increasing the quantity of primary and secondary\nfollicles in the model of endometriosis in mice.<\/p>\n\n\n\n

In this study, the number of tertiary\nfollicles increased significantly in the therapy group as well, with the T3\ngroup having the greatest number. This shows that the administration of\nnanocurcumin could increase the number of tertiary follicles in endometriosis mice model (Figure 1).<\/p>\n\n\n\n

Most of the time,\nthere are two phases of tertiary\/antral follicular growth. Early follicle\ngrowth can be linked to an increase in granulosa cell numbers and,\nconsequently, an increase in the granulosa cell layer during the first phase,\nwhich is marked by a slow growth stage2<\/sup>6<\/sup>. For the development of oocyte capacity, this period is\ncrucial2<\/sup>7<\/sup>.\nThe second phase is marked by fast growth in follicles larger than 2\u20135 mm, and\nit seems that antral development, rather than an increase in granulosa cell\ncount, is the cause of this follicular expansion. Until ovulation takes place\nin this follicle, the antrum’s diameter increases exponentially2<\/sup>8<\/sup>.\nSufficient LH pulses and FSH hormones regulate this second stage2<\/sup>9<\/sup>.\nRegarding endometriosis, the study conducted recently demonstrated that\nendometriosis can decrease the number of antral follicles30<\/sup>.\nResearch has also shown that many factors that may be responsible, including\nreactive oxygen species, free iron and proteolytic enzymes31<\/sup> of endometriosis can infiltrate\ninto the tissue surrounding the cyst, which then decreases ovarian reserve30<\/sup>.\nThus, this study succeeded in proving that the administration of nanocurcumin could\nimprove folliculogenesis by increasing the number of tertiary follicles in mice\nmodel of endometriosis.<\/p>\n\n\n\n

Additionally,\nthere was a tendency for the T3 group’s Graafian follicle count to grow,\nhowever the results of this study did not show a significant difference across\nall groups. Likewise, in the corpus luteum group, there were no significantly\ndifferent numbers.<\/p>\n\n\n\n

In mammals, after ovulation, the follicle will develop into the corpus luteum (CL). The primary job of the CL is to synthesize progesterone, which is required for both the development and maintenance of pregnancy as well as the creation of an appropriate uterine environment for the peri-implantation conceptus (embryo and related extra-embryonic membranes). Reactive oxygen species (ROS) have been shown to play a major role in defining the age of CL at which folliculogenesis interference can result in luteal phase abnormalities32<\/sup>. It is suspected that antioxidants play an important role in CL physiology during the estrus\/menstrual cycle33<\/sup>. Since luteal phase abnormalities can affect fertility by impeding implantation and the development of early conception, in both humans and animals, nanocurcumin with its antioxidant properties may show a positive effect in improve folliculogenesis in endometriosis. Our findings, which revealed no discernible variation in the quantity of corpus luteum and Graafian follicles, might be the consequence of the insufficient dosage of nanocurcumin used in this investigation to enhance folliculogenesis to this extent. From the previous results, it appears that the increase in the number of primary, secondary and tertiary follicles depends on the dose of nanocurcumin given. Therefore, further studies are needed to determine the optimal dose of nanocurcumin to improve the folliculogenesis process.<\/p>\n\n\n\n

Effect of treatment on MDA Level<\/strong><\/p>\n\n\n\n

Table 2: The average and deviation from the mean of MDA levels in mice with endometriosis treated with nanocurcumin therapy were examined.<\/strong><\/p>\n\n\n\n\n\n\n\n\n
\n

Group<\/p>\n<\/td>\n

\n

MDA (Mean\u00b1SD)<\/p>\n<\/td>\n<\/tr>\n

\n

Control (+)<\/p>\n<\/td>\n

\n

39.57c<\/sup>\u00b12.27<\/p>\n<\/td>\n<\/tr>\n

\n

Treatment 1 (T1)<\/p>\n<\/td>\n

\n

38.38c<\/sup>\u00b12.00<\/p>\n<\/td>\n<\/tr>\n

\n

Treatment 2 (T2)<\/p>\n

Treatment 3 (T3)<\/p>\n<\/td>\n

\n

20.78b<\/sup>\u00b14.58<\/p>\n

13.88a<\/sup>\u00b11.30<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Notes: Different superscripts (a,b,c) in the same column show significant differences between treatments (p<0.05).<\/p>\n\n\n

Table 2 exhibits the results obtained from calorimetric ELISA analysis of MDA levels. It was observed that group C(+) demonstrated the highest MDA level, amounting to 39.57\u00b12.27 ng\/ml. Conversely, MDA levels decreased in treatment groups T1, T2, and T3, registering as 38.38\u00b12.00 ng\/ml, 20.78\u00b14.58 ng\/ml, and 13.88\u00b11.30 ng\/ml, respectively, with T2 and T3 displaying statistical significance (p<0.05) in comparison to groups C (+) and T1 (Table 2).<\/p>\n\n\n\n

The elevated\nlevels of MDA in the control group led to a disturbance in the follicle\ndevelopment process. Based on the results presented in the below table, an\nincrease in MDA levels is associated with a decrease in the number of\npre-antral, antral, and CL follicles. In this research, the MDA\nlevels decreased as the nanocurcumin dosage increased. The decrease in MDA\nlevels was significant in the T2 and T3 groups with the lowest decrease in the\nT3 group. This shows that nanocurcumin can have a positive effect by reducing\noxidative stress in endometriosis as indicated by a decrease in MDA levels. Futhermore, elevated MDA\nlevels in the control group disrupted follicle development, resulting in\ndecreased numbers of pre-antral, antral, and corpus luteum follicles.<\/p>\n\n\n\n

The primary active\ningredient in turmeric, curcumin, belongs to the curcuminoid family and has\nbeen utilized in traditional medicine for many years. Asian cultures have been\nusing curcumin for a long time, and it hasn’t been shown to be poisonous.\nCurcumin (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione),\nderived from the rhizome of Curcuma spp., has antioxidant properties1<\/sup>3<\/sup>.\nCurcumin as a nanoparticle has better bioavailability and stability than native\ncurcumin molecules21<\/sup> and provides a better therapeutic effect\nefficiency on target tissues, than native curcumin22<\/sup>,2<\/sup>3<\/sup>.\nThis study succeeded in proving that the administration of nanocurcumin can\ncause a decrease in MDA levels in the peritoneal fluid of mice model of\nendometriosis.<\/p>\n\n\n\n

MDA is a\ndialdehyde compound which is the end product of lipid peroxidation in the body.\nHigh MDA concentration indicates an oxidation process in the cell membrane. The\nchemically stable nature of MDA makes this compound more often used as a marker\nof oxidative stress than other compounds1<\/sup>5<\/sup>.<\/p>\n\n\n\n

Endometriosis is\nknown to cause oxidative stress and is a potential factor involved in the\npathophysiology of endometriosis6<\/sup>. Excessive ROS, including superoxide, hydroxyl,\nand hydrogen peroxide, are produced during severe oxidative stress and can harm\nproteins, DNA, and other parts of the cell1<\/sup>6<\/sup>.\nThe body forms a defense in the form of antioxidant complexes that collectively\nact against free radicals. Additionally, unchecked lipid peroxidation brought\non by oxidative stress has the potential to damage DNA and directly inhibit\nproteins, both of which can harm cells1<\/sup>7<\/sup>.\nSince MDA is a persistent by product\nof lipid peroxidation, it can be utilized as a proxy for total lipid\nperoxidation. MDA and SOD are regarded as biological indicators of oxidative\nstress1<\/sup>8<\/sup>.<\/p>\n\n\n\n

Like in many other\ncells, the intraovarian environment is directly harmed by oxidative stress,\nwhich is brought on by an imbalance between the synthesis and breakdown of ROS.\nIn addition, by\nthe fifth month of fetal life, all primary oocytes have produced and are\ninactive until meiosis I is finished, which is a process that lasts for decades\nleaving the oocyte vulnerable to chronic oxidative damage. Several studies have\ndemonstrated that granulosa cell (GC) apoptosis, corpus luteum degradation, and\nworsening of oocyte quality are all caused by accumulation of ROS in the ovary.\nAdditionally, it lessens oocyte-GC communication, which impacts the development\nof preovulatory oocytes1<\/sup>9<\/sup>.\nFolliculogenesis, meiosis,\nand ovulation are all significantly impacted by the lipid peroxidation cascade\nreaction, which is typically the cause of oxidative damage to the ovaries20<\/sup>.<\/p>\n\n\n\n

Curcumin\ninhibiting the process of apoptosis while the mechanism may be through multiple\npathways including inhibition of activation of the transcription factor NF-k\u00df\nwith various results, suppression of inflammatory activity through the\nsuppression of TNF-\u03b1 directly or through its antioxidant effects in endometriosis35<\/sup>.\nHigh levels of MDA, pro-inflammatory cytokines\n(IL-6, TNF-\u03b1, and IL-1\u03b2), angiogenic factors (IL-8 and VEGF), monocyte\nchemoattractant protein-1 (MCP-1), and oxidized LDL (ox-LDL) were detected in\nthe peritoneal fluid of endometriosis patients36<\/sup>. Curcumin\nto the culture medium of peritoneal\nfluid from infertile women with endometriosis\nresulted in more improved GDF9 and\nKit Ligand expression37<\/sup>. Curcumin inhibit the induction of pro-inflammatory cytokines, angiogenic cytokines\nand macrophage migration inhibitory factor by NF-kB in in vitro<\/em> model. Several recent studies also found the modulatory effect\nof curcumin on several important molecular targets\n(TNF, IL-1, IL-6) and enzyme (COX-2)38,39<\/sup>. In\naddition, curcumin can also lower anti-apoptotic genes expression, antioxidants and anti-angiogenesis effects40,41<\/sup>. <\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Administering nanocurcumin for 14\ndays resulted in a reduction of MDA levels and an enhancement of\nfolliculogenesis. Specifically, the administration of nanocurcumin at a dosage\nof 10nm\/KgBW led to decreased MDA levels and improved folliculogenesis. This\ninvestigation effectively demonstrated the ability of nanocurcumin administration\nto enhance folliculogenesis by increasing the quantity of tertiary follicles in\na mouse model of endometriosis.<\/p>\n\n\n\n

Acknowledgments<\/strong><\/p>\n\n\n\n

The authors\nare grateful to the authorities Universitas Airlangga and Faculty of Veterinary\nMedicine Universitas Airlangga, Surabaya, East Java, Indonesia.<\/p>\n\n\n\n

Conflict of interest<\/strong><\/p>\n\n\n\n

All authors\ndeclare that there is no conflict of interest.<\/p>\n\n\n\n

Funding<\/strong><\/p>\n\n\n\n

The authors\nreceived financial support for the Implementation of Internal Research\nUniversitas Airlangga Number 978\/UN3\/2022 and publication of this article.<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

  1. Zieli\u0144ski K, Drabczyk D, Kunicki M, Drzyzga D, Kloska A, and Rumi\u0144ski J. Evaluating the risk of endometriosis based on patients’ self-assessment questionnaires. Reprod. Biol. Endocrinol., 2023; 21(1):102-113.
    CrossRef<\/a><\/li>
  2. Baldi A, Campioni M, and Signorile P. G. Endometriosis: pathogenesis, diagnosis, therapy and association with cancer (review). Oncol. Rep., 2008; 19(4): 843-846.
    CrossRef <\/a><\/li>
  3. Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil. Steril., 2012; 98(3): 591-598.
     CrossRef <\/a><\/li>
  4. Allaire C, Bedaiwy M. A,   and Yong P. J. Diagnosis and management of endometriosis. CMAJ 2023; 195(10): E363\u2013E371.
    CrossRef <\/a><\/li>
  5. Broi M. G. D, Ferriani R. A, and Navarro P. A. Ethiopathogenic mechanisms of endometriosis-related infertility. JBRA Assist. Reprod., 2019; 23(3):273-280.
    CrossRef <\/a><\/li>
  6. Giudice L.C. Clinical practice. Endometriosis. N. Engl. J. Med., 2010; 362(25); 2389-2398.
     CrossRef <\/a><\/li>
  7. Burney R.O., and Giudice, L.C. Pathogenesis and pathophysiology of endometriosis. Fertil Steril., 2012; 98(3): 511-519.
     CrossRef <\/a><\/li>
  8. Macer M. L, and Taylor H. S. Endometriosis and Infertility: A review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am., 2012; 39(4): 535\u2013549.
     CrossRef <\/a><\/li>
  9. Donnez J, Binda M. M, Donnez O, and Dolmans M. M. Oxidative stress in the pelvic cavity and its role in the pathogenesis of endometriosis. Fertil. Steril., 2016; 106(5): 1011-1017.
    CrossRef <\/a><\/li>
  10. Tan Z, Gong X, Wang C. C, Zhang T, and Huang J. Diminished ovarian reserve in endometriosis: insights from in vitro, in vivo, and human studies-a systematic review. Int. J. Mol. Sci., 2023; 24(21):15967.
    CrossRef <\/a><\/li>
  11. Agarwal A, Aponte-Mellado A, and Premkumar B. J. The effects of oxidative stress on female reproduction: a review. Reprod. Biol. Endocrinol., 2012; 29 (10):49-53.
    CrossRef <\/a><\/li>
  12. Mazaheri-Tirani M, Haghjou M. Reactive oxygen species (ROS), Total antioxidant capacity (AOC) and Malondialdehyde (MDA) make a triangle in evaluation of Zinc stress extension. J Anim. Plant. Sci., 2019; 29(3): 1100-1111. <\/li>
  13. Ob\u0142oza M, Milewska A, Botwina P, Szczepa\u0144ski A, Medaj A, Bonarek P, Szczubia\u0142ka K, Pyr\u0107 K, and Nowakowska M. Curcumin-Poly(sodium 4-styrenesulfonate) Conjugates as Potent Zika Virus Entry Inhibitors. ACS. Appl. Mater. Interfaces., 2024; 16(5):5426-5437.
    CrossRef <\/a><\/li>
  14. Swarnakar S, and Paul S. Curcumin arrests endometriosis by downregulation of matrix metalloproteinase-9 activity. Indian J. Biochem. Biophys,. 2009; 46(1): 59-65. <\/li>
  15. Grotto D, Maria L. S, and Valentini J. Importance of the lipid peroxidation biomarkers and methodological aspects FOR malondialdehyde quantification. Qu\u00edmica Nova., 2009; 32: 169-174.
     CrossRef <\/a><\/li>
  16. Skulachev V. P, Vyssokikh M. Y, Chernyak B. V, Mulkidjanian A. Y, Skulachev M. V, Shilovsky G. A, Lyamzaev K. G, Borisov V. B, Severin F. F, and Sadovnichii V. A. Six Functions of Respiration: Isn’t It Time to Take Control over ROS Production in Mitochondria, and Aging Along with It?. Int. J. Mol. Sci., 2023; 24(16):12540. 
    CrossRef <\/a><\/li>
  17. Spiteller G. The important role of lipid peroxidation processes in aging and age dependent diseases. Mol. Biotechnol., 2007; 37(1): 5-12.
    CrossRef <\/a><\/li>
  18. Mao C, Yuan J. Q., Lv Y-B., Gao X, Gao X, Yin Z. X, Kraus  V. B, Si Luo J. S, Chei C. L, Matchar D. B,  Zeng Y, and Shi X. M. Associations between superoxide dismutase, malondialdehyde and all-cause mortality in older adults: a community-based cohort study. BMC Geriatrics., 2019; 19(1): 104. 
    CrossRef <\/a><\/li>
  19. Yang L, Chen Y, Liu Y, Xing Y, Miao C, Zhao Y, Chang X, and Zhang Q. The role of oxidative stress and natural antioxidants in ovarian aging. Front. Pharmacol., 2020; 11: 617843. 
    CrossRef <\/a><\/li>
  20. Maclaran K, and Nikolaou D. Early ovarian ageing. Obstet. Gynaecol., 2019; 21(2): 107-116.
    CrossRef <\/a><\/li>
  21. Singh A. T, Ghosh M, Forte T. M, Ryan R. O, and Gordon L. I. Curcumin nanodisk-induced apoptosis in mantle cell lymphoma. Leuk. Lymphoma., 2011; 52(8): 1537-1543.
    CrossRef <\/a><\/li>
  22. Boretti A. Curcumin-based fixed dose combination products for cholesterol management: a narrative review. ACS Pharmacol. Transl. Sci., 2024;7(2):300-308.
    CrossRef <\/a><\/li>
  23. Wen C, Zhou Y, Zhou C, Zhang Y, Hu X, Li J, and Yin H. Enhanced radiosensitization effect of curcumin delivered by PVP-PCL nanoparticle in lung cancer. J. Nanomater., 2017: 1-8
    CrossRef <\/a><\/li>
  24. Bothun A. M, Gao Y, Takai Y, Ishihara O, Seki H, Karger B, Tilly J. L, and Woods D. C. Quantitative proteomic profiling of the human ovary from early to mid-gestation reveals protein expression dynamics of oogenesis and folliculogenesis. Stem. Cells. Dev., 2018; 27(11):723-735. 
     CrossRef <\/a><\/li>
  25. Ciani F, Cocchia N, d’Angelo D, Tafuri S. Influence of ROS on Ovarian Functions. New Discoveries in Embryology. Edited by Bin Wu. IntechOpen Limited 5 Princes Gate Court, London, SW7 2QJ, United Kingdom. 2015.
     CrossRef <\/a><\/li>
  26. Dey P, Monferini N, Donadini L, Lodde V, Franciosi F, Luciano A. M. Method of isolation and in vitro culture of primordial follicles in bovine animal model. Methods. Mol. Biol., 2024; 2770:171-182.
    CrossRef <\/a><\/li>
  27. Wang P, Paquet \u00c9. R, and Robert C. Comprehensive transcriptomic analysis of long non-coding RNAs in bovine ovarian follicles and early embryos. PLoS One., 2023;18(9):e0291761.
    CrossRef <\/a><\/li>
  28. Arroyo A, Kim B, and Yeh J. Luteinizing hormone action in human oocyte maturation and quality: signaling pathways, regulation, and clinical impact. Reprod. Sci., 2020; 27(6): 1223\u20131252. 
    CrossRef <\/a><\/li>
  29. Mihm M, and Bleach E. C. Endocrine regulation of ovarian antral follicle development in cattle. Anim Reprod Sci., 2003; 78(3-4), 217-237.
     CrossRef <\/a><\/li>
  30. Tian Z, Zhang Y, Zhang C, Wang Y, Zhu H. L. Antral follicle count is reduced in the presence of endometriosis: a systematic review and meta-analysis. Reprod. Biomed. Online., 2021; 42(1): 237-247.
    CrossRef <\/a><\/li>
  31. Sanchez A. M, Papaleo E, Corti L, Santambrogio P, Levi S, Vigan\u00f2 P, Candiani M, and Panina-Bordignon P. Iron availability is increased in individual human ovarian follicles in close proximity to an endometrioma compared with distal ones. Hum. Reprod., 2014; 29(3): 577-583.
    CrossRef <\/a><\/li>
  32. Yan F, Zhao Q, Li Y, Zheng Z, Kong X, Shu C, Liu Y, Shi Y. The role of oxidative stress in ovarian aging: a review. J. Ovarian. Res., 2022; 15:100-120.
     CrossRef <\/a><\/li>
  33. Al-Gubory K. H, Garrel C, Faure P, and Sugino N. Roles of antioxidant enzymes in corpus luteum rescue from reactive oxygen species-induced oxidative stress. Reprod. Biomed. Online., 2012; 25(6):551-60.
    CrossRef <\/a><\/li>
  34. Kumar, V., Kumar, R., Jain, V.K. Preparation and characterization of nanocurcumin based hybrid virosomes as a drug delivery vehicle with enhanced anticancerous activity and reduced toxicity. Sci Rep., 2021; 11:368.
     CrossRef <\/a><\/li>
  35. Panjaitan, B.C., Sa\u2019adi, A., Hendarto, H., Widjiati. comparison of ovarial malondialdehyde (MDA) level between endometriosis rat given with and without curcumine supplementation. MOGI., 2012; 20(1): 30-34.<\/li>
  36. Lu, J., Wang, Z., Cao, J., Chen, Y., Dong, Y. A novel and compact review on the role of oxidative stress in female reproduction. Reprod. Biol. Endocrinol. RBE., 2018; 16:80.
     CrossRef <\/a><\/li>
  37. Hendarto, H., Widyanugraha, MYA., Widjiati, W. Curcumin improves growth factors expression of bovine cumulus oocyte complexes cultured in peritoneal fluid of women with endometriosis. Int. J. Reprod. BioMed. 2018; 16: 775\u2013782.
    CrossRef <\/a><\/li>
  38. Wieser F., Cohen M., Gaeddert A. Evolution of medical treatment for endometriosis:  back to the  roots. Hum.Reprod.Update., 2007; 13(5): 487-499.
     CrossRef <\/a><\/li>
  39. Grummer, R. Animal models in endometriosis research. Hum.Reprod.Update., 2006; 12(5): 641-649.
     CrossRef <\/a><\/li>
  40. Sharma, R.A., Gescher, A.J., Steward, W.P. Curcumin the story so far. Eu.J.Cancer., 2005; 41: 1955-1968.
    CrossRef <\/a><\/li>
  41. Joe, B., Vijaykumarand, M., Lokes, RB. Biological properties of curcumin-celluler and molecular mechanisms of action. Crit Rev Food Sci Nutr. 2004; 44(2):97-111.
     CrossRef <\/a><\/li><\/ol>\n","protected":false},"excerpt":{"rendered":"

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