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Boron is primarily used in industrial applications, with recent interest revolving around its effects on metabolism. In this study, we administered boric acid (BA), which has positive effects on reproduction, in conjunction with feed supplementation to serve as a model for experimental animal development and breeding. The pregnancy performance, offspring development, and biochemical effects of mice given feed supplemented with BA at concentrations of 0 (control group), 250, and 500 ppm (BA groups) were investigated. A total of 18 female Balb-C mice were utilized for pregnancy. The mice were given the BA-supplemented feed during a period encompassing three weeks of pregnancy and three weeks of lactation. The numbers and weights of offspring born in cages on days 19-21 were determined. Blood and tissue samples were collected from the offspring during the third week postnatal, and the malondialdehyde (MDA) and total antioxidant and oxidant status (TAS, TOS, and OSI) levels were determined. A significant increase in female offspring was observed in the groups born to mice fed with BA compared to the control group. Positive development in organ weights was observed in the 250-ppm BA group. The 250-ppm group exhibited a significant increase in TAS compared to the control group, while TOS and MDA levels showed a decrease. Also, the levels of BA groups were found to decrease in both the OSI index serum and organ samples compared to the control group. Thus, the use of 250-ppm BA demonstrated positive effects on female offspring production, organ development, and antioxidant levels., (© 2024. The Author(s).)

Boric acid (BA) has antimicrobial properties and is used to combat bacterial infections, including Enterobacteria. However, the molecular mechanisms and cellular responses to BA are still unknown. This genomics study aims to provide new information on the genes and molecular mechanisms related to the antimicrobial effect of BA in Escherichia coli. The Keio collection of E. coli was used to screen 3985 single-gene knockout strains in order to identify mutant strains that were sensitive or hypersensitive to BA at certain concentrations. The mutant strains were exposed to different concentrations of BA ranging from 0 to 120 mM in LB media. Through genome-wide screens, 92 mutants were identified that were relatively sensitive to BA at least at one concentration tested. The related biological processes in the particular cellular system were listed. This study demonstrates that intrinsic BA resistance is the result of various mechanisms acting together. Additionally, we identified eighteen out of ninety-two mutant strains (Delta_aceF, aroK, cheZ, dinJ, galS, garP, glxK, nohA, talB, torR, trmU, trpR, yddE, yfeS, ygaV, ylaC, yoaC, yohN) that exhibited sensitivity using other methods. To increase sensitivity to BA, we constructed double and triple knockout mutants of the selected sensitive mutants. In certain instances, engineered double and triple mutants exhibited significantly amplified effects. Overall, our analysis of these findings offers further understanding of the mechanisms behind BA toxicity and intrinsic resistance in E. coli., (© 2024. The Author(s).)

3-chloro-1,2-propanediol (3-MCPD) is a member of the group of pollutants known as chloropropanols and is considered a genotoxic carcinogen. Due to the occurrence of 3-MCPD, which cannot be avoided in multiplexed food processes, it is necessary to explore novel agents to reduce or prevent the toxicity of 3-MCPD. Many recent studies on boron compounds reveal their superior biological roles such as antioxidant, anticancer, and antigenotoxic properties. In the current investigation, we have evaluated in vitro cytotoxic, oxidative, and genotoxic damage potential of 3-MCPD on human whole blood cultures and the alleviating effect of boric acid (BA) and borax (BX) for 72 h. In our in vitro experiments, we have treated blood cells with BA and BX (2.5, 5, and 10 mg/L) and 3-MCPD (at IC 50 of 11.12 mg/l) for 72 h to determine the cytotoxic damage potential by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and lactate dehydrogenase (LDH) release assays. Oxidative damage was assessed using total antioxidant capacity (TAC) and malondialdehyde (MDA) levels. Genotoxicity evaluations were performed using chromosome aberrations (CAs) and 8-hydroxy deoxyguanosine (8-OHdG) assays. The result of our experiments showed that the 3-MCPD compound induced cytotoxicity, oxidative stress, and genotoxicity in a clear concentration-dependent manner. BA and BX reduced cytotoxicity, oxidative stress, and genotoxicity induced by 3-MCPD. In conclusion, BA and BX are safe and non-genotoxic under the in vitro conditions and can alleviate cytotoxic, oxidative, and genetic damage induced by 3-MCPD in the human blood cells. Our findings suggest that dietary boron supplements may offer a novel strategy for mitigating hematotoxicity induced by xenobiotics, including 3-MCPD., (© 2024. The Author(s).)

DNA double-strand break (DSB) repair genes interact with tumor stemness- and resistance-associated processes in cancer stem cells (CSCs). Therefore, targeting DNA DSB genes in cancer treatment is important for the CSC phenotype. Although the anti-cancer effect of boric acid (BA) has been studied, its effect on DNA DSB is unclear. Moreover, no studies investigate BA's effects on DNA DSB of lung cancer stem cells (LC-SCs). To fill the gap, we aimed to assess the effects of BA on A549 cancer stem cells. CSCs were isolated from human non-small cell lung cancer cells (A549) and characterized by flow cytometry. Different concentrations of BA (at doses ranging from 1 to 100 mM) were applied to cancer stem cells. Cytotoxic activities were determined using the cell viability assay (MTT assay) at 24 and 48 h. Expression levels of DNA DSB genes that BRCA1, BRCA2, RAD51, KU70/80, ATM, and XRCC4 were evaluated by RT-qPCR. Additionally, immunofluorescence staining analysis was exploited for caspase-3 and E-cadherin. ATM expression increased significantly (p < 0.001). No significant change was observed in the expression of other genes. Moreover, BA up-regulated caspase-3 and E-cadherin expression. Consequently, we can say that BA affects DNA DSB and the apoptotic abilities of LC-SCs., (© 2024. The Author(s).)

Breast cancer pathology ranks second in mortality among women worldwide due to the resistance of cancer stem cells in tumor tissue to radiotherapy and chemotherapy and their effective DNA damage response system (DDR). Targeting the expression of DNA double-strand break (DSB) repair genes in breast cancer stem cells (BC-SCs) is essential for facilitating their elimination with conventional therapies. This study aims to investigate the effects of boric acid (BA) on the expression of DNA DSB repair genes in BC-SCs, which has not been studied in the literature before. BS-SCs were isolated by the MACS method and characterized by flow cytometry. The effects of BA on BC-SCs' DNA DSB repair genes were deciphered by cell viability assay, inverted microscopy, and RT-qPCR. While the expression of the BRCA1 and BRCA2 was upregulated, the expression of the ATM (p < 0.001), RAD51 (p < 0.001), and KU70 (p < 0.001) was downregulated in dose-treated BC-SCs (p < 0.001) to the qPCR results. Consequently, BA affects some of the DNA DSB repair genes of breast cancer stem cells. Findings from this study could provide new insights into the potential therapeutic application of BA in BC-SC elimination and cancer intervention., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Boric acid (BA) is an essential trace element that is required to support the metabolic pathways in plants, humans, and animals. The present study investigates the in vitro development and quality of single-cell mouse embryos in a BA-added culture medium after cryopreservation using the solid-surface vitrification method. For this purpose, the pronuclear-stage embryos derived from superovulated C57Bl/6j mouse strains and the one-cell embryos were then cryopreserved using the solid-surface vitrification (SSV) method. After thawing, the embryos were cultured in a BA-added medium at 37 °C in a 5% CO 2 environment until the blastocyst stage. The resulting in vitro development rates of the embryos in the control group, SSV group, and SSV + 1.62 × 10 -4 μM BA group were 68.11% (36/59), 40.16% (16/48), and 64.92% (28/48) respectively, indicating that the BA supported the in vitro development of the embryos cryopreserved using the SSV method. Our results suggest that the addition of boric acid to the culture media increased the development rate of the embryos that were vitrified using the SSV method., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

T-cell acute lymphoblastic leukemia (T-ALL) is a type of acute lymphoblastic leukemia from early T-cell progenitors. Interest grows in creating less toxic agents and therapies for chemo-resistant T-ALL cancer. Recently, elemental boron has special properties useful in the creation of new drugs. Studies have revealed the cytotoxic properties of boric acid (BA) on cancer, but not fully understood. We aimed to investigate the effect of BA on cell proliferation, apoptosis, and oxidative stress in the Jurkat cells. The effects of BA on cell viability were determined by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay for 24-48-72 h. The impact of BA on apoptosis was analyzed by acridine orange/ethidium bromide. Expression of apoptosis regulatory genes (Bcl-2, Bax, Caspase-3-8-9) and apoptotic miRNA (miR-21) was used by real-time quantitative polymerase chain reaction (RT-qPCR). The total oxidant status (TOS), total antioxidant status (TAS), and the oxidative stress index (OSI) value were calculated for oxidative stress. We determined the cytotoxic activity of BA on Jurkat cells by using XTT and defined the IC 50 concentration (802.7 μg/mL) of BA. The findings clearly show that BA inhibited Jurkat cell proliferation dose-dependently. BA induced apoptosis through downregulated anti-apoptotic genes, and upregulated pro-apoptotic genes. Additionally, we found that BA significantly reduced the expression of miR-21 (p<0.001). Our findings demonstrated that different doses of BA increased TAS levels while decreasing TOS levels in Jurkat cells. Our study suggests that BA might be potential anti-cancer agent candidate in ALL via inhibition of cell proliferation, induced apoptosis, and reducing the amounts of anti-oxidants in cells., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In our study, we aimed to examine possible prophylactic (P) or therapeutic (T) effects of boric acid (BA) on lipopolysaccharide (LPS) induced liver and kidney damages. Thirty-two rats were divided into four groups as control, LPS, BAP+LPS, and LPS+BAT. BA was given orally to the rats one hour before the intraperitoneal LPS administration in the BAP+LPS group and one hour after the LPS administration in the LPS+BAT group. Malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-6 (IL-6), IL-10, reduced glutathione (GSH), total oxidant and antioxidant status (TOS and TAS), semaphorin-3A (SEMA3A), cytochrome c (CYCS), and caspase-3 (CASP3) parameters were determined by ELISA method to monitor inflammation, oxidative stress, and apoptosis in the liver and kidney tissues of rats. In addition, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine (CREA), C-reactive protein (CRP), gamma glutamyl transferase (GGT), glucose (GLU), sodium (Na), potassium (K), and chlorine (Cl) biochemical parameters were measured in rat serums to monitor liver and kidney functions. Liver and kidney tissues were also examined histopathologically and immunohistochemically. All data were statistically analyzed. Our histological, biochemical, inflammatory, oxidative stress, and apoptotic findings showed that LPS causes serious damage to liver and kidney tissues. Boric acid application brought about significant improvements on the parameters. However, this improvement was seen in the BAP+LPS group, and the results of the LPS+BAT group were insufficient to improve. Our results showed that boric acid administration is effective on severe liver and kidney damage caused by LPS. It has been concluded that prophylactic application is more effective, while therapeutic application is insufficient., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glioblastoma (GBM) is a common and highly lethal form of brain cancer. Temozolomide (TMZ) is the primary chemotherapy used for GBM, but it has limited effectiveness, with about half of the patients developing resistance. Iron regulatory proteins (IRPs) modulate genes involved in iron metabolism, while the nuclear receptor coactivator 4 (NCOA4) controls iron metabolism through a process called ferritinophagy. In this study, we investigated whether boric acid increases chemosensitivity mediated by ferritinophagy via the NCOA4 and IRP2 signaling pathways in TMZ-resistant GBM cells. First, we generated TMZ-resistant GBM cells (A172-R and T98G-R cells). Next, we investigated the effects of boric acid on cell viability, proliferation, cell cycle, and cell morphology in these cells. Additionally, following boric acid treatment, we analyzed the expression and protein levels of various biochemical markers in these cells. Boric acid treatment in A172-R and T98G-R cells suppressed cell viability and proliferation, arrested these cells in the G1/G0 cell cycle, and induced morphological differences. Boric acid increased NCOA4, IRP2, iron, and malondialdehyde (MDA) levels in A172-R and T98G-R cells, while glutathione (GSH) and glutathione peroxidase 4 (GPx4) levels decreased. Moreover, boric acid treatment increased intracellular iron levels and lipid peroxidation by inducing NCOA4 and IRP2 expression levels in TMZ-resistant cells. According to our results, boric acid may regulate chemosensitivity in A172-R and T98G-R cells mediated by NCOA4 and IRP2. In conclusion, the manipulative effects of boric acid on the ferritinophagy pathway hold the potential to sensitize TMZ-resistant GBM cells to chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ovarian ischemia is a gynecological emergency that occurs as a result of ovarian torsion, affects women of reproductive age, and reduces ovarian reserve. The current study was designed to investigate the effect of boric acid taken in different ways on histopathological changes, autophagy, oxidative stress, and DNA damage caused by ischemia and reperfusion in the ovary of adult female rats. We established seven groups of 70 adult female rats: untreated control, intraperitoneal boric acid group (IpBA), oral boric acid group (OBA), ischemia/reperfusion group (ischemia/2 h reperfusion; OIR), ischemia/reperfusion and local boric acid group (OIR + LBA), ischemia/reperfusion and intraperitoneal boric acid group (OIR + IpBA), and ischemia/reperfusion and oral boric acid group (OIR + OBA). On the 31st day of the experimental procedure, both ovaries were harvested for histologic (hematoxylen and eosin and Masson trichrom), biochemical (ELISA and AMH, MDA, SOD, and CAT analyses), and comet evaluation. In the OIR group, hemorrhage, edema, inflammation, and diminished follicle reserve were seen in the ovary. Boric acid treatment reduced the ovarian ischemia/reperfusion damage, and the follicles exhibited similar morphological features to the control group. Moreover, boric acid treatment decreased the levels of Hsp70, NF-KB, COX-2, and CD31, which increased as a result of OIR. On the other hand, SCF and AMH levels, which decreased as a result of OIR, increased with boric acid treatment. The levels of autophagy markers (Beclin-1, LC3, and p62) reached values close to those of the control group. According to the biochemical findings, it was concluded that boric acid is also effective on oxidative stress, and the AMH level was particularly high in the OIR + OBA group, consistent with the immunohistochemical staining result. In addition, it was observed that the DNA damage caused by OIR reached values close to those of the control group, especially in the OBA after OIR. This study showed the therapeutic effects of boric acid on OIR injuries; thus, boric acid may be a potential therapeutic agent for ovarian protection and fertility preservation in cases that may cause ovarian torsion., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Boric acid (BA) is a naturally occurring weak Lewis acid containing boron, oxygen, and hydrogen elements that can be found in water, soil, and plants. Because of its numerous biological potentials including anti-proliferation actions, the present investigates the chemopreventive possessions of BA on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. Thirty laboratory rats were divided into 5 groups: negative control (A) received two subcutaneous inoculations of normal saline and nourished on 10% Tween 20; groups B-E had two injections of 15 mg/kg azoxymethane followed by ingestion of 10% Tween 20 (B, cancer control), inoculation with intraperitoneal 35 mg/kg 5-fluorouracil injection (C, reference group), or ingested with boric acid 30 mg/kg (D) and 60 mg/kg (E). The gross morphology results showed significantly increased total colonic ACF in cancer controls, while BA treatment caused a significant reduction of ACF values. Histopathological evaluation of colons from cancer controls showed bizarrely elongated nuclei, stratified cells, and higher depletion of the submucosal glands than that of BA-treated groups. Boric acid treatment up-surged the pro-apoptotic (Bax) expression and reduced anti-apoptotic (Bcl-2) protein expressions. Moreover, BA ingestion caused upregulation of antioxidant enzymes (GPx, SOD, CAT), and lowered MDA contents in colon tissue homogenates. Boric acid-treated rats had significantly lower pro-inflammatory cytokines (TNF-α and IL-6) and higher anti-inflammatory cytokines (IL-10) based on serum analysis. The colorectal cancer attenuation by BA is shown by the reduced ACF numbers, anticipated by its regulatory potentials on the apoptotic proteins, antioxidants, and inflammatory cytokines originating from AOM-induced oxidative damage., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study aimed to examine the anti-inflammatory properties of boric acid (BA) in treating knee osteoarthritis (KOA) in rats, evaluating its biochemical and histopathological therapeutic effects. A KOA rat model was induced by injecting monosodium iodoacetate into the knee joint. Random assignment was performed for the experimental groups as follows: group-1(control), group-2(KOA control), group-3 (BA:4 mg/kg, orally), group-4(BA:10 mg/kg, orally), group-5(BA:4 mg/kg, intra-articularly), and group-6(BA:10 mg/kg, intra-articularly). The rats received 100 µL of BA intra-articularly on days 1, 7, 14, and 21 or 1 mL orally once a day (5 days/week) for 4 weeks. Serum levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and activity of matrix metalloproteinase-13 (MMP-13) were measured. Histopathological and immunohistochemical analyses were performed on knee joint samples using specific antibodies for IL-1β, TNF-α, MMP-13, and nitric oxide synthase-2 (NOS-2). Group-2 exhibited higher serum IL-1β and TNF-α levels and MMP-13 activity than group-1 (P < 0.05). However, IL-1β and TNF-α levels and MMP-13 activity were lower in all treatment groups than in group-2, with statistically significant reductions observed in groups-4, 5, and 6. Histopathologically, group-2 displayed joint space narrowing, cartilage degeneration, and deep fissures. Groups-5 and 6 demonstrated significant joint space enlargement, articular cartilage tissue regeneration, and immunostaining patterns similar to those in group-1. Immunohistochemically, group-2 showed significant increases in IL-1β, TNF-α, MMP-13, and NOS-2 expression. However, all treatment groups exhibited reductions in these expression levels compared to group-2, with statistically significant decreases observed in groups-5 and 6 (P < 0.01). BA shows potential efficacy in reducing inflammation in experimental KOA model in rats. It may be a promising therapeutic agent for KOA, warranting further clinical studies for validation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, we reported boric acid's protective effects on the quality of nonylphenol (NP)-exposed oocytes. Female rats were classified into 4 groups: control, boric acid, NP, and NP+boric acid. Histopathological studies and immunohistochemical analysis of anti-müllerian hormone (AMH), mechanistic target of rapamycin (mTOR), Sirtuin1 (SIRT1), stem cell factor (SCF) studies were done. The comet assay technique was utilized for DNA damage. The ELISA method was used to determine the concentrations of oxidative stress indicators (SOD, CAT, and MDA), ovarian hormone (INH-B), and inflammation indicators (IL-6 and TNF-α). Boric acid significantly reduced the histopathological alterations and nearly preserved the ovarian reserve. With the restoration of AMH and SCF, boric acid significantly improved the ovarian injury. It downregulated SIRT1 and upregulated the mTOR signaling pathway. It provided DNA damage protection. Ovarian SOD, CAT levels were decreased by boric acid. Boric acid co-administration significantly reduced NP's MDA, IL-6, and TNF-activities. This results imply that boric acid has a protective role in ovarian tissue against NP-mediated infertility., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The study aimed to evaluate the therapeutic effect of boric acid (BA) in experimentally induced septic arthritis. A total of 30 rats, 6 rats in each group (5 groups), were used in the study. No treatment was applied to the rats in the control group. Only BA was administered intraperitoneally (IP) to the rats in the bor group. Escherichia coli was administered at a single dose of 25 μL, 1 × 10 10  cfu/rat from the right foot pad of the rats, via intra-articular route, to the mice in the arthritis, arthritis-bor, and arthritis-antb groups. Then, BA at a dose of 50 mg/kg and cefazolin at a dose of 25 mg/kg were administered to the rats in the arthritis-bor and arthritis-antb groups, respectively, for 7 days via the IP route. At the end of the study, all animals were euthanized following the ethical rules. Blood and tissue samples were taken from the rats for biochemical and histopathological analyses. The levels of GSH, MDA, Endoglin, Endocan, and TNF-β markers were measured in the blood samples taken. A significant decrease was observed in MDA and Endoglin levels in the boric acid-administered group compared with the arthritis group, while a significant increase was observed at the GSH level. Histopathologically, it was determined that the reactive surrounding tissue response in the bor group was significantly reduced. As a result, a significant decrease in inflammation was found biochemically and histopathologically in the groups treated with BA., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Synaptosomes are used as an ex vivo model in the investigation of neuronal transmission and neurodegenerative processes. In this study, we aimed to determine the protective effects of boric acid (BA) and curcumin, which have antioxidant and anti-inflammatory properties, on Aβ1-42 induced neurodegenerative damage. Synaptosomes obtained from the rat cerebral cortex were divided into five groups: control, 10 μM Aβ1-42, 10 μM Aβ1-42 + 25 mM BA, 10 μM Aβ1-42 + 10 μM curcumin, and 10 μM Aβ1-42 + 25 mM BA+10 μM curcumin. Synaptosomes treated with Aβ1-42 caused a significant decline in synaptophysin levels and increase in malondialdehyde (MDA) levels, acetylcholinesterase (AChE) activities, DNA fragmentation values, and nitric oxide (NO) levels compared with the control group (P < 0.01). Synaptosomes treated with BA showed a significant reduction in MDA and NO levels against Aβ1-42 exposure (P < 0.01). In addition, curcumin treatment has been found to cause a significant reduction in AChE activities and MDA levels in synaptosomes (P < 0.05). Co-administration of BA and curcumin on synaptosomes exposed to Aβ1-42 resulted in a significant decrease in DNA fragmentation values, MDA levels, and AChE activities. Curcumin and BA + curcumin combination showed an enhancement in synaptophysin levels of Aβ1-42-induced synaptosomes (P < 0.01). The results showed that BA and curcumin had protective effects on rat brain synaptosomes against Aβ1-42 exposure. BA and curcumin treatment can have abilities to prevent the alterations of the cholinergic system and inhibit oxidative stress in the cerebral cortex synapses of Aβ1-42 exposed., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Boric acid and omega-3 are used as essential elements for both animal and human health. Many researchers have shown these beneficial effects on cardiac and inflammatory markers. This study aims to evaluate cardiac protective effect of boric acid and omega-3 against MI (myocardial infarction), probably due to the suppression of pro-inflammatory cytokines of natriuretic peptides in rats. Fifty male Sprague-Dawley rats were randomly divided into five groups: control, MI, MI+boric acid, MI+omega-3, and MI+boric acid+omega-3. Saline solution (2 ml/day), omega-3 (800 mg/kg/day), and boric acid (100 mg/kg/day)+omega-3 (800 mg/kg/day) were orally administered to the relevant groups throughout the 28 days. To constitute the MI model, the rats were exposed to isoproterenol-HCl (ISO) (200 mg/kg, S.C.) on the 27th and 28th. In the MI group, serum levels of CK-MB, BNP, and TNF-α are increased significantly. Also, ST waves and heart rates were higher in the MI than the control. These results demonstrate that biochemical results healed in MI+boric acid, MI+omega-3, and MI+boric acid+omega-3 groups compared MI group. ECG and light microscope results supported the findings as well. The statistical analysis showed that boric acid and/or omega-3 has protective effects on cellular damage in MI.

Ischemia/reperfusion (I/R) injury is associated with a strong inflammatory and oxidative stress response to hypoxia and reperfusion that impair organ function. We aimed to investigate the role of oxidative stress, renal inflammation, and apoptosis in the injury of the kidney tissue after ischemic reperfusion, and the protective effect of dose-dependent boric acid administration. For this purpose, 35 Sprague Dawley albino rats were divided into five groups of seven animals in each group: Sham, I/R and I/R + boric acid (BA) (i.p at doses of 50, 100, and 200 mg/kg). All animals underwent nephrectomy (the right kidney was removed) and were expected to recover for 15 days. After recovery, each animal received 45 min of ischemia. BA was injected intraperitoneally 10 min before reperfusion and a 24-h reperfusion procedure was performed. Sham group only underwent surgical stress procedure. In order to investigate the oxidative stress induced by I/R injury and antioxidant effects of different BA doses in the kidney tissue, TAS, TOS, MDA, SOD, CAT, and GSH levels were measured. DNA fragmentation, cytochrome C levels, caspase 3 activity were measured to determine apoptotic index in tissue. IL-6 and TNF-α levels were measured in the evaluation of inflammation. Hematoxylin-eosin and TUNEL staining was performed for histopathological examinations. As a result, increased oxidative stress, inflammation, and apoptosis after I/R were decreased with different doses of BA treatment. The application of high-dose BA was found to be lower in anti-apoptotic, anti-inflammatory, and antioxidant effects than in the low-dose groups.

Boric acid is known to regulate the proliferation of cancer cells. Prostate cancer is among the types of cancer with high mortality in men. There are a few numbers of studies investigating the effects of boric acid on prostate cancer cells. The objective of the present study was to assess the effects of boric acid at concentrations higher than that can be achieved in blood by dietary intake on DU-145 human prostate cancer cells for 24 h. Firstly, we determined the cytotoxic activity of boric acid (0 to 12.5 mM) on DU-145 human prostate cancer cells by using 3-(4, 5-dimethylthiazol, 2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) and defined the IC50 concentration of boric acid. Then, by employing the doses found in MTT, the levels of antioxidant-oxidant molecules and apoptotic proteins were measured and morphological changes were evaluated. We have concluded that boric acid caused oxidative stress, inhibition of cell growth, apoptosis, and morphological alterations in a concentration-dependent manner in DU-145 cells. Furthermore, treatments with increasing boric acid concentrations decreased the antioxidant levels in cells. We actually revealed that boric acid, known as an antioxidant, may prevent cell proliferation by acting as an oxidant in certain doses. Although the high IC50 concentration of boric acid is perceived to be negative, we think it provides important background for subsequent studies.

Ischemia reperfusion (I/R) injury which causes kidney dysfunction is one of the most studied diseases directly linked to oxidative stress. In this regard, it is important to protect cells against damage by inducing antioxidant response. Herein, we aimed to evaluate the therapeutic roles and possible mechanisms of propolis and boric acid in kidney I/R injury based on relevant basic research and clinical studies. Sprague-Dawley rats were subjected to 50 min of ischemia followed by 3 h of reperfusion. Animals were randomly divided into a control group (the abdominal wall was just opened and closed), an I/R injury group, the propolis intervention group (200 mg/kg, intragastric administration, 1 h before ischemia), boric acid intervention group (14 mg/kg, intragastric administration 1 h before ischemia), and the propolis + boric acid intervention group (intragastric administration 1 h before ischemia). Kidney function, the antioxidant defensive system, and renal damage were assessed. In addition, the oxidative stress and inflammatory status were estimated in renal tissue. Furthermore, DNA damageand apoptosis were detected by immunohistochemistry. When compared with I/R group, propolis alone and especially propolis + boric acid groups significantly improved functional parameters. While the antioxidant response was increased, renal injury size and apoptosis were significantly decreased in both groups. Also, the MDA and TNF-α levels besides the 8-OHdG formation were downregulated. According to these outcomes, it can be said that especially propolis together with boric acid ameliorates kidney injury caused by I/R through acting as an antioxidant, anti-inflammatory, and antiapoptotic agent. In conclusion, propolis alone and its combination with boric acid could be developed as therapeutic agents against serious renal I/R injuries.

Boron is abundant in vegetables, nuts, legumes, and fruit and intake is associated with reduced risk of cancer and DNA damage and increased antioxidant status. Blood boric acid (BA) levels are approximately 10 μM BA in men at the mean US boron intake. Treatment of DU-145 human prostate cancer cells with 10 μM BA stimulates phosphorylation of elongation initiation factor 2α (eIF2α) at Ser51 leading to activation of the eIF2α/ATF4 pathway which activates the DNA damage-inducible protein GADD34. In the present study, we used MEF WT and MEF PERK (±) cells to test the hypothesis that BA-activated eIF2α phosphorylation requires protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activates Nrf2 and the antioxidant response element (ARE). BA (10 μM) increased phosphorylation of eIF2α Ser51 in MEF WT cells at 1 h, but not in MEF Perk -/- cells exposed for as long as 6 h. GCN2 kinase-dependent phosphorylation of eIF2α Ser51 was activated in MEF PERK -/- cells by amino acid starvation. Nrf2 phosphorylation is PERK dependent and when activated is translocated from the cytoplasm to the nucleus where it acts as a transcription factor for ARE. DU-145 cells were treated with 10 μM BA and Nrf2 measured by immunofluorescence. Cytoplasmic Nrf2 was translocated to the nucleus at 1.5-2 h in DU-145 and MEF WT cells, but not MEF PERK -/- cells. Real-time PCR was used to measure mRNA levels of three ARE genes (HMOX-1, NQO1, and GCLC). Treatment with 10 μM BA increased the mRNA levels of all three genes at 1-4 h in DU-145 cells and HMOX1 and GCLC in MEF WT cells. These results extend the known boric acid signaling pathway to ARE-regulated genes. The BA signaling pathway can be expressed using the schematic [BA + cADPR → cADPR-BA → [[ER] i Ca 2+ ↓] → 3 pathways: PERK/eIF2αP → pathways ATF4 and Nrf2; and [[ER] i Ca 2+ ↓] → ER stress → ATF6 pathway. This signaling pathway provides a framework that links many of the molecular changes that underpin the biological effects of boron intake.

The nuclear-related factor 2 (Nrf2) pathway is the most important mechanism in antioxidant capacity, which regulates the cell's redox homeostasis. In addition, Nrf2 pathway also can inhibit cell apoptosis. The mechanism of boron actions on various organs is well documented. But, it is not known whether boron can also regulate the Nrf2 pathway in the kidneys. Therefore, in this research, the actions of boron on the kidneys of ostrich chicks, especially the antioxidant effects, have been studied. The ostrich chicks were divided into six groups and supplemented with boric acid (BA) (source of boron) in the drinking water (0, 40, 80, 160, 320, 640 mg respectively) to examine apoptotic, antioxidant, biochemical, and histochemical alterations induced by boron administration in the ostrich chick's kidney. The cellular apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. The relative antioxidant enzymes (T-AOC, MDA, GSH-Px, SOD, GR, CAT) and biochemical indices (ALT, AST, ALP, CK, LDH, BUN, CREA, UA) in the kidney were determined by spectrophotometric method. The expression of three important genes in the antioxidant pathway (Nrf2, HO-1, GCLc) was measured by quantitative real-time PCR (qPCR), and the localization of key regulator Nrf2 was examined by immunohistochemistry (IHC) method. Western blotting was also performed to further validate our results. Our results revealed that low doses of boron (up to 160 mg) had positive effect, while high doses (especially 640 mg) caused negative effect on the development of the kidney. The cellular apoptosis was in a biphasic manner by altering the boron quantities. The low doses regulate the oxidative and enzyme activity in the kidney. The IHC and western blot showed maximum localization of Nrf2 in 80 mg/L BA dose group. Furthermore, supplementation of boron at low doses upregulated the expression of genes involved in the antioxidant pathway. Taken together, the study demonstrated that low levels of boron (up to 160 mg) inhibited the cell apoptosis, regulate the enzyme activity, and improved the antioxidant system, thus may encourage the development of the ostrich chick's kidney, while a high amount of boron especially 640 mg/L promoted cell apoptosis and reduced the antioxidant capacity, thus caused negative effect to the ostrich chick's kidney.

In this study, we evaluated the effect of boron (B) as boric acid (BA) on body weight (b.w.); blood glucose; plasma insulin; lipase and paraoxonase (PON1) activities; and serum triglyceride, total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, lipid peroxidation (MDA), and total antioxidant capacity (TAC) in streptozotocin (STZ)-induced experimental diabetes in rats. Sixty Wistar albino rats (200-250 g) were divided into six groups of ten. The groups received the following treatment: group 1, control group; group 2, 50 mg/kg (b.w.) i.p. STZ-induced diabetes; group 3, 5 mg/kg (b.w.) B; group 4, 10 mg/kg (b.w.) B; group 5, diabetes + 5 mg/kg (b.w.) B; and group 6, diabetes + 10 mg/kg (b.w.) B. The experiment lasted 4 weeks. Increased serum MDA levels with diabetes were significantly reduced and although it is not statistically significant, serum TAC levels approached to values of control group; also, insignificant increases were observed in HDL cholesterol levels in experimental diabetic rats with treatment 5 and 10 mg/kg B. Furthermore, body weight, plasma insulin, and lipase activities increased insignificantly, blood glucose and serum LDL cholesterol decreased significantly, and total cholesterol levels decreased insignificantly in the diabetes + 10 mg/kg B group. There was no difference between the groups in terms of plasma PON1 activities and serum triglyceride levels. In conclusion, B may have beneficial effects on some biochemical parameters changes in experimental diabetes, and in order to determine the full effect of this element on the metabolism, further studies are required which use various dosages and compounds of B.

Trichophyton rubrum is a common human dermatophyte that is the causative agent of 80-93% of fungal infections of the skin and nails. While dermatophyte infections in healthy people are easily treatable with over-the-counter medications, such infections pose a higher risk for patients with compromised immune function and impaired regenerative potential. The efficacy of boric acid (BA) for the treatment of vaginal yeast infections prompted an investigation of the effect of BA on growth and morphology of T. rubrum. This is of particular interest since BA facilitates wound healing, raising the possibility that treating athlete's foot with BA, either alone or in combination with other antifungal drugs, would combine the benefits of antimicrobial activity and tissue regeneration to accelerate healing of infected skin. The data presented here show that BA represses T. rubrum growth at a concentration reported to be beneficial for host tissue regeneration. Oxygen exposure increases BA toxicity, and mycelia growing under BA stress avoid colonizing the surface of the growth surface, which leads to a suppression of aerial mycelium growth and surface conidia formation. BA penetrates into solid agar matrices, but the relative lack of oxygen below the substrate surface limits the effectiveness of BA in suppressing growth of embedded T. rubrum cells.

Fruits, nuts, legumes, and vegetables are rich sources of boron (B), an essential plant nutrient with chemopreventive properties. Blood boric acid (BA) levels reflect recent B intake, and men at the US mean intake have a reported non-fasting level of 10 μM. Treatment of DU-145 prostate cancer cells with physiological concentrations of BA inhibits cell proliferation without causing apoptosis and activates eukaryotic initiation factor 2 (eIF2α). EIF2α induces cell differentiation and protects cells by redirecting gene expression to manage endoplasmic reticulum stress. Our objective was to determine the temporal expression of endoplasmic reticulum (ER) stress-activated genes in DU-145 prostate cells treated with 10 μM BA. Immunoblots showed post-treatment increases in eIF2α protein at 30 min and ATF4 and ATF6 proteins at 1 h and 30 min, respectively. The increase in ATF4 was accompanied by an increase in the expression of its downstream genes growth arrest and DNA damage-induced protein 34 (GADD34) and homocysteine-induced ER protein (Herp), but a decrease in GADD153/CCAAT/enhancer-binding protein homologous protein (CHOP), a pro-apoptotic gene. The increase in ATF6 was accompanied by an increase in expression of its downstream genes GRP78/BiP, calreticulin, Grp94, and EDEM. BA did not activate IRE1 or induce cleavage of XBP1 mRNA, a target of IRE1. Low boron status has been associated with increased cancer risk, low bone mineralization, and retinal degeneration. ATF4 and BiP/GRP78 function in osteogenesis and bone remodeling, calreticulin is required for tumor suppressor p53 function and mineralization of teeth, and BiP/GRP78 and EDEM prevent the aggregation of misfolded opsins which leads to retinal degeneration. The identification of BA-activated genes that regulate its phenotypic effects provides a molecular underpinning for boron nutrition and biology.

Boron is absorbed by the digestive and respiratory system, and it was considered that it is converted to boric acid (BA), which was distributed to all tissues above 90 %. The biochemical essentiality of boron element is caused by boric acid because it affects the activity of several enzymes involved in the metabolism. DNA damage repair mechanisms and oxidative stress regulation is quite important in the transition stage from normal to cancerous cells; thus, this study was conducted to investigate the protective effect of boric acid on DNA damage and wound healing in human epithelial cell line. For this purpose, the amount of DNA damage occurred with irinotecan (CPT-11), etoposide (ETP), doxorubicin (Doxo), and H 2 O 2 was determined by immunofluorescence through phosphorylation of H2AX (Ser139) and pATM (Ser1981) in the absence and presence of BA. Moreover, the effect of BA on wound healing has been investigated in epithelial cells treated with these agents. Our results demonstrated that H2AX (Ser139) foci numbers were significantly decreased in the presence of BA while wound healing was accelerated by BA compared to that in the control and only drug-treated cells. Eventually, the results indicate that BA reduced the formation of DNA double strand breaks caused by agents as well as improving the wound healing process. Therefore, we suggest that boric acid has important therapeutical effectiveness and may be used in the treatment of inflammatory diseases where oxidative stress and wound healing process plays an important role.

We explored the ability of local and systemic applications of boric acid (BA) to reduce the numbers of methicillin-resistant Staphylococcus aureus (MRSA) in a rat model of tibial osteomyelitis (OM), and compared boric acid with vancomycin (V). Implant-associated osteomyelitis was established in 35 rats. After 4 weeks, at which time OM was evident both radiologically and serologically in all animals, the rats were divided into five groups of equal number: group 1, control group (no local application of BA or other medication); group 2, V group; group 3, local BA + V group; group 4, local BA group; and group 5, local + systemic BA group. Serum total antioxidant status, and the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6, were measured. Pathological changes attributable to bone OM were evaluated using a grading system. Bacterial colony-forming units (CFUs) per gram of bone were counted. The lowest bacterial numbers were evident in group 3, and the bacterial numbers were significantly lower than that of the control group in all four test groups (p < 0.001). Group 3 also had the least severe bone infection (OM score 1.7 ± 1.1, p < 0.05). Upon histological and microbiological evaluation, no significant difference was evident between groups 2 and 3. Total antioxidant levels were significantly different in all treatment groups compared to the control group. Microbiological and histopathological evaluation showed that systemic or local application of BA was effective to treat OM, although supplementary V increased the effectiveness of BA.

Boric acid (BA) has positive effects on bone tissue. In this study, the effects of BA on fracture healing were evaluated in an animal model. Standard closed femoral shaft fractures were created in 40 male Sprague-Dawley rats under general anesthesia. The rats were allocated into five groups (n = 8 each): group 1, control with no BA; groups 2 and 3, oral BA at doses of 4 and 8 mg/kg/day, respectively; group 4, local BA (8 mg/kg); and group 5, both oral and local BA (8 mg/kg/day orally and 8 mg/kg locally). After closed fracture creation, the fracture line was opened with a mini-incision, and BA was locally administered to the fracture area in groups 4 and 5. In groups 2, 3, and 5, BA was administered by gastric gavage daily until sacrifice. The rats were evaluated by clinical, radiological, and histological examinations. The control group (group 1) significantly differed from the local BA-exposed groups (groups 4 and 5) in the clinical evaluation. Front-rear and lateral radiographs revealed significant differences between the local BA-exposed groups and the control and other groups (p < 0.05). Clinical and radiological evaluations demonstrated adequate agreement between observers. The average histological scores significantly differed across groups (p = 0.007) and were significantly higher in groups 4 and 5 which were the local BA (8 mg/kg) and both oral and local BA (8 mg/kg/day orally and 8 mg/kg locally), respectively, compared to the controls. This study suggests that BA may be useful in fracture healing. Further research is required to demonstrate the most effective local dosage and possible use of BA-coated implants.

Spinal fusion is among the most frequently applied spinal surgical procedures. The goal of the present study was to evaluate whether the local administration of boric acid (BA) improves spinal fusion in an experimental spinal fusion model in rats. Currently, there is no published data that evaluates the possible positive effects if the local administration of BA on posterolateral spinal fusion. Thirty-two rats were randomly divided into four independent groups: no material was added at the fusion area for group 1; an autogenous morselized corticocancellous bone graft was used for group 2; an autogenous morselized corticocancellous bone graft with boric acid (8.7 mg/kg) for group 3; and only boric acid was placed into the fusion area for group 4. The L4-L6 spinal segments were collected at week 6, and the assessments included radiography, manual palpation, and histomorphometry. A statistically significant difference was determined between the groups with regard to the mean histopathological scores (p = 0.002), and a paired comparison was made with the Mann-Whitney U test to detect the group/groups from which the difference originated. It was determined that only the graft + BA practice increased the histopathological score significantly with regard to the control group (p = 0.002). Whereas, there was no statistically significant difference between the groups in terms of the manual assessment of fusion and radiographic analysis (respectively p = 0.328 and p = 0.196). This preliminary study suggests that BA may clearly be useful as a therapeutic agent in spinal fusion. However, further research is required to show the most effective dosage of BA on spinal fusion, and should indicate whether BA effects spinal fusion in the human body.

Bone marrow stromal cells (BMSCs) have been well established as an ideal source of cell-based therapy for bone tissue engineering applications. Boron (B) is a notable trace element in humans; so far, the effects of boron on the osteogenic differentiation of BMSCs have not been reported. The aim of this study was to evaluate the effects of boron (0, 1, 10,100, and 1,000 ng/ml) on osteogenic differentiation of human BMSCs. In this study, BMSCs proliferation was analyzed by cell counting kit-8 (CCK8) assay, and cell osteogenic differentiation was evaluated by alkaline phosphatase (ALP) activity assay, Von Kossa staining, and real-time PCR. The results indicated that the proliferation of BMSCs was no different from the control group when added with B at the concentration of 1, 10, and 100 ng/ml respectively (P > 0.05); in contrast, 1,000 ng/ml B inhibited the proliferation of BMSCs at days 4, 7, and 14 (P < 0.05). By ALP staining, we discovered that BMSCs treated with 10 and 100 ng/ml B presented a higher ALP activity compared with control (P < 0.05). By real-time PCR, we detected the messenger RNA expression of ALP, osteocalcin, collagen type I, and bone morphogenetic proteins 7 were also increased in 10 and 100 ng/ml B treatment groups (P < 0.05). The calcium depositions were increased in 1 and 10 ng/ml B treatment groups (P < 0.05). Taken all together, it was the first time to report that B could increase osteogenic effect by stimulating osteogenic differentiation-related marker gene synthesis during the proliferation and differentiation phase in human BMSCs and could be a promising approach for enhancing osteogenic capacity of cell-based construction in bone tissue engineering.

There are now considerable evidences that boric acid has reproductive and developmental toxicity, but it is uncertain whether such toxicity is caused by estrogen-like effect. Our objective is to determine the estrogen-like effect of boric acid. Proliferation assay of MCF-7 human breast cancer cells, uterotrophic assay, measure assay of the estradiol (E2), proliferation assay of mucous membrane cells, and assay of estrogen receptor were conducted in this study. Boric acid could increase the weight of uterus of ovariectomized SD rats and the height of epithelium cells of mucous membrane, enhance the expression of the proliferating cell nucleus antigen, and reduce the density of estrogen receptors. However, boric acid could not affect the level of estradiol in serum and stimulate the proliferation of MCF-7 human breast cancer cells. In this study, boric acid exhibited the estrogen-like effect in vivo.

Postmenopausal women may benefit from dietary interventions in order to increase bone strength and prevent fractures. Dietary boron (B) may be beneficial for optimal calcium metabolism and, as a consequence, optimal bone metabolism. The present study evaluated the effects of boron, in the form of boric acid, with or without 17beta-estradiol (E2) supplementation (via subcutaneous implant), in ovariectomized (OVX) aged 13- mo-old F-344 rats. Boric acid was administered by gavage at a subtoxic dose (8.7 mg B/kg/d) for 40 d. Results indicate that serum level of minerals as well as osteocalcin (a marker of bone resorption) are dependent to a greater extent on the hormonal status of the animals than on boron supplementation. Boron treatment increased the E2-induced elevation of urinary calcium and magnesium. Bone mineral density (BMD) of the L5 vertebra and proximal femur was highest in the E2-treated groups; no increase in BMD was conferred by boron treatment. By histomorphometry of the proximal tibial metaphysis, osteoblastic, osteoid, and eroded surfaces were significantly suppressed by E2 treatment, but not by boron treatment. In biomechanical testing of femur and vertebra, neither E2 nor boron treatment significantly increased bone strength. At the levels given, boron alone provided no protection against OVX-induced osteopenia. In addition, combination therapy (B + E2) provided no additional benefits over those of 17beta-estradiol treatment alone in this aged rat model.

It has been shown that boric acid has well-defined biological effects such as stimulation of wound healing in vivo, release of growth factors and cytokines, and increase of the extracellular matrice turnover. We examined its action at the molecular level, using cell-free systems of transcription (isolated placenta nuclei) and translation (wheat germ extract). We found that 10 mM boric acid greatly increased RNA synthesis, measured by absorbance at 260 nm (x 6.4) or by [3H]-UTP uptake (x 11). Full-length functional mRNA was produced because proteins of 14-80 kDa were translated. Among these proteins, factors involved in angiogenesis and, subsequently, in wound healing (VEGF and TGFbeta) were identified by slot blot, whereas growth factors such as FGF1 and TNFalpha were not detected. These results demonstrate that boron may contribute to biological cell activities at both the transcription and translation levels. However, the mechanism of action is still not known.