Naringin attenuates oxaliplatin-induced nephrotoxicity and hepatotoxicity: A molecular, biochemical, and histopathological approach in a rat model.

Oxaliplatin (OXL) is a significant therapy agent for the worldwide increase in cancer cases. Naringin (4',5,7-trihydroxy flavonon 7-rhamnoglucoside, NRG) has a wide range of biological and pharmacological activities, including antioxidant and anti-inflammatory potentials. This research aimed to investigate NRG activity in OXL-induced hepatorenal toxicity. Accordingly, OXL (4 mg/kg b.w.) in 5% glucose was injected intraperitoneally on the first, second, fifth, and sixth days, and NRG (50 and 100 mg/kg b.w.) was given orally 30 min before to treatment. Biochemical, genetic, and histological methods were utilized to investigate the function tests, oxidant/antioxidant status, inflammation, apoptosis, and endoplasmic reticulum (ER) stress pathways in kidney and liver tissues. Administration of NRG demonstrated an antioxidant effect by increasing the activities of OXL-induced reduced antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and decreasing the elevated lipid peroxidation parameter malondialdehyde levels. Nuclear factor-κB, tumor necrosis factor-α, interleukin-1ß, and inducible nitric oxide synthase levels increased in OXL administered groups but reduced in NRG-treated groups. In the OXL-administered groups, NRG reduced the apoptosis-inducing factors Caspase-3 and B-cell lymphoma 2 (Bcl-2)-associated X protein levels, while elevating the antiapoptotic factor Bcl-2 levels. OXL triggered prolonged ER stress by increasing the levels of ER stress parameters activating transcription factor 6, protein kinase R-like ER kinase, inositol-requiring enzyme 1α, and glucose-regulated protein 78. Therefore, with the NRG administration, this activity was reduced and the ER stress level decreased. Taken together, it was found that OXL induced toxicity by increasing the levels of urea and creatinine, alanine transaminase, aspartate aminotransferase, and alkaline phosphatase activities, inflammation, apoptosis, ER stress, and oxidants in the liver and kidney tissue, and NRG had a protective effect by reversing the deterioration in these pathways.

Assessment of serum calprotectin as a marker of inflammation in cattle with traumatic reticuloperitonitis.

Calprotectin (CP) is an inflammatory marker. The aim of the current study was to investigate oxidative stress and changes in CP in cattle with traumatic reticuloperitonitis (TRP). The study was divided into two groups, experimental (TRP) and healthy control group, with 10 animals in each group. Total leucocyte count, neutrophil and lymphocyte counts were higher in the TRP group compared to the control group and this increase was statistically significant (P < 0.001). The level of malondialdehyde (MDA) in TRP group was statistically significantly higher than the control group (P < 0.001). The level of glutathione (GSH) in the TRP group was statistically significantly lower than in the control group (P < 0.001). Serum Amyloid A (SAA) and CP values were higher in the TRP group and this difference was statistically significant (P < 0.001). It was concluded as a result of ROC analysis that CP, which has similar values with SAA, can be used diagnostically to confirm the inflammatory status in cattle with TRP.

Long-term results of breast cancer patients who received IOERT as boost during BCS: A single-institution retrospective analysis.

Objectives: Intraoperative electron radiotherapy (IOERT) applied as boost to the tumor bed during breast conserving surgery is advantageous in terms of local recurrence in breast cancer patients. In addition, it has other advantages over the adjuvant boost RT such as no risk of tumor bed change, ease of sequencing radiotherapy chemotherapy, and reduced workload of the radiotherapy clinic. This study aimed to evaluate the long-term results of our patients who were treated with this method in our institution and are still being followed up. Material and Methods: One hundred and three patients enrolled in this study received IOERT equivalent to 10 Gy as boost during BCS and were subsequently given adjuvant WBI according to the biological subtype of the tumor systemic therapy. These patients were analyzed using their files and hospital records. Patients were evaluated for overall survival, local recurrence, distant metastasis, and cosmetic outcome (using LENT-SOMA scale). Results: Median age was 53,5 (27-74), mean follow-up time was 75 (48-106) months. Mean pathological tumor size was 18 mm (4-30), 90 of the patients had invasive ductal carcinoma, eight of them were lobular and five of them had mixed histological structure. Ninety-three of the patients presented histological grade II, 15 grade III; 74 patients were luminal A-like, 15 luminal B-like, eight HER2 positive and six triple negative breast cancer. According to the LENT-SOMA scale, 35 had grade 0, 42 each had grade I, 23 had grade II, and two had grade III. All patients underwent whole breast irradiation after surgery, 81 received chemotherapy and 90 endocrine therapy. There was one local recurrence, distant recurrence was seen in four patients and one patient died of non-breast cancer causes. Overall survival was %99, and event free survival %96. Conclusion: IOERT for breast cancer treatment during BCS is a safe option with low chronic toxicity and the cosmetic outcome gets better over time.

Prognostic potential of inflammatory markers, oxidative status, thrombocyte indices, and renal biochemical markers in neonatal calf diarrhoea-induced systemic inflammatory response syndrome.

The study aimed to assess the prognostic value of inflammatory markers, indicators of oxidative stress, thrombocyte indices, and renal biochemical markers in neonatal calf diarrhoea (NCD) induced by systemic inflammatory response syndrome (SIRS) upon admission. A prospective, observational, and case-control study was conducted on 56 calves diagnosed with NCD. Mean concentrations of interleukin-6 (IL-6), malondialdehyde (MDA), glutathione (GSH), mean platelet volume (MPV), platelet distribution width (PDW), blood urea nitrogen (BUN), and creatinine (Crea) were measured. Furthermore, the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were also calculated for SIRS survivors [SIRS (survivor)] and non-survivors [SIRS (non-survivor)] induced by NCD. A prognostic cut-off value for predicting the prognosis of the SIRS's induced by NCD was obtained via receiver operating characteristic (ROC) curve analysis. Upon admission, the SIRS (non-survivor) calves had significantly higher (P < .001) average levels of IL-6, MDA, BUN, Crea, MPV, and PDW compared to the SIRS (survivor) calves and significantly lower (P < .001) average levels of GSH. Despite an apparent increase in the NLR and PLR values of calves diagnosed with SIRS, no significant difference was found between the survival and non-survivor SIRS cases. Positive predictive values (PPVs) for survival were determined as 100 %, 100 %, 80 %, 100 %, 80 %, and 80 %, respectively, using cut-off values of IL-6 (≤259.67 ng/L), MDA (≤2.87 nmol/mL), MPV (≤12.5 fL), PDW (≤34.25 %), BUN (≤168.3 mg/dL), and Crea (≤2.11 mg/dL). The determined threshold values are those obtained upon admission to the hospital. Based on the sensitivity, specificity, and PPVs derived from the ROC analysis, it has been concluded that IL-6, MDA, MPV, PDW, BUN, and Crea are the most relevant biomarkers used for predicting the prognosis of NCD-induced SIRS in calves. Furthermore, it is also noteworthy that IL-6 exhibited the highest effectiveness among all biomarkers.

Hesperidin has a protective effect on paclitaxel-induced testicular toxicity through regulating oxidative stress, apoptosis, inflammation and endoplasmic reticulum stress.

Paclitaxel (PTX) is widely used to treat a number of malignancies, although it has toxic side effects. Hesperidin (HES) has a wide range of biological and pharmacological properties, including anti-inflammatory and antioxidant abilities. This research aims to investigate the role of HES in PTX-induced testicular toxicity. For 5 days, 2 mg/kg/bw i.p. of PTX was administered to induce testicular toxicity. Rats were administered oral dosages of 100 and 200 mg/kg/bw HES for 10 days after PTX injection. The mechanisms of inflammation, apoptosis, endoplasmic reticulum (ER) stress, and oxidants were investigated using biochemical, genetic, and histological techniques. As a result of PTX administration, decreased antioxidant enzyme (superoxide dismutase, catalase, and glutathione peroxidase) activities and increased malondialdehyde level were regulated, and the severity of oxidative stress was reduced. NF-κB, IL-1ß and TNF-α levels, which are among the increased inflammation parameters caused by PTX, decreased with HES administration. Although AKT2 gene expression decreased in PTX administered rats, it was determined that HES administration up-regulated AKT2 mRNA expression. Anti-apoptotic Bcl-2 decreased with PTX administration, and apoptotic Bax and Caspase-3 increased while HES administration reverted these effects towards control level. As a result of toxicity, the increase in ATF6, PERK, IRE1α, GRP78 levels caused prolonged ER stress, and this activity was diminished with HES and tended to regress. While all data were evaluated, Paclitaxel caused damage by increasing inflammation, apoptosis, ER stress and oxidant levels in testicular tissue, and Hesperidin showed a protective effect by correcting the deterioration in these levels.

Investigation of hemogram, oxidative stress, and some inflammatory marker levels in neonatal calves with escherichia coli and coronavirus diarrhea.

Calf diarrhea is the most common disease affecting calves in the neonatal period resulting in economic losses. Although predisposing factors play a role in the etiology of the disease, in most cases, different pathogens are involved in the development of the infection. In this study, hemogram data, glutathione and malondialdehyde levels were examined to determine lipid peroxidation and glutathione levels in E. coli- and coronavirus-infected calves. Serum amyloid A and calprotectin levels were also analyzed to determine inflammatory status. The study included a total of 45 female Montofon calves aged 0-1 week, including the E. coli group (15 calves), the coronavirus group (15 calves), and the control group (15 calves). Analysis revealed that total leukocyte, neutrophil, lymphocyte, malondialdehyde, serum amyloid A, and calprotectin levels increased in the coronavirus-infected calves compared with the E. coli group and the control group. In contrast, the levels of glutathione, one of the antioxidant markers, decreased. In conclusion, the main findings related to the determination of inflammation and oxidative status were characterized by the presence of E. coli and coronavirus diarrhea, and it is suggested that future studies may be guided by the fact that inflammatory conditions are higher in viral disease than in bacterial infection.

Evaluation of protective effects of quercetin against cypermethrin-induced lung toxicity in rats via oxidative stress, inflammation, apoptosis, autophagy, and endoplasmic reticulum stress pathway.

Cypermethrin (CYP), a type II synthetic pyrethroid, is the most widely used insecticide worldwide. Inhalation of it may cause side effects. This study is aimed to examine potential protection of quercetin (QUE) which is a well-known antioxidant in CYP-induced lung toxicity. Accordingly, 35 Spraque Dawley male rats were divided into five equal groups as follows: I-Control group, II-QUE group (50 mg/kg/b.w. QUE), III-CYP group (25 mg/kg/b.w. CYP), IV-CYP + QUE 25 (25 mg/kg/b.w. CYP + 25 mg/kg/b.w. QUE), V-CYP + QUE (25 mg/kg/b.w. CYP + 50 mg/kg/b.w. QUE) were treated with oral gavage throughout 28 days. CYP intoxication was associated with increased malondialdehyde level while glutathione concentration, activities of glutathione peroxidase, superoxide dismutase, and catalase reduced. CYP adminisitration caused of apoptosis in the lung by up-regulating caspase-3 and Bax levels and down-regulating Bcl-2. CYP also caused of endoplasmic reticulum (ER) stress by increasing mRNA transcript levels of PERK, IRE1, ATF6, and GRP78. Additionally, it was observed that CYP administration activated IL-6/JAK2/STAT3/MAPK14 signaling pathway and levels of IL-1ß, NF-κB, TNF-α, and iNOS in the lung tissue. Therefore, it was determined that CYP administration triggered autophagy by upregulating LC3A and LC3B mRNA transcript levels. Moreover, the protein levels of NF-κB, caspase-3, Bax, Bcl-2, and cytochorme-c were examined by Western blot analysis. However, co-treatment with QUE at a dose of 25 and 50 mg/kg considerably protective oxidative stress, inflammation, apoptosis, ER stress, autophagy, and IL-6/JAK2/STAT3/MAPK14 signaling pathway in lung tissue. Overall, the findings of this study suggest that lung damage associated with CYP toxicity could be protected by QUE administration.

Hesperidin Attenuates Oxidative Stress, Inflammation, Apoptosis, and Cardiac Dysfunction in Sodium Fluoride-Induced Cardiotoxicity in Rats.

Excessive fluoride intake has been reported to cause toxicities to brain, thyroid, kidney, liver and testis tissues. Hesperidin (HSP) is an antioxidant that possesses anti-allergenic, anti-carcinogenic, anti-oxidant and anti-inflammatory activities. Presently, the studies focusing on the toxic effects of sodium fluoride (NaF) on heart tissue at biochemical and molecular level are limited. This study was designed to evaluate the ameliorative effects of HSP on toxicity of NaF on the heart of rats in vivo by observing the alterations in oxidative injury markers (MDA, SOD, CAT, GPX and GSH), pro-inflammatory markers (NF-κB, IL-1ß, TNF-α), expressions of apoptotic genes (caspase-3, -6, -9, Bax, Bcl-2, p53, cytochrome c), levels of autophagic markers (Beclin 1, LC3A, LC3B), expression levels of PI3K/Akt/mTOR and cardiac markers. HSP treatment attenuated the NaF-induced heart tissue injury by increasing activities of SOD, CAT and GPx and levels of GSH, and suppressing lipid peroxidation. In addition, HSP reversed the changes in expression of apoptotic (caspase-3, -6, -9, Bax, Bcl-2, p53, cytochrome c), levels of autophagic and inflammatory parameters (Beclin 1, LC3A, LC3B, NF-κB, IL-1ß, TNF-α), in the NaF-induced cardiotoxicity. HSP also modulated the gene expression levels of PI3K/Akt/mTOR signaling pathway and levels of cardiac markers (LDH, CK-MB). Overall, these findings reveal that HSP treatment can be used for the treatment of NaF-induced cardiotoxicity.

Neuromodulatory effects of hesperidin against sodium fluoride-induced neurotoxicity in rats: Involvement of neuroinflammation, endoplasmic reticulum stress, apoptosis and autophagy.

Fluoride is an element with toxic properties and has been proven to have some adverse effects on many soft tissues, including brain tissue. This study aims to evaluate the protective effects of hesperidin on sodium fluoride (NaF)-induced neurotoxicity in rats by biochemical and molecular methods. The animals were randomly divided into five groups of seven rats each as Control, hesperidin, NaF (600 ppm), NaF + hesperidin (100 mg/kg, b.w.), and NaF + hesperidin (200 mg/kg, b.w.), respectively; orally for two weeks. Hesperidin reduced lipid peroxidation and increased activities of SOD, CAT and GPx and levels of GSH in NaF-induced brain tissue. Hesperidin also showed anti-inflammatory and anti-autophagic effects by decreasing levels of NF-κB, IL-1B, TNF-α, Beclin-1, LC3A, and LC3B in NaF-induced brain tissue. Moreover, hesperidin was able to down-regulate the mRNA transcript levels of apoptosis and endoplasmic reticulum stress markers such as caspase-3, Bax, Bcl-2, PERK, IRE1, ATF6, and GRP78 in NaF-induced neurotoxicity. Hesperidin also reduced the adverse effects caused by NaF by modulating the PI3K/Akt/mTOR signaling pathway. These results demonstrate that hesperidin exhibits neuroprotective effects against NaF-induced neurotoxicity in rats by ameliorating inflammation, apoptosis, autophagy, and endoplasmic reticulum stress.

Investigation of the effects of hesperidin administration on abamectin-induced testicular toxicity in rats through oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, autophagy, and JAK2/STAT3 pathways.

In this study, the potential effects of hesperidin (HES) on chronic toxicity caused by abamectin (ABM) in the testicular tissue were investigated through oxidative stress, inflammation, endoplasmic reticulum stress (ERS), apoptosis, and autophagy pathways. Male Sprague Dawley rats were used in the study. Animals in the ABM group were orally administered 1 mg/kg ABM every other day for 28 days, while HES used against ABM was given at 100 or 200 mg/kg 30 min after ABM administration for 28 days. Markers of oxidative stress, inflammation, ERS, apoptosis, and autophagy in the testicular tissues removed after the animals are sacrificed were analyzed using biochemical, real-time polymerase chain reaction (RT-PCR), or western blot techniques. The results obtained showed that ABM caused oxidative stress, and triggered ERS, inflammation, apoptosis, and autophagy. On the other hand, HES showed antioxidant effect by increasing superoxide dismutase, catalase, glutathione peroxidase enzyme activities, and glutathione levels in testis tissue and attenuated lipid peroxidation. Accordingly, MAPK14 reduced the NF-κB, IL-1ß, TNF-α, and IL-6 expression levels, presenting an anti-inflammatory effect. In addition, Bax protected against apoptosis and autophagy by reducing the caspase-3, beclin-1, LC3A, and LC3B expressions, and increasing Bcl-2 expression. It was observed that HES also interrupted the JAK2/STAT3 signaling pathway by suppressing IL-6 expression. Taken into consideration together, HES provided significant protection against the destruction caused by ABM in testicular tissue with antioxidant, anti-inflammatory, antiapoptotic, and anti-autophagic effects. Thus, it was revealed that HES has the potential to serve as an alternative treatment option in ABM toxicity.

Morin protects against acrylamide-induced neurotoxicity in rats: an investigation into different signal pathways.

The presented study investigates the effects of morin against toxicity induced by acrylamide (ACR) in the brains of Sprague Dawley rats. In this study, neurotoxicity was induced by orally administering 38.27 mg/kg/b.w ACR to rats through gastric gavage for 10 days. Morin was administered at the same time and at different doses (50 and 100 mg/kg/b.w) with ACR. Biochemical and Western blot analyses showed that ACR increased malondialdehyde (MDA), p38α mitogen-activated protein kinase (p38α MAPK), nuclear factor kappa-B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), p53, caspase-3, bcl-2 associated X protein (Bax), Beclin-1, light chain 3A (LC3A), and light chain 3B (LC3B) levels and decreased those of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), b-cell lymphoma-2 (Bcl-2), mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt) in brain tissue and therefore induced neurotoxicity by causing oxidative stress, inflammation, apoptosis, and autophagy. On the other hand, it was determined that morin positively affected the levels of these markers by displaying antioxidant, anti-inflammatory, anti-apoptotic, and anti-autophagic properties and had a protective effect on ACR-induced neurotoxicity. As a result, morin is an effective substance against brain damage caused by ACR, yet further studies are needed to use it effectively.

Modulatory effects of carvacrol against cadmium-induced hepatotoxicity and nephrotoxicity by molecular targeting regulation.

AIM: Cadmium (Cd) is a toxic heavy metal that causes severe toxic effects on different tissues including liver and kidney. Therefore the research for alternatives to reduce the damage caused by Cd has substantial importance. This study was performed to examine the possible modulatory effects of carvacrol (CRV) against Cd-induced hepatorenal toxicities and the possible mechanisms underlying these effects. MATERIALS AND METHODS: In the present study, 35 male Wistar rats were randomly divided into 5 groups. The rats were treated with Cd (25 mg/kg) and treated with CRV (25 and 50 mg/kg body weight) for 7 consecutive days. KEY FINDINGS: CRV could modulate Cd-induced elevations of ALT, ALP, AST, urea, creatinine, MDA and enhance antioxidant enzymes' activities such as SOD, CAT, and GPx, and GSH's level. CRV also reversed the changes in levels of inflammatory biomarker and apoptotic genes that include NF-κB, Bcl-3, MAPK-14, iNOS, COX-2, MPO, PGE2, Bax, Bcl-2, P53, Caspase-9, Caspase-6 and Caspase-3 in both tissues. The levels of 8-OHdG in the Cd-induced liver and kidney tissues were modulated after CRV treatment. Furthermore, CRV treatment considerably lowered Cd, Na, Fe, and Zn content while increased K, Ca, Mg and Cu contents in both tissues as compared to the Cd-exposed rats. SIGNIFICANCE: The results of the present study revealed that CRV supplementation could be a promising strategy to protect the liver and kidney tissues against Cd-induced oxidative damage, inflammation and apoptosis.

Hyperfractionated accelerated radiotherapy in locally advanced head and neck cancers.

PURPOSE: Head and neck cancers are rapidly proliferating and relatively radiosensitive tumors. The increase in the number of daily fractions and the decrease in total treatment time give promising results in clinical practice. PATIENTS AND METHODS: 20 patients diagnosed with head and neck cancer between August 2000 and July 2001 participated in this study. Median age was 63 years (range: 42-78). The tumors were mainly located in the larynx (40%), and in the hypopharynx (25%). Daily doses of 1.5 Gy thrice a day in 6-h intervals were given on each of 12 consecutive days with the exception of weekends. RESULTS: Median follow-up was 22 months (range: 1-62). The overall response rate was 90%, and grade IIII early toxicity was 24%. No grade IV early toxicity was observed. Grade IV late toxicity was observed just in 1 case. 5-year rates for locoregional recurrence, distant metastasis, progression-free survival, and overall survival were 45, 20, 20, and 25%, respectively. CONCLUSION: Our schedule was acceptable regarding the toxicity. However, the high incidence of locoregional failures urges us to modify the treatment modality.