Objectives:This study investigated the protective effect of zinc supplementation on insulin release via modulation of the High Mobility Group Box 1 (HMGB1)/Toll-like receptor 2 (TLR2)/mitogen-activated protein kinase (MAPK) signaling pathway in streptozotocin (STZ)-induced pancreatic β-cell injury, a commonly used model of type 1 diabetes. Materials and Methods:Human pancreatic β-cells (1.1B4) were divided into five groups: Control, Diabetes, Diabetes + Zinc, Diabetes + Box A, and Diabetes + Zinc + Box A. Diabetes was induced with STZ (20 mM, four hours, type-1), followed by treatment with zinc (30 μM) and/or Box A (100 ng/l). Cellular oxidative stress, apoptosis, mitochondrial membrane potential (MMP), cell viability, and insulin secretion were measured. Protein expressions of HMGB1, TLR2/4, extracellular signal-regulated kinases 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) were analyzed using western blotting. Results:Zinc supplementation restored MMP and total antioxidant status (TAS), reduced apoptotic cell death, and enhanced TLR2 and ERK1/2 expression suppressed by STZ. Combined zinc and Box A treatment markedly increased insulin secretion under both hypo- and hyperglycemic conditions. Conclusion:Zinc exerts protective effects against STZ-induced β-cell damage, likely through modulation of the HMGB1/TLR2/MAPK axis. These findings highlight the therapeutic potential of zinc supplementation in protecting pancreatic β-cell function in diabetes mellitus.

This review discusses ATP-sensitive potassium (KATP) channels, which connect intracellular energy metabolism to cellular electrical activity and play crucial roles in various physiological processes, particularly in the pancreas and cardiovascular system. KATP channels open when ATP levels decrease during metabolic stress, such as ischemia, helping to protect the heart from injury by maintaining membrane potential and preventing calcium overload. These channels are found in multiple cell types across the cardiovascular system, influencing vascular tone and cardiac excitability. The review highlights the need for further research into the specific expression of KATP channel subunits in humans and the consequences of ischemic events on their functionality. Additionally, it explores the interplay between glycolysis and KATP channels, suggesting that glycolytic ATP can modulate KATP channel activity while emphasizing the cardioprotective effects during ischemic events. The potential for KATP channel openers (KCOs) as therapeutic agents for ischemic heart disease is noted, particularly in improving outcomes in patients undergoing cardiac procedures. Challenges remain in developing specific KCOs with minimal side effects, but advances in precision medicine may enhance targeted therapies in the future. Overall, KATP channels represent promising targets for enhancing cardiovascular health.

Objective: High-mobility group box-1 (HMGB1), known as an abundant and highly conserved nuclear protein, plays a pivotal role in initiating inflammation, tissue healing, and the immune response following various forms of cell damage. The chemokine C-X-C motif chemokine ligand 12 (CXCL12) forms a signaling axis known as CXCL12/ CXCR4/CXCR7, along with the receptors CXCR4 and CXCR7. Our study aimed to explore the connection between HMGB1 and the involved chemokine axis, CXCR4, CXCL12, and CXCR7, in the context of adriamycin-induced cardiotoxicity. Materials and Methods: We performed RNA interference to suppress HMGB1 expression in H9c2 cardiac myoblast cells. Adriamycin, an anti-tumor antibiotic known for causing cardiotoxicity, was used in conjunction with HMGB1 suppression. We investigated the combined and individual effects of these factors. Gene expression analysis was conducted through qRT-PCR 36 and 48 h post-treatment. Results: Adriamycin treatment increased the expression of CXCL12, CXCR4, and CXCR7. Notably, our study observed significant changes in gene expression when HMGB1 was downregulated and adriamycin was administered. These findings suggest potential molecular mechanisms associated with adriamycin-induced cardiotoxicity, emphasizing the significance of the CXCR4/CXCL12 axis and the impact of HMGB1 modulation. Conclusion: Our study provides insights into the molecular interplay between HMGB1 and the CXCL12/CXCR4/CXCR7 ligand-receptor axis in the context of adriamycin-induced cardiotoxicity. The results shed light on further research to enhance therapeutic approaches or advance new strategies to address this cardiotoxicity.

Doxorubicin (DOX)-induced cardiotoxicity is a well known clinical problem, and many investigations have been made of its possible amelioration. We have investigated whether diazoxide (DIA), an agonist at mitochondrial ATP-sensitive potassium channels (mitoKATP), could reverse DOX-induced apoptotic myocardial cell loss, in cultured rat cardiomyocytes. The role of certain proteins in this pathway was also studied. The rat cardiomyocyte cell line (H9c2) was treated with DOX, and also co-treated with DOX and DIA, for 24 h. Distribution of actin filaments, mitochondrial membrane potential, superoxide dismutase (SOD) activity, total oxidant and antioxidant status (TOS and TAS, respectively), and some protein expressions, were assessed. DOX significantly decreased SOD activity, increased ERK1/2 protein levels, and depolarised the mitochondrial membrane, while DIA co-treatment inhibited such changes. DIA co-treatment ameliorated DOX-induced cytoskeletal changes via F-actin distribution and mitoKATP structure. Co-treatment also decreased ERK1/2 and cytochrome c protein levels. Cardiomyocyte loss due to oxidative stress-mediated apoptosis is a key event in DOX-induced cytotoxicity. DIA had protective effects on DOX-induced cardiotoxicity, via mitoKATP integrity, especially with elevated SUR2A levels; but also by a cascade including SOD/AMPK/ERK1/2. Therefore, DIA may be considered a candidate agent for protecting cardiomyocytes against DOX chemotherapy.

The aim of this study was to investigate the protective and therapeutic effects of thymoquinone against the negative effects of varicocele on testicular tissue and sperm morphology. Five groups were formed by random selection from a total of 40 adult male Wistar rats (n = 8). Thymoquinone (5 mg/kg/day) was administered intraperitoneally to the varicocele-dimethyl sulfoxide-olive oil-thymoquinone (VT) group and the sham-thymoquinone group. At the end of the 60th day, all groups were anaesthetised and the left testis was removed from the body quickly. One half of the testis tissue, which was divided into two, was separated for biochemical and Western blot analysis, while the other half were fixed in Bouin's fixative. As a result of biochemical, molecular and histopathological analyses, a statistically significant increase was found in the varicocele group testicular tissues in the malondialdehyde level, apoptotic index, Bax expression, cytochrome c expression and Bax/Bcl-2 ratio compared with the sham group. In addition, histopathological changes characterised by partial or complete degeneration of the germinal epithelium were observed in the seminiferous tubules in the same group. Total oxidant status level and sperm count with abnormal morphology increased in varicocele group, whereas total antioxidant status level decreased. In the VT group, all of the biochemical, molecular and histopathological changes detected in the varicocele group were statistically significantly reduced. When the findings obtained in this study are evaluated, it can be said that thymoquinone has the potential to be used as a preventive and therapeutic pharmacological agent in the medical treatment of varicocele. Although the exact mechanism of action of thymoquinone has not been fully elucidated, the findings obtained in this study support the view that thymoquinone showed a cytoprotective effect by reducing apoptosis, oxidative stress and lipid peroxidation.

Background: Mobile phones as an electronic device which are emitting radiofrequency-electromagnetic field (RF-EMF). In this study was intend to determine the contingent effects of cell phone induced RF-EMF on testicular tissue in adolescence. Materials and Methods: Rats in the RF-EMF group were exposed to 900 MHz RF-EMF, while sham and control rats were not. After the completion of the test steps, the testicular tissues which were rapidly removed from the body of sacrificed rats were examined by using histopathological and biochemical methods. Testicular tissues cut to 5 mu m thickness undergo routine histological procedures. Thus, histopathological evaluation will be completed. Malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) levels in testicular tissues were measured by biochemical methods to determine whether oxidative stress occurred or not. Results: Histopathologic findings were not observed in any of the studied groups. There was also no difference between the groups in terms of localization of androgen and estrogen receptors. The incidence of apoptotic index and TUNEL-positive cells was similar in all three groups. In the RF-EMF group, although the levels of MDA and CAT were significantly higher, GSH levels were lower than the other groups. There was no essential difference between the groups in terms of SOD level. Conclusions: The obtained results of this study showed that exposed to 900 MHz RF-EMF in adolescents caused oxidative stress in the testes, but testicular damage which is caused to oxidative stress is remained too low to be detected by histopathological methods in this study.

OBJECTIVE:Maternal mood disorders such as postpartum depression (PPD) can negatively affect the lives not only of mothers but also of partners. The purpose of this study investigates emotional behavior and hippocampal apoptosis alterations of the male live with a postpartum depressed female.METHODS:Pregnant rats in the stress group were exposed to restraint stress (RS). The male rats who shared the same cages were not exposed to RS. To explain the consequences of depressive-like behavior and anxiety, animals were exposed to the forced swim test (FST), open-field test (OFT), and elevated plus maze (EPM). The apoptotic cell number was detected by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP biotin nick-end labeling (TUNEL) staining.RESULTS:According to FST, PPD caused more immobility, reduced swimming, and climbing compared to control groups in the stressed female and male (p < 0.05). For the crossing number of squares in the center area, the main effect of the group was significant (p < 0.05). Stressed groups have a higher crossing number of squares in the center area compared to control groups. In the OFT, there was a significant increase in the time spent in the center area in the stress female and male group compared to the control female and male group (p < 0.05). For the EPM, time spent in the close arms was increased in the control male and stress male compared to the stress female group (p < 0.05). Female and male rats with PPD demonstrated apoptosis in neuron and glial cells in the hippocampus.CONCLUSIONS:The present study demonstrates that RS results in PPD in females. Furthermore, it implicates RS as a potential risk factor for the development of postpartum mood disorder in males. Most of the studies on paternal PPD have been done by using self-report questionnaires. Studies on physiological and hormonal changes during the postpartum period among fathers would provide information on biological factors of depression.

Vulnerable areas like the hippocampus are sensitive to insults such as sleep deprivation (SD); they are also susceptible to environmental enrichment. Much evidence is accumulating that chronic sleep deprivation causes alterations in the hippocampus that responsible for spatial memory. However, there is conflicting about the differences between acute and chronic SD results. The purpose of this study was to determine the protective effects of mild treadmill exercise on acute SD rats. Four groups were created as control, exercise, sleep deprivation, exercise + sleep deprivation. Multiple platforms method was used to induce REM sleep deprivation (RD) for 48 h. The exercise was applied five days per week for four weeks (5 x 4). For the first and second weeks, the length of the exercise was 15 min in two sessions (5 min interval) followed by 15 min in three, 15 min in four sessions. Morris water maze (MWM) was used as a spatial memory test. Gene level was determined by using the qPCR technique. Malondialdehyde (MDA) content in the hippocampus was measured as an extent of peroxidative damage to lipids by using the ELISA method. 48 h RD impaired long-term spatial memory significantly. Mild, regular treadmill exercise ameliorated the detrimental effects of acute sleep deprivation on memory. There was no significant difference in MDA between groups. Hippocampal gene expression did not show any changes in all groups. Lack of correlation between memory impairment and levels of genes in the hippocampus is likely to be related to the differences in behavioral and genetic mechanisms.

The present study investigates the toxicity of the herbicide tribenuron methyl (TBM) as an anthropogenic agent and ammonia as an abiotic factor on Daphnia magna at environmentally relevant concentrations. These stressors may coexist in surface waters in agricultural regions. To achieve this objective, D. magna were exposed to TBM at a nominal concentration of 0.81 μg/L in association with a low ammonia (LA) concentration of 0.65 mg/L and a high ammonia (HA) concentration of 1.61 mg/L in acute toxicity tests of 96-h duration and chronic toxicity tests of 21-day duration. The D. magna also were exposed to TBM, HA, and LA singly. The D. magna were analysed for various biomarkers of sublethal toxicity. Glutathione peroxidase (GPx), glutathione S-transferase (GST), cholinesterase (ChE) enzyme activities, and levels of thiobarbituric acid reactive substances (TBARS) and total protein were determined spectrophotometrically. Mitochondrial membrane potential (MMP) was analysed by microscopy with fluorescence staining. Cytochrome c and 5′ AMP-activated protein kinase (AMPK) were analysed by Western blotting. Morphometric properties were examined microscopically. This is the first study in which AMPK, an indicator of intracellular energy, was measured in D. magna. GST and ChE enzyme activities and TBARS and total protein levels did not change during acute exposures (i.e., 96 h) in all treatments. GPx activity increased in D. magna from the HA + TBM treatment compared with single-exposure groups. The level of cytochrome c protein was elevated in D. magna from the LA and LA + TBM treatments. AMPK protein levels increased in all treatments with daphnids, except in the LA group. MMP was depolarised in D. magna from all treatments, whereas the most notable change was observed in HA + TBM mixture group in chronic exposures. The results show that GST and ChE may not be sensitive biomarkers for evaluating the sublethal toxic effects to D. magna exposed to environmentally relevant concentrations of ammonia and TBM. Acute and chronic exposure to ammonia and TBM probably caused an energetic crisis in D. magna. Therefore, AMPK and MMP are promising biomarkers for these toxicants.

PURPOSEAdriamycin (ADR) is a commonly used anti-cancer drug. ADR has toxic effects on cardiomyocytes and leads to heart failure. However, the underlying mechanism(s) by which ADR causes heart failure is still not clarified exactly. The aim of present study is to investigate whether ADR-induced heart failure is mediated via HMGB1/TLR4 to initiate the apoptosis through MAPK/AMPK pathways.METHODSH9c2 cell line was used to create four groups as a control, HMGB1 inhibition, ADR, ADR+HMGB1 inhibition. Silencing HMGB1 was performed with specific small interfering RNA. ADR was used at 2 µM concentration for 36 and 48 hours. Protein and genes expressions, apoptosis was measured.RESULTSAlthough ADR decreased AMPK, pAMPK, ERK1/2, pERK1/2, p38, JNK protein expression, ADR+HMGB1 inhibition led to change those protein expressions. The effect of silencing of HMGB1 prevented apoptosis induced by ADR in the cells. HMGB1 caused changes a kind of posttranscriptional modification on the TLR4 receptor. This posttranscriptional modification of TLR4 receptor led to decreased AMPK protein level, but phosphorylated-AMPK. This alternation of AMPK protein caused enhancing of JNK protein, resulting from the decline of p38 and ERK protein levels. Eventually, JNK triggered apoptosis by a caspase-dependent pathway. The number of TUNEL positive and active caspase 8 cells at ADR was high, although HMGB1 silencing could decrease the cell numbers.CONCLUSIONSInhibition of HMGB1 might prevent the lose of the cardiac cell by inhibition of apoptotic pathway, therefore HMGB1 plays an essential role as amplifying on ADR toxicity on the heart by TLR4.

The aim of this study was to investigate the oxidative and apoptotic potential of fluoxetine, a widely used antidepressant in Turkey and the world, and of its metabolite norfluoxetine on a model non-target organism, Daphnia magna to see how exposure to this group of antidepressants (specific serotonin reuptake inhibitors) could affect the aquatic environment in which they end up. Juvenile D. magna specimens were chronically exposed to fluoxetine and norfluoxetine alone and in combination at concentrations found in the aquatic environment (0.091 and 0.011 μg/L, respectively) and to their 10-fold environmental concentrations for 21 days. Another group of 17-day-old animals were subacutely exposed to 100-fold environmental concentrations for four days. After exposure, we measured their glutathione peroxidase (GPx) and cholinesterase (ChE) activities, thiobarbituric acid-reactive substances (TBARS), and total protein content spectrophotometrically, while mitochondrial membrane potential (MMP) was analysed by fluorescence staining, and cytochrome c and ERK1/2 protein content by Western blotting. This is the first-time cytochrome c and ERK1/2 were determined at the protein level in D. magna. We also measured their carapace length, width, and caudal spine length microscopically. At environmental concentrations fluoxetine and norfluoxetine caused an increase in ChE activity and brood production. They also caused a decrease in juvenile carapace length, width, and caudal spine length and depolarised the mitochondrial membrane. At 10-fold environmental concentrations, GPx activity, lipid peroxidation levels, cytochrome c, and ERK1/2 protein levels rose. The most pronounced effect was observed in D. magna exposed to norfluoxetine. Norfluoxetine also decreased brood production. Similar effects were observed with subacute exposure to 100-fold environmental concentrations. However, total protein content decreased. All this confirms that fluoxetine and norfluoxetine have oxidative and apoptotic potential in D. magna. Daphnia spp. have a great potential to give us precious insight into the mechanisms of environmental toxicants, but there is still a long way to go before they are clarified in these organisms.

Yüksek mobilite grup kutusu 1 (HMGB1) histon olmayan DNA proteini olup, kısaca DAMP olarak ifade edilen (Damage-associated molecular pattern) tehlike sinyali veya alarmı olarak görev yapar. Hasarlanmış veya kanserli hücrelerden salınan HMGB1, gelişmiş glikasyon son ürünleri için reseptör (RAGE) ve Toll benzeri reseptörlerine (TLRs) bağlanarak mitojenle aktive olan kinaz (MAPK)’ları aktive ederek hücre içi etkilerini oluşturur. HMGB1 kanser ilaçlarına karşı gelişen dirençte önemli rol oynar. Aynı zamanda, yumuşak doku kanserlerine karşı kullanılan ilaçlardan biri olan adriyamisinin (ADR) neden olduğu kalp yetmezliğinin gelişiminde de önemli rol oynağına dair kanıtlar mevcuttur. Dolayısıyla HMGB1 kanser tedavisinde ilaçlara karşı gelişen direncin ve/veya ilacın toksik etkisine karşı iyi bir terapötik ajan adayıdır. Bu derlemenin amacı, HMGB1 ile kanser ve tedavisinde kullanılan bir ilaç olan ADR arasındaki ilişkiyi açıklamaktır.

Şeker hastalığı olarak bilinen diyabet, çeşitli komplikasyonları (kalp ve dolaşım hastalıkları, kanser ve buna benzer hastalıklar) beraberinde getiren, insan hayatını olumsuz yönde etkileyen metabolik bir hastalıktır. Genel olarak diyabet tip I ve tip II olmak üzere iki büyük alt grupta toplanan bir hastalıktır. Tip I diyabette beta (β) hücrelerinin apoptoz ile kaybı insülin salgısının azalmasında önemli bir mekanizmadır. Leptin de insülin gibi antiapoptotik ve proliferatif hormonlardan biridir. Dahası düşük leptin ve insülin tedavisinin sadece yüksek doz insülin kullanımına oranla kan şekerinin tamponlanmasında daha etkili olduğu bildirilmektedir. Fakat leptinin tip I diyabetteki bu etkisi/etkileri hala gizemini korumaktadır. Leptinin tip I diyabetteki önemli etkisinden biri de yağların β oksidasyonunun artmasına neden olarak, kan şekerinin tamponlanmasını da sağları. Bu da insülin direncinin oluşmasının azalmasına neden olmaktadır. Ayrıca leptinin insülinin anabolik etkilerini taklit ettiği gibi diyabette meydana gelen ketoasidozu önlediği de vurgulanmaktadır. Dolayısıyla leptin tedavisi, zorunlu yüksek doz insülin kullanımı azaltılmasına olanak tanıyabilmektedir. Bu derleme, literatürdeki leptin ve diyabet arasındaki

AIMS:Doxorubicin, an anticancer drug, has a toxic effect on many tissues such as heart, pancreas, liver, kidney, and testis. The aim of current study is to investigate whether melatonin would be protective in doxorubicin-induced beta (β) cell toxicity via HMGB1/TLR2/TLR4/MAPK/NF-қB signaling pathway.MAIN METHODS:Human pancreatic β cell (1.1B4) was used in the present study. Four experimental groups were created as control, melatonin (10 μM), doxorubicin (2 μM) and the combination of melatonin with doxorubicin. Following 24-h treatment, Mitogen-activated protein kinase (MAPKs), Toll like receptors (TLRs) including TLR2 and TLR4, pro-and anti-apoptotic protein expression levels were determined by western blotting. Total antioxidant (TAS), oxidant status (TOS) and oxidative stress index (OSI) of the cells as well as superoxide dismutase (SOD) levels were determined. Active caspase-8 activity was measured and TUNEL staining was performed to study apoptotic pathways. Mitochondrial membrane potential (MMP), some protein expressions and F-actin distribution were analyzed.KEY FINDINGS:Doxorubicin caused to depolarize MMP, resulting in enhancing apoptosis by activation of caspase-8 via MAPKs/NF-кB pathway via elevation of TOS and decreasing TAS. Also, doxorubicin destroyed F-actin distribution and elevated TLR2 and some apoptotic proteins, including Bax. However, co-treatment of melatonin with doxorubicin could reverse depolarization of MMP and inhibition of apoptosis through MAPK/NF-кB signaling by decreasing TOS and increasing TAS. The co-treatment reversed the alternations of TLR2, TLR4, MAPKs and apoptotic protein expressions induced by doxorubicin.SIGNIFICANCE:Melatonin could be a good candidate against pancreatic β cell toxicity-induced by doxorubicin through TLR2/TLR4/MAPK/NF-кB pathways.

Cancer prevalence is scaling up each year. Anthracycline groups are still the best chemotherapeutic agent. The most popular anticancer drug in the group is doxorubicin (DOX). Unfortunately, DOX has potent toxicity on noncancerous tissues, e.g., heart, kidneys, etc. However, it is well documented that the severest toxicity of the drug affects heart tissue. Of course, some reasons have been suggested why and/or how the heart is so vulnerable to toxicity. The primary mechanism responsible for DOX’s cardiospecific toxicity remains unidentified so far; however, mitochondrial dysfunction induced by DOX is now considered one of the leading reasons for DOX’s toxicities and undesired side effects. Mitochondrial reactive oxygen production in the heart is a significant contributor to developing mitochondrial dysfunction-exposed DOX based on a variety of evidence. The objective of this review chapter is to critically evaluate and highlight the role of mitochondria in the development of DOX-induced cardiotoxicity.

Abstract Context: Cardiovascular dysfunctions such as life-threatening arrhythmias are one of the main reasons of mortality and morbidity in diabetic patients Objective: We aimed to investigate the long-term effects of resveratrol, berberine and glibenclamide combinations on the ischemia/reperfusion (I/R) induced arrhythmias in streptozotocin (STZ)-induced diabetic rats and to investigate the role of myocardial KATP channel in the possible anti-arrhythmic actions of the treatments. Methods: Two days after induction of diabetes, diabetic rats were treated with resveratrol [5 mg/kg, intraperitoneally (i.p.)], berberine (10 mg/kg, i.p) and glibenclamide (5 mg/kg, i.p) for 6 weeks. On the 43th day, experimental animals were subjected to 6-min ischemia and 6-min reperfusion in vivo. Results: The protein expression of Kir6.2 subunits was downregulated in the diabetic hearts. However, all drug treatments restored the protein expression of Kir6.2 subunits. Resveratrol alone and its combination with glibenclamide decreased the arrhythmia score, the arrhythmic period and the incidence of other types of arrhythmias during the reperfusion period. Conclusions: The combination of resveratrol with glibenclamide may alleviate reperfusion-induced arrhythmias via an underlying mechanism not be only associated with the restoration of the protein expression of Kir6.2 subunits but also associated with the other subunits or ion channels underlying cardiac action potential.