Nimbolide prevents myocardial damage by regulating cardiac biomarkers,antioxidant level,and apoptosis signaling against doxorubicin‐induced cardiotoxicity in rats

The current work planned to assess the protecting properties of nimbolide against doxorubicin (DOX)‐treated myocardial damage. Myocardial damage was produced with 2.5 mg/kg of DOX given on alternative days (14 days). Thiobarbituric acid reactive substances (TBARS) levels of a lipid peroxidative marker were elevated, whereas reduced body weight, heart weight, blood pressure indices and reduced levels of antioxidants like glutathione‐S‐transferase, superoxide dismutase, catalase, glutathione peroxidase, glutathione, and glutathione reductase were observed in the heart tissue of DOX‐treated animals. DOX‐treated animals showed augmented levels of cardiac markers likes monocyte chemotactic protein‐1, interferon‐gamma, aspartate transferase, creatine kinase, lactate dehydrogenase, creatine kinase‐muscle/brain, heart‐type fatty acid‐binding protein, glycogen phosphorylase isoenzyme BB, transforming growth factor‐β, brain natriuretic peptide, myoglobin, and cTnI in serum. Histopathological assessment confirmed the DOX‐induced cardiotoxicity. Furthermore, DOX‐induced rats showed augmented inflammatory mediators (nuclear factor‐κB [NF‐kB], tumor necrosis factor‐α [TNF‐α], and interleukin‐1β [IL‐1β]) and increased PI3K/Akt signaling proteins (PI3K, p‐Bad/Bad, caspase‐3, and p‐Akt), whereas decreased oxidative markers (HO‐1 and NQO‐1) and p‐PTEN were observed. Nimbolide‐supplemented rats showed reduced activity/levels of cardiac markers and TBARS levels in serum and heart tissue. Levels of enzymatic and nonenzymatic antioxidants were augmented in the heart tissue of nimbolide‐supplemented rats. Nimbolide influence decreased apoptosis, inflammation, and enhanced antioxidant markers through the modulation of p‐Bad/Bad, caspase‐3, PI3K, p‐Akt, TNF‐α, NF‐kB, IL‐1β, HO‐1, NQO‐1, and p‐PTEN markers. The histopathological explanations were observed to be in line with biochemical analysis. Therefore, the finding of current work was that nimbolide has a defensive effect on the myocardium against DOX‐induced cardiac tissue damage.     

Alpha lipoic acid prevents doxorubicin‐induced nephrotoxicity by mitigation of oxidative stress,inflammation, and apoptosis in rats

This study aimed to evaluate the protective effects of alpha lipoic acid (ALA) against doxorubicin (DOX)‐induced nephrotoxicity in rats. A single dose of DOX (7.5 mg/kg i.v.) induced nephrotoxicity evidenced by significant elevations in kidney weight, kidney/body weight ratio, serum urea, creatinine, tumor necrosis factor alpha, and renal contents of malondialdehyde, nitric oxide, cyclooxygenase‐2, and caspase‐3. Also, it causes significant reduction in final body weight, serum albumin, renal contents of reduced glutathione and superoxide dismutase activity. Histopathological changes in the kidney tissue confirmed the nephrotoxic effect. In contrast, pretreatment with ALA (50 mg/kg, orally) for 14 days before DOX and for 7 days after DOX administration mitigated renal toxicity evidenced by greater improvement in the examined oxidative stress, inflammation, and apoptosis parameters. In conclusion, ALA had promising protective effects against DOX‐induced nephrotoxicity that might be attributed to its antioxidant, anti‐inflammatory, and antiapoptoic activities.     

Resveratrol,a polyphenol phytoalexin,protects against doxorubicin‐induced cardiotoxicity

Doxorubicin is the mainstay of treatment for various haematological malignancies and solid tumours. However, its clinical application may be hampered by dose‐dependent cardiotoxicity. The mechanism of doxorubicin‐induced cardiotoxicity may involve various signalling pathways including free radical generation, peroxynitrite formation, calcium overloading, mitochondrial dysfunction and alteration in apoptosis and autophagy. Interestingly, the use of resveratrol in combination with doxorubicin has been reported to prevent cardiac toxicity as well as to exert a synergistic effect against tumour cells both in vivo and in vitro. Thus, the aim of this review is to summarize current knowledge and to elucidate the protective effect of resveratrol in doxorubicin‐induced cardiotoxicity.     

TLR9 deficiency alleviates doxorubicin‐induced cardiotoxicity via the regulation of autophagy

Doxorubicin is a commonly used anthracycline chemotherapeutic drug. Its application for treatment has been impeded by its cardiotoxicity as it is detrimental and fatal. DNA damage, cardiac inflammation, oxidative stress and cell death are the critical links in DOX‐induced myocardial injury. Previous studies found that TLR9‐related signalling pathways are associated with the inflammatory response of cardiac myocytes, mitochondrial dysfunction and cardiomyocyte death, but it remains unclear whether TLR9 could influence DOX‐induced heart injury. Our current data imply that DOX‐induced cardiotoxicity is ameliorated by TLR9 deficiency both in vivo and in vitro, manifested as improved cardiac function and reduced cardiomyocyte apoptosis and oxidative stress. Furthermore, the deletion of TLR9 rescued DOX‐induced abnormal autophagy flux in vivo and in vitro. However, the inhibition of autophagy by 3‐MA abolished the protective effects of TLR9 deletion on DOX‐induced cardiotoxicity. Moreover, TLR9 ablation suppressed the activation of p38 MAPK during DOX administration and may promote autophagy via the TLR9‐p38 MAPK signalling pathway. Our study suggests that the deletion of TLR9 exhibits a protective effect on doxorubicin‐induced cardiotoxicity by enhancing p38‐dependent autophagy. This finding could be used as a basis for the development of a prospective therapy against DOX‐induced cardiotoxicity.     

Thymoquinone attenuates doxorubicin‐cardiotoxicity in rats

Contrary to the fact that doxorubicin is a powerful chemotherapeutic agent for the treatment of neoplastic diseases, cardiotoxicity is too important to be ignored. Thymoquinone serves as a powerful free radical scavenger. In the study, the effects of thymoquinone against doxorubicin‐cardiotoxicity will be evaluated. Forty rats were divided into five groups. Group I: control group (n = 8); group II: olive oil group (n = 8); group III: thymoquinone group (n = 8); given 10 mg/kg thymoquinone intraperitoneally per day throughout the experiment; group IV: doxorubicin group (n = 8); injected with a single dose of 15 mg/kg ip doxorubicin on the 7th day of the experiment; group V: doxorubicin + thymoquinone group (n = 8); administered with 10 mg/kg thymoquinone per day during the experiment and 15 mg/kg doxorubicin ip on the 7th day. The experiment was planned for 14 days. Immunohistochemically, heat shock protein (HSP) 70 and HSP90, glucose‐regulated protein 78 (GRP78), caspase‐3 were stained. We made terminal deoxynucleotidyl transferase dUTP nick end labeling for apoptotic evaluation. Total oxidant status (TOS) levels and total antioxidant status (TAS) were measured in the heart tissue. Atrial natriuretic peptide (ANP) and pro‐B type natriuretic peptide (proBNP) were evaluated. In the study, HSP70, HSP90, GRP78, and caspase‐3 levels increased in group IV. TOS and TAS levels were significant compared to group I. Doxorubicin significantly increased ANP and NT‐proBNP levels. Thymoquinone revealed significant differences in these values. Thymoquinone can be an important cardioprotective agent against doxorubicin‐cardiotoxicity.     

Protective effect of proanthocyanidins against doxorubicin‐induced nephrotoxicity in rats

Doxorubicin (DOX) exerts toxic effects in several organs particularly kidney. The present study aimed to assess the protective effect of proanthocyanidins (PAs) against DOX‐induced nephrotoxicity in rats. A single dose of DOX (7.5 mg/kg, i.v.) significantly increased kidney weight, kidney/body weight ratio, serum urea, creatinine, tumor necrosis factor alpha levels, and kidney contents of malondialdehyde, nitric oxide, cyclooxygenase‐2, and caspase‐3 activity with significant reduction in final body weight, serum albumin, kidney contents of reduced glutathione (GSH), and superoxide dismutase activity as compared with control group. In contrast, pretreatment with PAs (200 mg/kg, p.o.) for 14 days before DOX and for 7 days after DOX ameliorated kidney function and oxidative stress parameters. Histopathological evidence confirmed the protective effects of PAs from the tissue damage induced by DOX. In conclusion, PAs have a multi‐nephroprotective effect that might be attributed to its antioxidant, anti‐inflammatory, and antiapoptoic activities.     

Palliative effect of curcumin on doxorubicin‐induced testicular damage in male rats

This study aimed to investigate the effect of curcumin (CUR) on doxorubicin (DOX)‐induced testicular damage in male rats. Thirty‐five adult male Wistar rats were used. Control group was received saline for 7 days. CUR group received CUR for 7 days. DOX group received single dose DOX on the 5th day. DOX+ CUR‐100 group received 100 mg/kg/day CUR for 7 days and DOX injection on the 5th day. DOX + CUR‐200 group received 200 mg/kg/day CUR for 7 days and DOX injection on the 5th day. DOX treatment decreased in sperm motility rate, live sperm percentages, cellular antioxidants, and increased malondialdehyde (MDA) levels, necrosis, degenerations, and slimming in seminiferous tubules, and DNA damages in testes by inducing oxidative stress. CUR treatment mitigated significantly these side effects when compared with DOX group in a dose‐dependent manner. In conclusion, CUR treatment can be used in the mitigation of DOX‐induced testicular toxicity.     

Silibinin ameliorates arsenic induced nephrotoxicity by abrogation of oxidative stress, inflammation and apoptosis in rats

Arsenic (As) is an environmental and industrial pollutant that affects various organs in human and experimental animals. Silibinin is a naturally occurring plant bioflavonoid found in the milk thistle of Silybum marianum, which has been reported to have a wide range of pharmacological properties. A body of evidence has accumulated implicating the free radical generation with subsequent oxidative stress in the biochemical and molecular mechanisms of As toxicity. Since kidney is the critical target organ of chronic As toxicity, we carried out this study to investigate the effects of silibinin on As-induced toxicity in the kidney of rats. In experimental rats, oral administration of sodium arsenite [NaAsO₂, 5?mg/(kg?day)] for 4?weeks significantly induced renal damage which was evident from the increased levels of serum urea, uric acid, creatinine with a significant (p?<?0.05) decrease in creatinine clearance. As also significantly decreased the levels of urea, uric acid and creatinine in urine. A markedly increased levels of lipid peroxidation markers (thiobarbituric acid reactive substances and lipid hydroperoxides) and protein carbonyl contents with significant (p?<?0.05) decrease in non-enzymatic antioxidants (total sulfhydryl groups, reduced glutathione, vitamin C and vitamin E) and enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase), Glutathione metabolizing enzymes (glutathione reductase and glutathione-6-phosphate dehydrogenase) and membrane bound ATPases were also observed in As treated rats. Co-administration of silibinin (75?mg/kg?day) along with As resulted in a reversal of As-induced biochemical changes in kidney accompanied by a significant decrease in lipid peroxidation and an increase in the level of renal antioxidant defense system. The histopathological and immunohistochemical studies in the kidney of rats also shows that silibinin (75?mg/kg?day) markedly reduced the toxicity of As and preserved the normal histological architecture of the renal tissue, inhibited the caspase-3 mediated tubular cell apoptosis and decreased the NADPH oxidase, iNOS and NF-κB over expression by As and upregulated the Nrf2 expression in the renal tissue. The present study suggests that the nephroprotective potential of silibinin in As toxicity might be due to its antioxidant and metal chelating properties, which could be useful for achieving optimum effects in As-induced renal damage.     

Effects of doxorubicin‐induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: Insights for future interventions

Anthracyclines is an effective chemotherapeutic treatment used for many types of cancer. However, high cumulative dosage of anthracyclines leads to cardiac toxicity and heart failure. Dysregulation of mitochondrial dynamics and function are major pathways driving this toxicity. Several pharmacological and non‐pharmacological interventions aiming to attenuate cardiac toxicity by targeting mitochondrial dynamics and function have shown beneficial effects in cell and animal models. However, in clinical practice, there is currently no standard therapy for the prevention of anthracycline‐induced cardiotoxicity. This review summarizes current reports on the impact of anthracyclines on cardiac mitochondrial dynamics and mitochondrial function and potential interventions targeting these pathways. The roles of mitochondrial dynamics and mitochondrial function in the development of anthracycline‐induced cardiotoxicity should provide insights in devising novel strategies to attenuate the cardiac toxicity induced by anthracyclines.     

Mitochondrial ROS‐induced ERK1/2 activation and HSF2‐mediated AT1R upregulation are required for doxorubicin‐induced cardiotoxicity

Doxorubicin (DOX), one useful chemotherapeutic agent, is limited in clinical use because of its serious cardiotoxicity. Growing evidence suggests that angiotensin receptor blockers (ARBs) have cardioprotective effects in DOX‐induced cardiomyopathy. However, the detailed mechanisms underlying the action of ARBs on the prevention of DOX‐induced cardiomyocyte cell death have yet to be investigated. Our results showed that angiotensin II receptor type I (AT₁R) plays a critical role in DOX‐induced cardiomyocyte apoptosis. We found that MAPK signaling pathways, especially ERK1/2, participated in modulating AT₁R gene expression through DOX‐induced mitochondrial ROS release. These results showed that several potential heat shock binding elements (HSE), which can be recognized by heat shock factors (HSFs), located at the AT₁R promoter region. HSF2 markedly translocated from the cytoplasm to the nucleus when cardiomyocytes were damaged by DOX. Furthermore, the DNA binding activity of HSF2 was enhanced by DOX via deSUMOylation. Overexpression of HSF2 enhanced DOX‐induced cardiomyocyte cell death as well. Taken together, we found that DOX induced mitochondrial ROS release to activate ERK‐mediated HSF2 nuclear translocation and AT₁R upregulation causing DOX‐damaged heart failure in vitro and in vivo.     

Platelet-rich plasma ameliorates neurotoxicity induced by silver nanoparticles in male rats via modulation of apoptosis,inflammation, and oxidative stress

The widespread use of silver in various forms raises concerns about its potential adverse effects. Silver nanoparticles (AgNPs) can enter the brain and subsequently induce neurotoxicity. As a source of diverse growth factors and for its cytoprotective properties, platelet-rich plasma (PRP) has received considerable attention in regenerative medicine. Our aim was to estimate the toxic effects of AgNPs on the rat brain and assess the possible protective effects of PRP against AgNPs induced neurotoxicity. A total of 40 adult male rats were divided into four groups (n = 10), namely the control, AgNPs, AgNPs+PRP, and auto-recovery groups. AgNPs were given intraperitoneally (i.p.) at a 10 mg/kg dose.bw daily for 28 days. PRP was given (a day after AgNPs treatment) i.p. at a dose of 0.5 mL/kg.bw twice weekly for 3 weeks. Rats in the auto-recovery group were left without treatment for 3 weeks after AgNP toxicity. Serum and brain tissue samples were collected for assessment of proinflammatory cytokines, oxidative stress markers, as well as the expression levels of apoptotic markers. Brain histopathological and immunohistochemistry examinations were done. AgNPs significantly increased oxidative stress markers and proinflammatory cytokines, decreased antioxidant defense markers, and induced apoptosis and histopathological brain injuries. However, PRP treatment restored brain oxidant/antioxidant balance, attenuated the inflammatory state, prevented apoptosis, and improved the brain histopathological lesions induced by AgNPs, with no significant improvements shown by auto-recovery group. Our data provided a novel protective effect for PRP against AgNPs-induced neurotoxicity due to its antioxidant, anti-inflammatory, and antiapoptotic effects.     

Curcumin ameliorates diclofenac sodium‐induced nephrotoxicity in male albino rats

Exposure to drugs often results in toxicity in the kidney which represents the major control system maintaining homeostasis of the body and thus is especially susceptible to xenobiotics. Nephrotoxicity is a life‐threatening side‐effect of nonsteroidal anti‐inflammatory drugs (NSAIDs). Diclofenac is one of the most frequently prescribed NSAIDs and have been reported to cause multiple organs damage. Curcumin (CUR) exhibits nephroprotective properties. Therefore, rats were divided into four groups; rats of groups 3 and 4 received diclofenac (100 mg/kg, i.m.), whereas rats of groups 2 and 4 received CUR (100 mg/kg, p.o.) for 3 days. Diclofenac revealed a significant increase in urea and creatinine levels and malondialdehyde concentration and marked reduction in catalase activity and reduced glutathione concentration. Histopathologically, diclofenac produced fatty changes and eosinophilic casts were detected in the renal tubules, those were attenuated by administration of CUR prior diclofenac.     

Retraction Note to: Silibinin ameliorates arsenic induced nephrotoxicity by abrogation of oxidative stress,inflammation and apoptosis in rats

Molecular Biology Reports -     

Lysyl oxidase propeptide sensitizes pancreatic and breast cancer cells to doxorubicin‐induced apoptosis

RAS mutations or its activation by upstream receptor tyrosine kinases are frequently associated with poor response of carcinomas to chemotherapy. The 18 kDa propeptide domain of lysyl oxidase (LOX‐PP) released from the secreted precursor protein (Pro‐LOX) has been shown to inhibit RAS signaling and the transformed phenotype of breast, pancreatic, lung, and prostate cancer cells in culture, and formation of tumors by Her‐2/neu‐driven breast cancer cells in a mouse xenograft model. Here, we tested the effects of LOX‐PP on MIA PaCa‐2 pancreatic cancer cells, driven by mutant RAS. In MIA PaCa‐2 cells in culture, LOX‐PP attenuated the ERK and AKT activities and decreased the levels of the NF‐κB p65 and RelB subunits and cyclin D1, which are activated by RAS signaling. In mouse xenograft growth, LOX‐PP reduced growth of tumors by these pancreatic cancer cells, and the nuclear levels of the p65 NF‐κB subunit and cyclin D1 proteins. While biological agents attenuate tumor growth when used alone, often they have additive or synergistic effects when used in combination with chemotherapeutic agents. Thus, we next tested the hypotheses that LOX‐PP sensitizes pancreatic and breast cancer cells to the chemotherapeutic agent doxorubicin. Purified LOX‐PP enhanced the cytotoxic effects of doxorubicin in pancreatic and breast cancer cells, as judged by ATP production, Cell Death ELISA assays, caspase 3 activation, PARP cleavage, and Annexin V staining. Thus, LOX‐PP potentiates the cytotoxicity of doxorubicin on breast and pancreatic cancer cells, warranting additional studies with a broader spectrum of current cancer treatment modalities. J. Cell. Biochem. 111: 1160–1168, 2010. © 2010 Wiley‐Liss, Inc.     

Curcumin‐galactomannosides mitigate alcohol‐induced liver damage by inhibiting oxidative stress,hepatic inflammation,and enhance bioavailability on TLR4/MMP events compared to curcumin

Alcoholic liver diseases are classified as one of the major reasons for worldwide morbidity and mortality. Curcuminoids exhibit a wide range of pharmacological activities that are beneficial for health, including hepatoprotective effects, but its clinical significance is limited due to poor oral bioavailability. In the present study, a novel formulation of curcumin as curcumin‐galactomannosides (CGM) with enhanced oral bioavailability alleviated alcohol‐induced liver damage in wistar rats with an increased potency compared to the unformulated natural curcuminoids (CM). Ethanol administration significantly elevated liver toxicity markers, lipid peroxidation and inflammatory markers with a simultaneous reduction in antioxidant defenses. Supplementation of CGM reversed all of the pathological effects of alcohol administration, almost close to the normal level, when compared with CM. Histopathology of liver tissue also confirmed the better protective effect of CGM, indicating the enhancement in antioxidant and anti‐inflammatory effects as a function of bioavailability.     

Hesperidin ameliorates cisplatin induced hepatotoxicity and attenuates oxidative damage,cell apoptosis,and inflammation in rats

Cisplatin is one of the most widely used chemotherapeutic anti-cancer drugs that is associated with multiple systemic toxicities limiting its use. The present study aimed to evaluate the hepato-protective effect of hesperidin against cisplatin-induced toxicity. Thirty-two adult male albino rats were equally split into four groups, the first group served as control received normal saline, the second group (CIS) received a single intraperitoneal dose of cisplatin (7.5 mg/kg bw) on the 22nd day of the experiment, the third group (HES) treated once daily with hesperidin (200 mg/kg bw, orally) for 21 days, and the last group (HES + CIS) pretreated once daily with hesperidin followed by a single intraperitoneal dose of cisplatin. Twenty-four hours later, samples were collected for further investigations. CIS-intoxication resulted in a significant decrease in the erythrogram along with thrombocytopenia leukopenia, and lymphopenia. Furthermore, CIS administration significantly elevated serum activity of liver enzymes, total, and indirect bilirubin as well serum glucose, total cholesterol, and triglycerides levels, meanwhile serum total protein, and globulin levels were significantly reduced. The hepatic MDA was markedly elevated with a concomitant decline in the hepatic antioxidant enzymes and severe alterations in the hepatic tissue architecture in CIS-intoxicated rats. Additionally, CIS-induced overexpression of hepatic Bax, caspase-3, and TNF-α, with no effect on hepatic expression of IL-10. Interestingly, HES pretreatment improved the CIS-induced hemato-biochemical, molecular and histopathological alterations. In conclusion, hesperidin hepato-protective effects against CIS might be mediated by its antioxidant, anti-inflammatory, and anti-apoptotic properties.     

Celecoxib prevents pressure overload‐induced cardiac hypertrophy and dysfunction by inhibiting inflammation,apoptosis and oxidative stress

To explore the effects of celecoxib on pressure overload‐induced cardiac hypertrophy (CH), cardiac dysfunction and explore the possible protective mechanisms. We surgically created abdominal aortic constrictions (AAC) in rats to induce CH. Rats with CH symptoms at 4 weeks after surgery were treated with celecoxib [2 mg/100 g body‐weight(BW)] daily for either 2 or 4 weeks. Survival rate, blood pressure and cardiac function were evaluated after celecoxib treatment. Animals were killed, and cardiac tissue was examined for morphological changes, cardiomyocyte apoptosis, fibrosis, inflammation and oxidative stress. Four weeks after AAC, rats had significantly higher systolic, diastolic and mean blood pressure, greater heart weight and enlarged cardiomyocytes, which were associated with cardiac dysfunction. Thus, the CH model was successfully established. Two weeks later, animals had impaired cardiac function and histopathological abnormalities including enlarged cardiomyocytes and cardiac fibrosis, which were exacerbated 2 weeks later. However, these pathological changes were remarkably prevented by the treatment of celecoxib, independent of preventing hypertension. Mechanistic studies revealed that celecoxib‐induced cardiac protection against CH and cardiac dysfunction was due to inhibition of apoptosis via the murine double mimute 2/P53 pathway, inhibition of inflammation via the AKT/mTOR/NF‐κB pathway and inhibition of oxidative stress via increases in nuclear factor E2‐related factor‐2‐mediated gene expression of multiple antioxidants. Celecoxib suppresses pressure overload‐induced CH by reducing apoptosis, inflammation and oxidative stress.     

CIRBP-OGFR axis safeguards against cardiomyocyte apoptosis and cardiotoxicity induced by chemotherapy

Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.     

Curcumin inhibits alloxan‐induced pancreatic islet cell damage via antioxidation and antiapoptosis

The present study elucidates the possible protective effects of curcumin on β‐cells damaged by oxidative stress and its significance in controlling diabetes mellitus in in vitro experiments. Pancreatic islet (RIN‐m5F) cells were treated with 25 mmol/L alloxan (AXN) to induce cell damage and the protective effects of curcumin were observed. The results showed that curcumin significantly promoted the cellular activity of AXN‐treated RIN‐m5F cells, decreased the ratio of apoptosis, downregulated the level of malondialdehyde, upregulated the levels of superoxide dismutase and reactive oxygen species, increased the expression of Bcl‐2, cleaved caspase‐3, and cleaved PARP1, and decreased the expression of Bax in AXN‐treated cells. These results suggest that curcumin inhibits AXN‐induced damage in RIN‐m5F cells via antioxidative and antiapoptotic mechanisms.     

CaMKII orchestrates endoplasmic reticulum stress and apoptosis in doxorubicin‐induced cardiotoxicity by regulating the IRE1α/XBP1s pathway

Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII) is implicated in the pathological progression of Dox‐induced cardiotoxicity. This study examined the hypothesis that CaMKII exacerbates Dox‐induced cardiotoxicity by promoting endoplasmic reticulum stress and apoptosis through regulation of the inositol‐requiring enzyme 1α (IRE1α)/spliced X‐box binding protein 1 (XBP1s) pathway. Our results demonstrated that CaMKII activation and IRE1α/XBP1s pathway were involved in Dox‐treated hearts. CaMKII inhibition with KN‐93 ameliorated Dox‐induced cardiac dysfunction and pathological myocardial changes. In addition, CaMKII inhibition prevented Dox‐induced endoplasmic reticulum stress and apoptosis. Moreover, CaMKII inhibition increased the expression of IRE1α and XBP1s in Dox‐treated hearts. The IRE1α inhibitor 4μ8C blocked the protective effect of CaMKII inhibition against Dox‐induced cardiotoxicity. Mechanistically, 4μ8C prevented the effects of CaMKII inhibition on Dox‐induced endoplasmic reticulum stress and apoptosis by inhibiting the expression of IRE1α and XBP1s. Additionally, treatment with rhADAMTS13 decreased the protein level of thrombospondin 1 (TSP1) and the phosphorylation of CaMKII in Dox‐treated human AC16 cardiomyocytes. Taken together, these results demonstrate that the ADAMTS13‐TSP1 axis regulates CaMKII activation and exacerbates Dox‐induced cardiotoxicity by triggering endoplasmic reticulum stress and apoptosis by inhibiting the IRE1α/XBP1s pathway.