Donepezil ameliorates gut barrier disruption in doxorubicin-treated rats.

An impact of donepezil against doxorubicin-induced gut barrier disruption and gut dysbiosis has never been investigated. Twenty-four male Wistar rats were divided into three groups. Each group was treated with either vehicle as a control, doxorubicin, or doxorubicin-cotreated with donepezil. Heart rate variability was assessed to reflect the impact of doxorubicin and donepezil. Then, animals were euthanized, and the ileum and its contents were collected in each case to investigate the gut barrier and gut microbiota, respectively. The microbiota-derived endotoxin, trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) in the serum were determined. An increase in the sympathetic tone, endotoxins, and TMAO levels with disruption of the gut barrier and a decrease in SCFAs levels were observed in doxorubicin-treated rats. Gut microbiota of doxorubicin-treated rats was significantly different from that of the control group. Donepezil treatment significantly decreased the sympathetic tone, restored the gut barrier, and reduced endotoxin and TMAO levels in doxorubicin-treated rats. Nonetheless, donepezil administration did not alter the gut microbiota profile and levels of SCFAs in doxorubicin-treated rats. Doxorubicin impaired the autonomic balance and the gut barrier, and induced gut dysbiosis, resulting in gut toxicity. Donepezil partially improved the doxorubicin-induced gut toxicity through balancing the autonomic disturbance.

Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.

Increasing global obesity rates and an aging population are independently linked to cardiac complications. Consequently, it is crucial to comprehensively understand the mechanisms behind these conditions to advance innovative therapies for age-related diseases. Mitochondrial dysfunction, specifically defects in mitochondrial fission/fusion processes, has emerged as a central regulator of cardiac complications in aging and age-related diseases (e.g., obesity). Since excessive fission and impaired fusion of cardiac mitochondria lead to disruptions in mitochondrial dynamics and cellular metabolism in aging and obesity, modulating mitochondrial dynamics with either fission inhibitors or fusion promoters has offered cardioprotection against these pathological conditions in preclinical models. This review explores the molecular mechanisms governing mitochondrial dynamics as well as the disturbances observed in aging and obesity. Additionally, pharmaceutical interventions that specifically target the processes of mitochondrial fission and fusion are presented and discussed. By establishing a connection between mitochondrial dynamism through fission and fusion and the advancement or mitigation of age-related diseases, particularly obesity, this review provides valuable insights into the progression and potential prevention strategies for such conditions.

Modulating Mitochondrial Dynamics Mitigates Cognitive Impairment in Rats with Myocardial Infarction.

BACKGROUND: We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI).

Objective: To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of enalapril. METHODS: Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle, enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study.

Results: MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group.

Conclusion: Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats.

Potential roles of 4HNE-adducted protein in serum extracellular vesicles as an early indicator of oxidative response against doxorubicin-induced cardiomyopathy in rats.

Late-onset cardiomyopathy is becoming more common among cancer survivors, particularly those who received doxorubicin (DOXO) treatment. However, few clinically available cardiac biomarkers can predict an unfavorable cardiac outcome before cell death. Extracellular vesicles (EVs) are emerging as biomarkers for cardiovascular diseases and others. This study aimed to measure dynamic 4-hydroxynonenal (4HNE)-adducted protein levels in rats treated chronically with DOXO and examine their link with oxidative stress, antioxidant gene expression in cardiac tissues, and cardiac function. Twenty-two male Wistar rats were randomly assigned to receive intraperitoneal injection of normal saline (n = 8) or DOXO (3 mg/kg, 6 doses, n = 14). Before and after therapy, serum EVs and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were determined. Tunable resistive pulse sensing was used to measure EV size and concentration. ELISA was used to assess 4HNE-adducted protein in EVs and cardiac tissues. Differential-display reverse transcription-PCR was used to quantitate cardiac Cat and Gpx1 gene expression. Potential correlations between 4HNE-adducted protein levels in EVs, cardiac oxidative stress, antioxidant gene expression, and cardiac function were determined. DOXO-treated rats showed more serum EV 4HNE-adducted protein than NSS-treated rats at day 9 and later endpoints, whereas NT-proBNP levels were not different between groups. Moreover, on day 9, surviving rats' EVs had higher levels of 4HNE-adducted protein, and these correlated positively with concentrations of heart tissue 4HNE adduction and copy numbers of Cat and Gpx1, while at endpoint correlated negatively with cardiac functions. Therefore, 4HNE-adducted protein in serum EVs could be an early, minimally invasive biomarker of the oxidative response and cardiac function in DOXO-induced cardiomyopathy.

Ferroptosis inhibitor improves cardiac function more effectively than inhibitors of apoptosis and necroptosis through cardiac mitochondrial protection in rats with iron-overloaded cardiomyopathy.

Iron overload cardiomyopathy (IOC) is the leading cause of death in cases of iron overload in patients. Previous studies demonstrated that iron overload led to cardiomyocyte dysfunction and death through multiple pathways including apoptosis, necroptosis and ferroptosis. However, the dominant cell death pathway in the iron-overloaded heart needs clarification. We tested the hypothesis that ferroptosis, an iron-dependent cell death, plays a dominant role in IOC, and ferroptosis inhibitor exerts greater efficacy than inhibitors of apoptosis and necroptosis on improving cardiac function in iron-overloaded rats. Iron dextran was injected intraperitoneally into male Wistar rats for four weeks to induce iron overload. Then, the rats were divided into 5 groups: treated with vehicle, apoptosis inhibitor (z-VAD-FMK), necroptosis inhibitor (Necrostatin-1), ferroptosis inhibitor (Ferrostatin-1) or iron chelator (deferoxamine) for 2 weeks. Cardiac function, mitochondrial function, apoptosis, necroptosis and ferroptosis were determined. The increased expression of apoptosis-, necroptosis- and ferroptosis-related proteins, were associated with impaired cardiac and mitochondrial function in iron-overloaded rats. All cell death inhibitors attenuated cardiac apoptosis, necroptosis and ferroptosis in iron-overloaded rats. Ferrostatin-1 was more effective than the other drugs in diminishing mitochondrial dysfunction and Bax/Bcl-2 ratio. Moreover, both Ferrostatin-1 and deferoxamine reversed iron overload-induced cardiac dysfunction as indicated by restored left ventricular ejection fraction and E/A ratio, whereas z-VAD-FMK and Necrostatin-1 only partially improved this parameter. These results indicated that ferroptosis could be the predominant form of cardiomyocyte death in IOC, and that inhibiting ferroptosis might be a potential novel treatment for IOC.

Vagus nerve stimulation and acetylcholinesterase inhibitor donepezil provide cardioprotection against trastuzumab-induced cardiotoxicity in rats by attenuating mitochondrial dysfunction.

Trastuzumab (Trz) is a targeted anticancer drug for human epidermal growth factor receptor 2 (HER2)-positive tumors, as Trz-induced cardiotoxicity (TIC) is commonly observed in Trz-treated patients. Since cardiac autonomic modulation with electrical vagus nerve stimulation (VNS) and acetylcholinesterase (AChE) inhibitors exerts cardioprotection against various heart diseases, the comparative effects of electrical VNS and an AChE inhibitor (donepezil) on cardiac and mitochondrial functions and programmed cell death pathways in TIC are not known. VNS devices were implanted in thirty-two male Wistar rats and were divided into 4 groups: (i) Control-Sham (CSham), (ii) Trz-Sham (TSham), (iii) Trz-VNS (TVNS), and (iv) Trz-donepezil (TDPZ). Rats in the Trz-treated groups were intraperitoneally injected with Trz (4 mg/kg/day) for 7 days, while CSham rats were injected with NSS. VNS devices were activated in the TVNS rats during the 7-day Trz treatment, but not in the sham rats. Rats in the TDPZ group received donepezil orally (5 mg/kg/day) for 7 days. At the end, left ventricular (LV) function and heart rate variability were evaluated, and heart tissue was collected for biochemical and histological analysis. Trz rats showed LV dysfunction and cardiac sympathovagal imbalance. In addition, mitochondrial function and dynamics were impaired in TIC rats. Trz also increased cardiomyocyte death by inducing apoptosis, pyroptosis, and ferroptosis. Electrical VNS and donepezil had similar efficacy in alleviating cardiac mitochondrial dysfunction, dynamic imbalances, and cardiomyocyte death, leading to improved LV function. These findings suggested that parasympathetic activation via either VNS or an AChE inhibitor could be a promising therapeutic intervention against TIC.

Acetylcholinesterase inhibition protects against trastuzumab-induced cardiotoxicity through reducing multiple programmed cell death pathways.

BACKGROUND: Trastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and ferroptosis have been identified as potential mechanisms underlying TIC, the roles of pyroptosis and necroptosis under TIC have never been investigated. It has been shown that inhibition of acetylcholinesterase function by using donepezil exerts protective effects in various heart diseases. However, it remains unknown whether donepezil exerts anti-cardiotoxic effects in rats with TIC. We hypothesized that donepezil reduces mitochondrial dysfunction, inflammation, oxidative stress, and cardiomyocyte death, leading to improved left ventricular (LV) function in rats with TIC. METHODS: Male Wistar rats were randomly assigned to be Control or Trz groups (Trz 4 mg/kg/day, 7 days, I.P.). Rats in Trz groups were assigned to be co-treated with either drinking water (Trz group) or donepezil 5 mg/kg/day (Trz + DPZ group) via oral gavage for 7 days. Cardiac function, heart rate variability (HRV), and biochemical parameters were evaluated. RESULTS: Trz-treated rats had impaired LV function, HRV, mitochondrial function, and increased inflammation and oxidative stress, leading to apoptosis, ferroptosis, and pyroptosis. Donepezil co-treatment effectively decreased those adverse effects of TIC, resulting in improved LV function. An in vitro study revealed that the cytoprotective effects of donepezil were abolished by a muscarinic acetylcholine receptor (mAChR) antagonist. CONCLUSIONS: Donepezil exerted cardioprotection against TIC via attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, leading to improved LV function through mAChR activation. This suggests that donepezil could be a novel intervention strategy in TIC.

Differential temporal therapies with pharmacologically targeted mitochondrial fission/fusion protect the brain against acute myocardial ischemia-reperfusion injury in prediabetic rats: The crosstalk between mitochondrial apoptosis and inflammation.

An imbalance of brain mitochondrial dynamics, increases in brain inflammation and apoptosis, and increasing cognitive dysfunction, have been reported as being associated with prediabetes and myocardial ischemia-reperfusion (IR) injury. Since inhibiting mitochondrial fission with Mdivi-1 or promoting fusion with M1 had cardioprotective effects in myocardial IR injury and obesity, the neuroprotective roles of Mdivi-1 and M1 when administered at different time points of myocardial IR injury in obese prediabetes have never been determined. Ninety-six male Wistar rats were fed with either a normal (ND: n = 8) or a high-fat diet to induce prediabetes (HFD: n = 88) for 12 weeks. At week 13, all rats were subjected to left anterior descending coronary artery ligation for 30 min, followed by reperfusion for 120 min. HFD rats were randomly divided into 10 groups and assigned into either a pre-ischemic group treated with vehicle (HFV), pre-ischemic, during-ischemic, or onset of reperfusion groups treated with either Mdivi-1 (MDV), M1, or combined (COM). Heart function was examined invasively, with the heart being terminated to investigate myocardial infarction. Brains were collected to determine mitochondrial functions, inflammation, apoptosis, and pathological markers. Mdivi-1, M1, and COM treatment at different periods exerted cardioprotection against myocardial IR injury in HFD-fed rats by reducing infarct size and left ventricular dysfunction. All interventions also improved all brain pathologies against myocardial IR injury in prediabetic rats. These findings suggest that differential temporal modulation of mitochondrial dynamics may be appropriate regimens for preventing heart and brain complications after myocardial IR injury in obese prediabetes.

Treatment with apoptosis inhibitor restores cognitive impairment in rats with myocardial infarction.

We previously reported that apoptosis is responsible for cognitive impairment in rats with myocardial infarction (MI). Acute administration of an apoptosis inhibitor (Z-vad) effectively reduced brain inflammation in rats with cardiac ischemia/reperfusion injury. However, the beneficial effects of Z-vad on cognitive function, brain inflammation, mitochondrial function, cell death pathways, and neurogenesis in MI rats have not been investigated. Male rats were divided into sham or MI groups (left anterior descending coronary ligation). A successful MI was determined by a reduction of ejection fraction <50 %. Then, MI rats were allocated to receive vehicle, enalapril (10 mg/kg, a positive control), and Z-vad (1 mg/kg) for 4 weeks. Cardiac function, cognitive function, and molecular analysis were investigated. MI rats exhibited cardiac dysfunction, cognitive impairment, blood brain barrier (BBB) breakdown, dendritic spine loss, which were accompanied by an upregulation of oxidative stress, mitochondrial dysfunction, and apoptosis. Chronic treatment with Z-vad attenuated cardiac dysfunction following MI to the same extent as enalapril. Z-vad successfully improved cognitive function and restored dendritic spine density in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction similar to enalapril. Moreover, Z-vad provided greater efficacy than enalapril in enhancing mitophagy, neurogenesis, synaptic proteins and reducing apoptosis in hippocampus of MI rats. Nevertheless, neither Z-vad nor enalapril increased BBB tight junction protein. In conclusion, treatment with an apoptosis inhibitor reduced cognitive impairment in MI rats via reducing oxidative stress, mitochondrial dysfunction, apoptosis, and restoring dendritic spine density, together with enhancing mitophagy and neurogenesis.

Acetylcholine receptor agonists effectively attenuated multiple program cell death pathways and improved left ventricular function in trastuzumab-induced cardiotoxicity in rats.

AIMS: Cardiotoxicity is a seriously debilitating complication of trastuzumab (TRZ) therapy in patients with cancer as a consequence of overexpression of the human epidermal growth factor receptor 2. Although most TRZ-induced cardiotoxicity (TIC) cases are reversible, some patients experience chronic cardiac dysfunction, and these irreversible concepts may be associated with cardiomyocyte death. Acetylcholine receptor (AChR) activation has been shown to exert cardioprotection in several heart diseases, but the effects of AChR agonists against TIC have not been investigated. MAIN METHOD: Forty adult male Wistar rats were randomized into 5 groups: (i) CON (0.9 % normal saline), (ii) TRZ (4 mg/kg/day), (iii) TRZ + α7nAChR agonist (PNU-282987: 3 mg/kg/day), (iv) TRZ + mAChR agonists (bethanechol: 12 mg/kg/day), and (v) TRZ + combined treatment (Combined PNU-282987 and bethanechol). KEY FINDINGS: The progression of TIC was driven by mitochondrial dysfunction, autophagic deficiency, and excessive myocyte death including by pyroptosis, ferroptosis, and apoptosis, which were significantly alleviated by α7nAChR and mAChR agonists. Interestingly, necroptosis was not associated with development of TIC. More importantly, the in vitro study validated the cytoprotective effects of AChR activation in TRZ-treated H9c2 cells, while not interfering with the anticancer properties of TRZ. All of these findings indicated that TRZ induced mitochondrial dysfunction, autophagic deficiency, and excessive myocyte death including pyroptosis, ferroptosis, and apoptosis, leading to impaired cardiac function. These pathological alterations were attenuated by α7nAChR and mAChR agonists. SIGNIFICANCE: α7nAChR and mAChR agonists might be used as a future therapeutic target in the mitigation of TIC.

Acute administration of myeloid differentiation factor 2 inhibitor and N-acetyl cysteine attenuate brain damage in rats with cardiac ischemia/reperfusion injury.

Inflammation and oxidative stress are mechanisms which potentially underlie the brain damage that can occur after cardiac ischemic and reperfusion (I/R) injury. 2i-10 is a new anti-inflammatory agent, acting via direct inhibition of myeloid differentiation factor 2 (MD2). However, the effects of 2i-10 and the antioxidant N-acetylcysteine (NAC) on pathologic brain in cardiac I/R injury are unknown. We hypothesized that 2i-10 and NAC offer similar neuroprotection levels against dendritic spine reduction through attenuation of brain inflammation, loss of tight junction integrity, mitochondrial dysfunction, reactive gliosis, and suppression of AD protein expression in rats with cardiac I/R injury. Male rats were allocated to either sham or acute cardiac I/R group (30 min of cardiac ischemia and 120 min of reperfusion). Rats in cardiac I/R group were given one of following treatments intravenously at the onset of reperfusion: vehicle, 2i-10 (20 or 40 mg/kg), and NAC (75 or 150 mg/kg). The brain was then used to determine biochemical parameters. Cardiac I/R led to cardiac dysfunction with dendritic spine loss, loss of tight junction integrity, brain inflammation, and mitochondrial dysfunction. Treatment with 2i-10 (both doses) effectively reduced cardiac dysfunction, tau hyperphosphorylation, brain inflammation, mitochondrial dysfunction, dendritic spine loss, and improved tight junction integrity. Although both doses of NAC effectively reduced brain mitochondrial dysfunction, treatment using a high dose of NAC reduced cardiac dysfunction, brain inflammation, and dendritic spine loss. In conclusion, treatment with 2i-10 and a high dose of NAC at the onset of reperfusion alleviated brain inflammation and mitochondrial dysfunction, consequently reducing dendritic spine loss in rats with cardiac I/R injury.

Recent Advances in Mitochondrial Fission/Fusion-Targeted Therapy in Doxorubicin-Induced Cardiotoxicity.

Doxorubicin (DOX) has been recognized as one of the most effective chemotherapies and extensively used in the clinical settings of human cancer. However, DOX-mediated cardiotoxicity is known to compromise the clinical effectiveness of chemotherapy, resulting in cardiomyopathy and heart failure. Recently, accumulation of dysfunctional mitochondria via alteration of the mitochondrial fission/fusion dynamic processes has been identified as a potential mechanism underlying DOX cardiotoxicity. DOX-induced excessive fission in conjunction with impaired fusion could severely promote mitochondrial fragmentation and cardiomyocyte death, while modulation of mitochondrial dynamic proteins using either fission inhibitors (e.g., Mdivi-1) or fusion promoters (e.g., M1) can provide cardioprotection against DOX-induced cardiotoxicity. In this review, we focus particularly on the roles of mitochondrial dynamic pathways and the current advanced therapies in mitochondrial dynamics-targeted anti-cardiotoxicity of DOX. This review summarizes all the novel insights into the development of anti-cardiotoxic effects of DOX via the targeting of mitochondrial dynamic pathways, thereby encouraging and guiding future clinical investigations to focus on the potential application of mitochondrial dynamic modulators in the setting of DOX-induced cardiotoxicity.

Gasdermin D-mediated pyroptosis in myocardial ischemia and reperfusion injury: Cumulative evidence for future cardioprotective strategies.

Cardiomyocyte death is one of the major mechanisms contributing to the development of myocardial infarction (MI) and myocardial ischemia/reperfusion (MI/R) injury. Due to the limited regenerative ability of cardiomyocytes, understanding the mechanisms of cardiomyocyte death is necessary. Pyroptosis, one of the regulated programmed cell death pathways, has recently been shown to play important roles in MI and MI/R injury. Pyroptosis is activated by damage-associated molecular patterns (DAMPs) that are released from damaged myocardial cells and activate the formation of an apoptosis-associated speck-like protein containing a CARD (ASC) interacting with NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), resulting in caspase-1 cleavage which promotes the activation of Gasdermin D (GSDMD). This pathway is known as the canonical pathway. GSDMD has also been shown to be activated in a non-canonical pathway during MI and MI/R injury via caspase-4/5/11. Suppression of GSDMD has been shown to provide cardioprotection against MI and MI/R injury. Although the effects of MI or MI/R injury on pyroptosis have previously been discussed, knowledge concerning the roles of GSDMD in these settings remains limited. In this review, the evidence from in vitro, in vivo, and clinical studies focusing on cardiac GSDMD activation during MI and MI/R injury is comprehensively summarized and discussed. Implications from this review will help pave the way for a new therapeutic target in ischemic heart disease.

GSDMD-mediated pyroptosis dominantly promotes left ventricular remodeling and dysfunction in post-myocardial infarction: a comparison across modes of programmed cell death and mitochondrial involvement.

BACKGROUND: Myocardial infarction (MI) has recently accounted for more than one-third of global mortality. Multiple molecular pathological pathways, such as oxidative stress, inflammation, and mitochondrial dysfunction, have been recognized as possible mechanisms in the development of MI. Furthermore, different phases of ischemic injury following the progression of MI were also associated with multiple types of programmed cell death (PCDs), including apoptosis, necroptosis, ferroptosis, and pyroptosis. However, it remains unknown whether which types of PCDs play the most dominant role in post-myocardial infarction (post-MI). METHOD: In this study, we used a preclinical rat model of MI induced by permanent left anterior descending coronary artery (LAD) ligation (n = 6) or a sham operated rat model (n = 6). After a 5-week experiment, cardiac function and morphology, mitochondrial studies, and molecular signaling analysis of PCDs were determined. RESULTS: Herein, we demonstrated that post-MI rats had considerably impaired cardiac geometry, increased oxidative stress, myocardial injuries, and subsequently contractile dysfunction. They also exhibited worsened cardiac mitochondrial function and dynamic imbalance. More importantly, we found that post-MI mediated abundant myocardial cell death through multiple PCDs, including apoptosis, necroptosis, and pyroptosis, but not ferroptosis. CONCLUSION: In this study, we provide the first insights into the mechanism of PCDs by pyroptosis, which is leveraged as the most dominant mode of cell death after MI.

Chronic Pharmacological Modulation of Mitochondrial Dynamics Alleviates Prediabetes-Induced Myocardial Ischemia-Reperfusion Injury by Preventing Mitochondrial Dysfunction and Programmed Apoptosis.

PURPOSE: There is an increasing body of evidence to show that impairment in mitochondrial dynamics including excessive fission and insufficient fusion has been observed in the pre-diabetic condition. In pre-diabetic rats with cardiac ischemia-reperfusion (I/R) injury, acute treatment with a mitochondria fission inhibitor (Mdivi-1) and a fusion promoter (M1) showed cardioprotection. However, the potential preventive effects of chronic Mdivi-1 and M1 treatment in a pre-diabetic model of cardiac I/R have never been elucidated. METHODS: Male Wistar rats (n = 40) were fed with a high-fat diet (HFD) for 12 weeks to induce prediabetes. Then, all pre-diabetic rats received the following treatments daily via intraperitoneal injection for 2 weeks: (1) HFDV (Vehicle, 0.1% DMSO); (2) HFMdivi1 (Mdivi-1 1.2 mg/kg); (3) HFM1 (M1 2 mg/kg); and (4) HFCom (Mdivi-1 + M1). At the end of treatment protocols, all rats underwent 30 min of coronary artery ligation followed by reperfusion for 120 min. RESULTS: Chronic Mdivi-1, M1, and the combined treatment showed markedly improved cardiac mitochondrial function and dynamic control, leading to a decrease in cardiac arrhythmias, myocardial cell death, and infarct size (49%, 42%, and 51% reduction for HFMdivi1, HFM1, and HFCom, respectively vs HFDV). All of these treatments improved cardiac function following cardiac I/R injury in pre-diabetic rats. CONCLUSION: Chronic inhibition of mitochondrial fission and promotion of fusion exerted cardioprevention in prediabetes with cardiac I/R injury through the relief of cardiac mitochondrial dysfunction and dynamic alterations, and reduction in myocardial infarction, thus improving cardiac function.

Melatonin and metformin counteract cognitive dysfunction equally in male rats with doxorubicin-induced chemobrain.

Melatonin (Mel) and metformin (Met) show beneficial effects in various brain pathologies. However, the effects of Mel and Met on doxorubicin (DOX)-induced chemobrain remain in need of elucidation. We aimed to investigate whether Mel and Met provide neuroprotective effects on glial dysmorphologies, brain inflammation, oxidative stress, brain mitochondrial dysfunction, apoptosis, necroptosis, neurogenesis, hippocampal dysplasticity, and cognitive dysfunction in rats with DOX-induced chemobrain. Thirty-two male Wistar rats were divided into 2 groups and received normal saline (NSS, as control, n = 8) or DOX (3 mg/kg/day; n = 24) by intraperitoneal (i.p.) injection on days 0, 4, 8, 15, 22, and 29. The DOX-treated group was divided into 3 subgroups receiving either vehicle (NSS; n = 8), Mel (10 mg/kg/day; n = 8), or Met (250 mg/kg/day; n = 8) by gavage for 30 consecutive days. Following this, cognitive function was assessed in all rats. The number of glial cells and their fluorescence intensity had decreased, while the glial morphology in DOX-treated rats showed a lower process complexity. Brain mitochondrial dysfunction, an increase in brain inflammation, oxidative stress, apoptosis and necroptosis, a decrease in the number of hippocampal dendritic spines and neurogenesis, and cognitive decline were also observed in DOX-treated rats. Mel and Met equally improved those brain pathologies, resulting in cognitive improvement in DOX-treated rats. In conclusion, concomitant treatment with either Mel or Met counteract DOX-induced chemobrain by preservation of glial morphology, brain inflammation, brain oxidative stress, brain mitochondrial function, hippocampal plasticity, and brain apoptosis. This study highlighted the role of the glia as key mediators in DOX-induced chemobrain.

Melatonin and metformin ameliorated trastuzumab-induced cardiotoxicity through the modulation of mitochondrial function and dynamics without reducing its anticancer efficacy.

Trastuzumab has an impressive level of efficacy as regards antineoplasticity, however it can cause serious cardiotoxic side effects manifested by impaired cardiac contractile function. Although several pharmacological interventions, including melatonin and metformin, have been reported to protect against various cardiovascular diseases, their potential roles in trastuzumab-induced cardiotoxicity remain elusive. We hypothesized that either melatonin or metformin co-treatment effectively attenuates trastuzumab-mediated cardiotoxicity through attenuating the impaired mitochondrial function and mitochondrial dynamics. Male Wistar rats were divided into control (normal saline, n = 8) and trastuzumab group (4 mg/kg/day for 7 days, n = 24). Rats in the trastuzumab group were subdivided into 3 interventional groups (n = 8/group), and normal saline, or melatonin (10 mg/kg/day), or metformin (250 mg/kg/day) were orally administered for 7 consecutive days. Cardiac parameters were determined, and biochemical investigations were carried out on blood and heart tissues. Trastuzumab induced left ventricular (LV) dysfunction by increasing oxidative stress, inflammation, and apoptosis. It also impaired cardiac mitochondrial function, dynamics, and autophagy. Treatment with either melatonin or metformin equally attenuated trastuzumab-induced cardiac injury, indicated by a marked reduction in inflammation, oxidative damage, cardiac mitochondrial injury, mitochondrial dynamic imbalance, autophagy dysregulation, and apoptosis, leading to improved LV function, as demonstrated by increased LV ejection fraction. Melatonin and metformin conferred equal levels of cardioprotection against trastuzumab-induced cardiotoxicity, which may provide novel and promising approaches for management of cardiotoxicity induced by trastuzumab.

Vagus nerve stimulation exerts cardioprotection against doxorubicin-induced cardiotoxicity through inhibition of programmed cell death pathways.

The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3 mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1 mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5 mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR.