Histone deacetylases (HDAC) catalyze the removal of acetylation modifications on histones and non-histone proteins, which regulates gene expression and other cellular processes. HDAC inhibitors (HDACi), approved anti-cancer agents, emerge as a potential new therapy for heart diseases. Cardioprotective effects of HDACi are observed in many preclinical animal models of heart diseases. Genetic mouse models have been developed to understand the role of each HDAC in cardiac functions. Some of the findings are controversial. Here, we provide an overview of how HDACi and HDAC impact cardiac functions under physiological or pathological conditions. We focus on in vivo studies of zinc-dependent classical HDACs, emphasizing disease conditions involving cardiac hypertrophy, myocardial infarction (MI), ischemic reperfusion (I/R) injury, and heart failure. In particular, we review how non-biased omics studies can help our understanding of the mechanisms underlying the cardiac effects of HDACi and HDAC.

Sirtuins (SIRTs) are a nicotinic adenine dinucleotide (+) -dependent histone deacetylase that regulates critical signaling pathways in prokaryotes and eukaryotes. Studies have identified seven mammalian homologs of the yeast SIRT silencing message regulator 2, namely, SIRT1-SIRT7. Recent in vivo and in vitro studies have successfully demonstrated the involvement of SIRTs in key pathways for cell biological function in physiological and pathological processes of the cardiovascular system, including processes including cellular senescence, oxidative stress, apoptosis, DNA damage, and cellular metabolism. Emerging evidence has stimulated a significant evolution in preventing and treating cardiovascular disease (CVD). Here, we review the important roles of SIRTs for the regulatory pathways involved in the pathogenesis of cardiovascular diseases and their molecular targets, including novel protein post-translational modifications of succinylation. In addition, we summarize the agonists and inhibitors currently identified to target novel specific small molecules of SIRTs. A better understanding of the role of SIRTs in the biology of CVD opens new avenues for therapeutic intervention with great potential for preventing and treating CVD.

Ischemic reperfusion injury (IRI) after liver transplantation is a common cause of early allograft dysfunction with high mortality. The purpose of this case report series is to highlight an unusual clinical course in which complete recovery can occur following the identification of severe hepatic IRI post-transplantation and the implications of this finding on management strategies in patients with IRI post-transplant. Here, we include three cases of severe IRI following liver transplantation that are putatively resolved without retransplantation or definitive therapeutic intervention. All patients recovered until their final follow-up visits to our institution and developed no significant complications from their injury throughout the course of patient care by our institution after discharge from the hospital.

Exosomes, which contain miRNA, have been receiving growing attention in cardiovascular therapy because of their role in mediating cell-cell communication, autophagy, apoptosis, inflammation, and angiogenesis. Several studies have suggested that miRNA derived from exosomes can be used to detect myocardial infarctions (MI) in patients. Basic research also suggests that exosomes could serve as a potential therapeutic target for treating acute myocardial infarction. Ischemia/reperfusion (IR) injury is associated with adverse cardiac events after acute MI. We aim to review the potential benefits and mechanisms of exosomes in treating MI and IR injury.

Complex regional pain syndrome type I (CRPS-I) is a condition that responds poorly to treatments. The role of omega-3 fatty acids in the treatment of inflammatory disorders is well described in the literature; however, few studies have evaluated its therapeutic benefits in different types of pain. We evaluated the potential antihyperalgesic and anti-inflammatory effects of preventive omega-3 supplementation in an animal model of CRPS-I. In experiment 1, Swiss female mice were supplemented for 30 days with omega-3 before the induction of the CRPS-I model and 14 days after. Mechanical hyperalgesia was evaluated at baseline and from the 4th to the 14th day after CPRS-I induction along with open field locomotor activity after 30 days of supplementation. In experiment 2, Swiss female mice were supplemented for 30 days with omega-3 and then subjected to the CRPS-I model. Twenty-four hours later the animals were euthanized, and tissue samples of the spinal cord and right posterior paw muscle were taken to measure pro-inflammatory cytokine TNF and IL-1β concentrations. Omega-3 supplementation produced antihyperalgesic and anti-inflammatory effects, as well as reducing pro-inflammatory cytokine concentrations, without altering the animals\' locomotion. No open field locomotor changes were found. The 30-day supplementation at the tested dose was effective in the CRPS-I model.

The study aimed to identify small molecules having potentiality in alleviating renal injury. Two natural compounds cyclo(Val-Pro) (1) and cyclo(Leu-Hydroxy-Pro) (2) were first evaluated under acute renal injury model of ischemic reperfusion at different doses of 25, 50 and 75 mg/kg body weight. Further, the compounds were subjected to antimycin A-induced ischemic in vitro study (NRK-52E cell lines). Both the compounds significantly decreased plasma IL-1β levels (P < 0.05). Also, the mRNA expression levels of inflammatory markers (TNF-α, IL-6 and IL-1β) and renal injury markers (KIM-1, NGAL, α-GST and π-GST) in the renal tissues were significantly alleviated (P < 0.01) along with the improvement in histological damage and control over neutrophil infiltration as a result of ischemic reperfusion. The in vitro study revealed the protective effect against antimycin A-induced cytotoxicity (P < 0.05) and antiapoptotic effect acting through the regulation of Bax, caspase 3 (pro and cleaved) and BCL2 with reduction in Annexin+PI+ cells. Further, the compound cyclo(Val-Pro) (1) was evaluated (50 mg/kg body weight dose) in chronic unilateral ureter obstruction model of renal injury in mice and TGF-β-induced in vitro fibrotic model (NRK-49F cell lines). Cyclo(Val-Pro) (1) significantly reduced the expression levels of fibrotic markers (collagen-1, α-SMA and TGF-β) and showed marked alleviation of renal fibrosis (sirius red staining). Also, the proliferation of TGF-β-induced NRK-49F cells was significantly reduced along with decreased levels of collagen-1 and α-SMA in immunohistochemistry studies. In conclusion, the compounds significantly abrogated ischemic injury by inhibiting renal inflammation and tubular epithelial apoptosis. Further, cyclo (Val-Pro) (1) exhibited significant anti-fibrotic activity through the inhibition of fibroblast activation and proliferation. Thus, these proline-based cyclic dipeptides are recommended as drug leads for treating renal injury.

Peripheral artery disease (PAD) is a common, yet serious, circulatory condition that can increase the risk of amputation, heart attack or stroke. Accurate identification of PAD and dynamic monitoring of the treatment efficacy of PAD in real time are crucial for optimizing therapeutic outcomes. However, current imaging techniques do not enable these requirements. Methods: A lanthanide-based nanoprobe with emission in the second near-infrared window b (NIR-IIb, 1500-1700 nm), Er-DCNPs, was utilized for continuous imaging of dynamic vascular structures and hemodynamic alterations in real time using PAD-related mouse models. The NIR-IIb imaging capability, stability, and biocompatibility of Er-DCNPs were evaluated in vitro and in vivo. Results: Owing to their high temporal-spatial resolution in the NIR-IIb imaging window, Er-DCNPs not only exhibited superior capability in visualizing anatomical and pathophysiological features of the vasculature of mice but also provided dynamic information on blood perfusion for quantitative assessment of blood recovery, thereby achieving the synergistic integration of diagnostic and therapeutic imaging functions, which is very meaningful for the successful management of PAD. Conclusion: Our findings indicate that Er-DCNPs can serve as a promising system to facilitate the diagnosis and treatment of PAD as well as other vasculature-related diseases.

Hypoxia inducible factor alpha (HIF1α) is associated with neuroprotection conferred by diet-induced ketosis, but the underlying mechanism remains unclear. In this study, we use a ketogenic diet in rodents to induce a metabolic state of chronic ketosis, as measured by elevated blood ketone bodies. Chronic ketosis correlates with neuroprotection in both aged and following focal cerebral ischemia and reperfusion (via middle cerebral artery occlusion, MCAO) in mouse and rat models. Ketone bodies are known to be used efficiently by the brain, and metabolism of ketone bodies is associated with increased cytosolic succinate levels that inhibits prolyl hydroxylases allowing HIF1α to accumulate. Ketosis also regulates inflammatory pathways, and HIF1α is reported to be essential for gene expression of interleukin 10 (IL10). Therefore, we hypothesized that ketosis-stabilized HIF1α modulates the expression of inflammatory cytokines orchestrating neuroprotection. To test changes in cytokine levels in rodent brain, 8-week-rats were fed either the standard chow diet (SD) or the KG diet for 4 weeks before ischemia experiments (MCAO) were performed and the brain tissues were collected. Consistent with our hypothesis, immunoblotting analysis shows IL10 levels were significantly higher in KG diet rat brain compared to SD, whereas the TNFα and IL6 levels were significantly lower in the brains of KG diet-fed group.

OBJECTIVE: To investigate the different changes in nociceptive activity between two animal models of trigeminal neuropathic pain: unilateral external carotid artery ischemic reperfusion and lingual nerve crush in rats.
METHODS: In this study, changes in nociceptive activity were investigated in unilateral external carotid artery ischemic reperfusion and lingual nerve crush models of trigeminal neuropathic pain in rats. Field excitatory postsynaptic potentials (fEPSPs) evoked by capsaicin application on the tongue of rats were recorded in the trigeminal nucleus caudalis. In addition, immunohistochemistry was performed in the trigeminal ganglia and trigeminal nucleus caudalis.
RESULTS: The fEPSP in unilateral external carotid artery ischemic reperfusion and lingual nerve crush rats was irregular relative to that in sham rats. In particular, the fEPSP spike in lingual nerve crush rats had a higher amplitude and shorter duration than that in sham rats. Unilateral external carotid artery ischemic reperfusion and lingual nerve crush also increased c-fos expression in the trigeminal nucleus caudalis. Upregulation of transient receptor potential vanilloid 1 in trigeminal ganglion was observed in unilateral external carotid artery ischemic reperfusion and lingual nerve crush rats, whereas upregulation of purinergic receptor subtype 3 in trigeminal ganglion was observed only in lingual nerve crush rats.
CONCLUSIONS: Although unilateral external carotid artery ischemic reperfusion and lingual nerve crush similarly increased nociceptive activity at the trigeminal nucleus caudalis, the fEPSPs and expression of nociceptive peripheral afferent neurons were different. Therefore, direct and indirect nerve injuries apparently induced the same nociceptive activity by different signaling responses dependent on nociceptive receptors.

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis.