HDAC2 activity was inhibited via conditional knockout of the Hdac2 gene in microglia or via administration of scriptaid. In vitro, a transwell co-culture model of microglia and oligodendrocytes also demonstrated that the HDAC inhibitor protected oligodendrocytes by modulating microglia polarization and mitigating neuroinflammation.
Intracerebral hemorrhage ICH is a devastating subtype of stroke with high mortality and morbidity. Indeed, after ICH, activated microglia polarize into either the classical M1 phenotype, secreting several pro-inflammatory cytokines, or the alternative M2 phenotype, producing anti-inflammatory factors that suppress the immune response and improve recovery after ICH.
All animals were provided free access to food and water. Animal group assignments were conducted at random using a lottery-drawing box. All main outcome studies, including neurobehavioral tests, electrophysiology, lesion volume, histology, and immunohistochemistry, were performed by investigators who were blind to group assignment and experimental conditions.
Animals that died during or after surgery were excluded from the studies. The results for body weight and survival rate in each group are shown in the Supplemental Table 1. Blood was obtained from each animal via a femoral artery catheter for subsequent intracranial injection and for analysis of pH, PaO 2 , PaCO 2 , and blood glucose.
Core body temperature was kept at The burr hole was filled with bone wax, and the skin incision was sutured. All counts were performed in a blinded fashion. Behavioral tests, including the corner turn test, the foot fault test, the wire hanging test, and the cylinder test, were performed to evaluate sensorimotor function, as described previously.
This procedure was repeated 20 times for each mouse. The percentage of right turns was calculated. The amount of time spent hanging was recorded and scored according to the following system: 0, fell off; 1, hung onto the bar with two forepaws; 2, hung onto the bar with added attempt to climb onto the bar; 3, hung onto the bar with two forepaws and one or two hind paws; 4, hung onto the bar with all four paws and with tail wrapped around the bar; 5, escaped to one of the supports.
The foot fault test was used to evaluate dysfunction of the forelimbs and hind limbs. Each fall and slip between the wires with weight-bearing steps was recorded as a forelimb or hind limb foot fault. The cylinder test was used to assess forelimb use and rotational asymmetry. Animals showing behavioral asymmetries were excluded from further analysis. All behavior tests were performed and evaluated by a blinded observer. The hidden platform test assessed the ability of the mice to find the platform without being able to directly see it, and the mice have to either remember its location relative to external spatial cues or perform a search.
Four trials were performed per day for five consecutive days with the location of the platform kept constant. Data were expressed as the time in seconds or latency to reach the submerged platform each day.
After the last day of the hidden platform test, a single s probe trial was performed. The time spent in the goal quadrant where the platform had been located and the swimming speed were both recorded.
All tests were performed by researchers blind to experimental group assignment. RT-PCR was performed as described previously. The sequences of the primer pairs for the M1and M2 phenotype genes are as follows in pairs, sense and antisense. CAPs in the CC were measured as described previously. Only the recording at 0. Input—output curves were generated by varying the intensity of the stimuli from 0.
Myelinated fiber amplitude was defined as the difference from the first peak to the first trough N1. Metabolic viability in vitro was assessed with the CCK8 assay. Cell death was evaluated using the LDH assay for loss of membrane integrity and release of LDH into the culture medium. Data were expressed as a percentage of the maximum LDH activity in control wells in which all cells were lysed with Triton. Electron microscopy was performed as described previously 38 to access myelin and axonal damage in the peri-hemorrhage area.
Next, tissues were washed in 0. Following serial dehydration in acetone, the tissue was embedded in epoxy resin. To examine both axonal damage and demyelination, we evaluated the number of myelinated axons per unit area and the g-ratio ratio of axonal diameter with myelin sheath and axonal diameter without myelin sheath as described previously.
Protein concentration was determined by a Bio-Rad protein assay kit. We detected the target proteins with Scion Image by using secondary antibodies, and the relative densities of the bands were analyzed with ImageJ version 1. A gating strategy was used to sort microglia Figure 3 d. Samples were gated on live singlets prior to identifying leukocytes via forward and side scatter. Cell suspensions were prepared from the ipsilateral hemisphere of each mouse.
Kolmogorov—Smirnov test was used to assess the normal distribution of the data. The HDAC2 cKO mice located a hidden platform faster over the five days of learning trials as denoted by a decrease latency to find the platform. HDAC2 cKO mice spent more time crossing over the correct location once the platform was removed on the final day of testing indicative of an improvement in memory function.
The results suggested that decreasing Hdac2 gene expression in microglia ameliorates cognitive impairment after ICH in addition to improving neurological function. The Morris water maze test was performed to measure cognitive deficits after ICH e—g. To further evaluate whether reducing Hdac2 expression in microglia preserved white matter integrity after ICH, we analyzed the ultrastructural changes in myelin sheath and axons.
To assess functional alterations in white matter, we examined the conduction of CAPs in myelinated axons.
After ICH, the N1 segment amplitude decreased, indicating damage to myelinated axons. Conditional knockout of the Hdac2 gene in microglia significantly attenuated the decrease in amplitude of the N1 segment Figure 2 f to h. The amplitude of the N1 component of the CAPs in response to increasing stimulus strength 0.
Then, we compared the N1 amplitude in response to a 0. To confirm the relationship between HDAC and inflammation after ICH in microglia, a gating strategy was used to sort microglia by flow cytometry Figure 3 d. Samples were gated on live singlets prior to identifying leukocytes by forward and side scatter. Our in vivo results demonstrated that knockout of the Hdac2 gene could preserve the myelin sheath and axonal function after ICH.
We observed that medium from cultured primary microglia that were stimulated by hemoglobin decreased the immunostaining intensity of MBP, indicating damage to the cultured oligodendrocytes. However, scriptaid inhibited the decrease in MBP immunostaining intensity Figure 4 b.
Consistent with the reduced MBP immunostaining, scriptaid also protected oligodendrocyte viability Figure 4 c , as assessed by LDH release and CCK8, coincident with a decrease in the gene expression of proinflammatory cytokines in vitro Figure 4 d. Scriptaid reduced this inflammatory response and attenuated WMI. Scriptaid-treated mice performed significantly better than vehicle mice in corner and cylinder test. Furthermore, assessment of learning and memory as measured by escape latency and quadrant distance, respectively, in the Morris water maze, indicated scriptaid significantly improved cognitive deficits after ICH Figure 5 e to g.
The scriptaid-treated mice located a hidden platform faster over the five days of learning trials as denoted by a decrease latency to find the platform. Scriptaid-treated mice spent more time crossing over the correct location once the platform was removed on the final day of testing indicative of an improvement in memory function.
In addition, the scriptaid-treated mice swim more distance in the same quadrant as the platform after training than vehicle mice after ICH.
Therefore, scriptaid can not only improve sensorimotor dysfunction but also reduce cognitive deficits after ICH. The above antibodies were purchased from Abcam.
SPSS This showed that the intervention of scriptaid could reduce the infarct volume of brain tissue to a certain extent, and had certain protective effect on neonatal rat HIBD. Rotarod test and wire hang test were used for neurobehavioral evaluation. The results of the neurobehavioral evaluation had showed that scriptaid could reduce nerve damage of HBID rat.
HDAC inhibition attenuated infarct volume and improved sensorimotor functions. There were 7 rats for each group in MRI, rotarod test and wire-hang test, 5 rats for each group in positioning navigation test and space exploration test. Morris water maze was an experimental device composed of a circular water tank and an automatic video analysis system. It could be used to detect the behavior and memory function of experimental animals, and could be used to indirectly assess neurobehavioral behavior.
The results of Morris water maze showed that the spatial learning and memory ability of rats after HBID was significantly reduced, but Scriptaid could improve them. Increased enzymatic activity of histone deacetylase can result in decreased histone acetylation.
Can the use of the HDAC inhibitor scriptaid reverse this pathological process and thereby exert a neuroprotective effect? HDAC inhibition increases the level of histone acetylation and prevents neuronal degeneration.
Neurodegenerative change is a common after-effect of HBID and usually results in irreversible damage to neurons. FluoroJadeC FJC is a fluorescent dye that combines with denatured neurons to glow green, whereas normal neurons do not glow green when combined with FJC. In addition, neuronal degenerative lesions often resulted in the loss of asymptotic structure and function of neurons. Microtubule-associated protein 2 MAP2 is a phosphoprotein that regulates the stability of microtubules.
It is mainly distributed in the cell bodies and dendrites of neurons and is considered to be a more specific marker of neuron dendrites. The main function of oligodendrocytes OLG is to surround the axons in the central nervous system, form an insulating myelin sheath structure, assist in the efficient and efficient transmission of bioelectric signals, and maintain and protect the normal functions of neurons.
Demyelinating disorders of the central nervous system can also cause neuronal damage or mental illness. Sphingomyelin basic protein MBP is a characteristic protein of mature oligodendrocytes.
HDAC inhibition protected oligodendrocytes indirectly through microglia. This suggested that HDAC inhibition could promote micropolarization of microglia into M2 microglia, and inhibited inflammatory responses. At present, there are no therapies or drugs that can cure the cognitive and motor deficits in HBID patients [ 22 , 23 ]. Another need to clarifyis that the degree of brain development in 7-day-old rats is basically the same as that of full-term newborns [ 24 ].
After 7 days of Scriptaid treatment, we found that Scriptaid could reduce the infarct volume of brain tissue to a certain extent, and had certain protective effect on neonatal rat HIBD. Scriptaid is a HDAC inhibitor, and histone acetylation is an important mechanism of gene transcription regulation and is mainly regulated by histone acetyltransferases HATs and histone deacetylases HDACs [ 25 , 26 ].
HATs can activate certain genes and promote transcription, but HDACs inhibit transcription by inhibiting the binding of gene promoters to transcriptional regulatory elements [ 10 ].
With the deepening of epigenetic studies, it had been found that histone deacetylase was closely related to the occurrence and development of tumors, nervous system diseases, and immune system diseases, so HDACs and their inhibitors HDACIs had attracted more and more attention and became a hot topic in the design and synthesis of new drugs [ 27 ]. Recently, a large number of HDACIs have been designed and synthesized for use in animal models of various neurodegenerative diseases [ 28 ].
Guohua Wang, et al. Previous work found [ 29 , 30 ] that HDAC inhibitors played an important role in multiple aspects of ischemic stroke injury mechanisms to reduce brain tissue damage and promote neuronal plasticity and functional recovery after ischemia by regulating histones and non-histone modifications, upregulate the expression of genes and proteins with neuroprotective functions and inhibit the expression of harmful genes and proteins [ 14 , 31 ].
In this paper, we found Scriptaid not only could increase the corresponding histone acetylation level significantly by inhibiting the activity of HDAC in brain tissue of HBID model mice, but also could reduce the number of degenerative neurons in cerebral infarction. The role of microglia in the central nervous system after injury is currently receiving widespread attention. Recent research results strongly supported the idea that microglia had both good and bad roles, and that these immune cells migrated to M1 or M2 subunits through different activation pathways [ 33 , 34 ].
However, a large number of studies had also shown that microglial released pro-inflammatory factors that could promote neurological dysfunction and cell death [ 35 , 36 ]. That means microglia could produce pro-inflammatory cytokines to promote cell damage, but at the same time could remove necrotic tissue to participate in the regeneration process [ 37 , 38 ]. In vivo it was demonstrated that HDAC inhibition by Scriptaid could promote micropolarization of microglia into M2 microglia, and inhibited inflammatory responses.
Here are two points we need to clarify with the reader. First, the neuroinflammation of the central nervous system is mainly mediated by microglia and giant salivary cells, and these two cells participate in mediating secondary cascade damage after brain injury [ 39 , 40 ]. Second, acute inflammation can exert many protective effects [ 20 ], but chronic inflammation can worsen the damage which is consistent with the traditional view of chronic inflammation [ 41 , 42 ]. We found Scriptaid could promote micropolarization of microglia into M2 microglia, and inhibited inflammatory responses after HBID.
All in all, our research provided a new possibility for the treatment of HBID. National Center for Biotechnology Information , U. Int J Clin Exp Pathol. Author information Article notes Copyright and License information Disclaimer. Received Nov 18; Accepted Jan This article has been cited by other articles in PMC. Abstract Background: Neonatal hypoxia-ischemia brain damage HBID can cause a series of neurological sequelae, such as movement and cognitive impairment, and there is currently no clinically effective treatment.
Keywords: Histone deacetylase inhibition, hypoxia-ischemia brain damage, Inflammation, microglial polarization, oligodendrocyte. Introduction Hypoxic-ischemic brain damage HIBD is the brain damage caused by suffocation during the perinatal period in newborns, and is one of the leading causes of neonatal death [ 1 ]. Cerebral infarction volume determination Magnetic resonance imaging MRI was used to detect the infarct volume.
Neurobehavioral tests Rotarod test Rotary rod test was performed as described previously [ 17 ]. Wire hang test Wire hang test was performed as described previously [ 18 ]. Morris water maze Positioning navigation test The rats faced the pool wall and entered the water at random from four different quadrants.
Space exploration test On the afternoon of the 5th day, the platform was removed. Cell viability and death The cell viability was measured by MTT assay. Table 1 RT-qPR primers.
Open in a separate window. Statistical analysis SPSS Figure 1. Scriptaid prevented neuronal degeneration Increased enzymatic activity of histone deacetylase can result in decreased histone acetylation. Figure 2. Scriptaid protected oligodendrocytes indirectly through microglia The main function of oligodendrocytes OLG is to surround the axons in the central nervous system, form an insulating myelin sheath structure, assist in the efficient and efficient transmission of bioelectric signals, and maintain and protect the normal functions of neurons.
Figure 3. Figure 4. Discussion At present, there are no therapies or drugs that can cure the cognitive and motor deficits in HBID patients [ 22 , 23 ]. In this scenario, synthetic target sequences complementary to specific miRNAs have been inserted in the UTRs of viral genes essential for replication. This approach promotes the degradation of the viral genome in healthy tissues, but not in cancer cells [ , , , ]. This targeting strategy depends on the small size of miRNAs that can be inserted into the viral genome without compromising normal replication in tumor tissues.
Its usefulness has been widely demonstrated and tissue specificity has been improved for many oncolytic viruses [ , , , , , ]. They reported an innovative strategy in which miRNAs mediated gene silencing [ ]. The results demonstrated that ICP27 protein level was higher in tumor cells than in healthy cells, indicating that this type of regulation could control HSV-1 by selectively killing NSCLC cells in vitro [ ].
Generally, miRNA was found to be upregulated in cancer cells [ ]. This study has shown that a viral gene under the control of miR limited viral replication in healthy cells, where miR was downregulated, and, at the same time, it induced a vigorous replication in cancer cells expressing miR [ ]. Many studies have used oncolytic adenovirus in combination with hepatic specific miRNAs, such as miR, to counteract hepatotoxicity and increase the virus specificity.
A first study was performed by Ylosmaki et al, which inserted the EA1 gene under the control of miR in serotype 5 adenovirus Ad5 [ ]. In this case, six copies of the target sequence for miR were used to prevent the replication of Ad5 in healthy liver tissue.
Differently from the wild-type Ad5, the engineered virus did not produce an increase in serum liver enzyme levels in infected mice. These results have prompted other studies that have combined miR with miR, also specific for hepatocytes and downregulated in cancer cells. This modification effectively inhibited adenoviral infection in healthy pancreatic tissue and, on the contrary, it has improved the viral anti-tumor activity in pancreatic tumors [ ].
Other genes essential to adenovirus replication have been regulated by miRNA target sequences, such as the gene encoding L5 protein: eight binding sequences for miRa have been added downstream. The mice treated with Ad-LmiRaT showed reduced adenovirus-induced hepatotoxicity and full lytic activity in tumor cells [ ]. Therefore, the control of the late proteins through miRNAs is also a strategy for improving viral selectivity. The presence of viral proteins in normal tissues could create immunogenic reactions, as well as inflammation and cell death.
It represents an undesirable effect, which thanks to the intervention of miRNAs can be shot down in normal cells, increasing the safety profile and therapeutic index in oncolytic virotherapy. Furthermore, the ability to introduce multiple miRNA elements into the same viral genome can simultaneously eliminate various off-target toxicities, and thus it could eliminate the toxicity coming from a systemic infection. Finally, by selecting miRNAs with high levels of expression and incorporating multiple copies into the viral genome, saturation phenomena or point mutations during infection can be avoided.
However, other studies and clinical trials will need to be performed before the therapeutic potential of this innovative approach and its safety can be assessed in humans. The recombinant virus, called 53a-CVB, showed minimal levels of toxicity in healthy tissues and, furthermore, retained its full oncolytic activity in xenotransplant mice with human lung cancer [ ]. A21 wild-type virus causes lethal myositis in tumor bearing mice. On the contrary, the recombinant virus retained its replication ability in cancer cells, causing total regression of subcutaneous tumors, and did not replicate in healthy cells expressing complementary miRNAs, thereby reducing myotoxicity, and retaining the oncolytic potential [ ].
Another member of the Picornaviridae family, Mengovirus, can cause encephalitis and myocarditis in multiple mammalian species. It has shown oncolytic activity but its use can also cause side effects. In order to improve the safety profile and reduce toxicity, Ruiz et al.
The recombinant virus was called VMCNC and retains a full oncolytic power if administered intratumor or intravenously [ ]. This study has shown that the simultaneous use of multiple targets for miRNA reduces the saturation potential of a single miRNA.
At the present, much evidence demonstrates that tumor cells are deregulated by epigenetic mechanisms, apart from genetic alterations. On the other hand, OVs are promising therapeutic agents which are developing in the cancer treatment field. They are great biotherapeutic platforms to be combined with epigenetic drugs, able to cut down cellular antiviral response, promote the destruction of cancer cells and potentiate the immune response Figure 1.
Although in many clinical trials, no mortality following virotherapy has been reported, except sporadically, the advancement of treatments in combination with other molecules, and the use of different oncolytic viruses, still raises safety concerns. Although genetic manipulation has improved the tropism of oncolytic viruses for cancer cells, it is possible to recur to genetic recombination or mutation with the consequent production of unexpected toxic effects.
However, many studies report that the effects of virotherapy are generally well-tolerated and that the most common side effects, when present, are flu-like. One of the main mechanisms of resistance to virotherapy is represented by innate immunity. Through the production of neutralizing antibodies, the immune system can limit the ability of the virus to replicate sufficiently to spread into neighboring tumor tissues.
In this case, the use of immunosuppressant drugs in the early stages of treatment could resolve the problem [ ]. Unfortunately, this option could exclude immunocompromised patients or people with active viral infections. In the last decade, studies on the development and improvement of OVs at the preclinical level have increased. Furthermore, new strategies adopted, such as the introduction of epigenetic modulators in virotherapy, are bringing more safety and selectivity to cancer cells, increasingly reducing collateral damage to healthy cells [ ].
However, an important feature reported by several studies is represented by viral pharmacodynamics and pharmacokinetics, which allows constant monitoring of the immune response and viral load, both essential for understanding the course of treatment and suggesting changes in the case of problems.
Moreover, apart from combining OVs with other molecules, it should be very interesting to combine virotherapy with standard cancer therapeutics like chemotherapy and radiotherapy, with the aim to improve time survival in advanced cancer patients. For example, in a Phase I trial by Mell et al. In this scenario, the prospects for the future will be to improve combinations and OVs, increase efficiency, safety, and treatment times, with particular attention to those tumors that are difficult to eradicate and resistant to chemotherapy.
Summarizes the effects of combinatorial treatment by the use of OVs, epigenetic modulators and miRNA. Created with BioRender. Additional in vitro and in vivo studies are needed in order to extend the panel of OVs and epigenetic modulators used to reach the clinic in the near future, to further improve their therapeutic impact. Conceptualization, M. All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U.
Journal List Cancers Basel v. Cancers Basel. Published online Jun 2. Find articles by Annalisa Chianese. Find articles by Annalisa Ambrosino. Find articles by Debora Stelitano. Find articles by Carla Zannella. Cristina Fillat, Academic Editor.
Author information Article notes Copyright and License information Disclaimer. Received Apr 10; Accepted May This article has been cited by other articles in PMC.
Abstract Simple Summary Cancer rates have been accelerating significantly in recent years. Introduction Cancer is a well-known serious health issue associated with high morbidity and mortality, second only to cardiovascular diseases in the world [ 1 ]. Table 1 Oncolytic viruses subjected to clinical trials. BioClever S.
Open in a separate window. Viral Families Most Used in Virotherapy 2. Herpesviridae Herpesviridae is a large family with about viruses causing disease in many animals, including humans, monkeys, fish, and birds [ , ]. Adenoviridae AdVs are naked viruses consisting of a linear double-stranded DNA of approximately 35 kb that encodes over 40 proteins [ ]. Reoviridae Reoviridae are naked viruses with double-stranded segmented RNA of approximately 10—12 kb. Parvoviridae Parvoviruses are small viruses belonging to the Parvoviridae family.
Paramyxoviridae Parainfluenza viruses are human pathogens belonging to the Paramyxoviridae family. Poxviridae Vaccinia virus VV belongs to the Poxviridae family. Picornaviridae Picornaviridae are viruses without an envelope and with an icosahedral capsid containing 32 capsomers. Adenoviridae HDACi also acts on the transcription and translation of adenoviruses, so a combination of adenovirus and HDACi can represent a fair compromise [ ]. Rhabdoviridae However, many cancer cells present residual innate activity that can generate resistance to viral propagation [ ].
Parvoviridae Important results have been obtained in cervical cancer and pancreatic duct adenocarcinoma by the combination of HDACi. Table 2 Oncolytic virotherapy in combination with epigenetic modulators used in cancer therapy. Adenoviridae Chen et al evaluated a new therapeutic approach for the treatment of tumors, which cannot be included in DNMT inhibition but it reflects similar purposes.
Rhabdoviridae Therapeutic studies have also been conducted to enhance the treatment of onco-hematological diseases such as acute T-cell lymphocytic leukemia.
Table 3 miRNA-regulated vectors used in virotherapy. Adenoviridae A first study was performed by Ylosmaki et al, which inserted the EA1 gene under the control of miR in serotype 5 adenovirus Ad5 [ ]. Conclusions At the present, much evidence demonstrates that tumor cells are deregulated by epigenetic mechanisms, apart from genetic alterations. Figure 1. Author Contributions Conceptualization, M. Funding This research received no external funding. Conflicts of Interest The authors declare no conflict of interest.
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