Multifunctional Photo-Cross-Linking Probes: From Target Protein Searching to Imaging Applications.

Despite advances in genome sequencing technology, the complete molecular interaction networks reflecting the biological functions of gene products have not been fully elucidated due to the lack of robust molecular interactome profiling techniques. Traditionally, molecular interactions have been investigated in vitro by measuring their affinity. However, such a reductionist approach comes with throughput constraints and does not depict an intact living cell environment. Therefore, molecular interactions in live cells must be captured to minimize false-positive results. The photo-cross-linking technique is a promising tool because the production of a temporally controlled reactive functional group can be induced using light exposure. Photoaffinity labeling is used in biochemistry and medicinal chemistry for bioconjugation, including drug and antibody conjugation, target protein identification of bioactive compounds, and fluorescent labeling of target proteins. This Account summarizes recent advances in multifunctional photo-cross-linkers for drug target identification and bioimaging. In addition to our group's contributions, we reviewed the most notable examples from the last few decades to provide a comprehensive overview of how this field is evolving. Based on cross-linking chemistry, photo-cross-linkers are classified as either (i) reactive intermediate-generating or (ii) electrophile-generating. Reactive intermediates generating photoaffinity tags have been extensively modified to target a molecule of interest using aryl azide, benzophenone, diazirine, diazo, and acyl silanes. These species are highly reactive and can form covalent bonds, irrespective of residue. Their short lifetime is ideal for the instant capture and labeling of biomolecules. Recently, photocaged electrophiles have been investigated to take advantage of their residue selectivity and relatively high yield for adduct formation with tetrazole, nitrobenzyl alcohol, o-nitrophenylethylene, pyrone, and pyrimidone. Multifunctional photo-cross-linkers for two parallel practical applications have been developed using both classes of photoactivatable groups. Unbiased target interactome profiling of small-molecule drugs requires a challenging structure-activity relationship study (SAR) step to retain the nature or biological activity of the lead compound, which led to the design of a multifunctional "minimalist tag" comprising a bio-orthogonal handle, a photoaffinity labeling group, and functional groups to load target molecules. In contrast, fluorogenic photo-cross-linking is advantageous for bioimaging because it does not require an additional bio-orthogonal reaction to introduce a fluorophore to the minimalist tag. Our group has made progress on minimalist tags and fluorogenic photo-cross-linkers through fruitful collaborations with other groups. The current range of photoactivation reactions and applications demonstrate that photoaffinity tags can be improved. We expect exciting days in the rational design of new multifunctional photo-cross-linkers, particularly clinically interesting versions used in photodynamic or photothermal therapy.

Fluorescent Phenotyping of Blood Cells Using a Differential Sensing Strategy: Differentiating Physiological Aging Stages and Neuro-Degenerative Disease Drugs.

Blood continually contributes to the maintenance of homeostasis of the body and contains information regarding the health state of an individual. However, current hematological analyses predominantly rely on a limited number of CD markers and morphological analysis. In this work, differentially sensitive fluorescent compounds based on TCF scaffolds are introduced that are designed for fluorescent phenotyping of blood. Depending on their structures, TCF compounds displayed varied responses to reactive oxygen species, biothiols, redox-related biomolecules, and hemoglobin, which are the primary influential factors within blood. Contrary to conventional CD marker-based analysis, this unbiased fluorescent phenotyping method produces diverse fingerprints of the health state. Precise discrimination of blood samples from 37 mice was demonstrated based on their developmental stages, ranging from 10 to 19 weeks of age. Additionally, this fluorescent phenotyping method enabled the differentiation between drugs with distinct targets, serving as a simple yet potent tool for pharmacological analysis to understand the mode of action of various drugs.

Repeated Infusions of Bone-Marrow-Derived Mesenchymal Stem Cells over 8 Weeks for Steroid-Refractory Chronic Graft-versus-Host Disease: A Prospective, Phase I/II Clinical Study.

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation associated with poor quality of life and increased morbidity and mortality. Currently, there are several approved treatments for patients who do not respond to steroids, such as ruxolitinib. Nevertheless, a significant proportion of patients fail second-line treatment, indicating the need for novel approaches. Mesenchymal stem cells (MSCs) have been considered a potential treatment approach for steroid-refractory cGVHD. To evaluate the safety and efficacy of repeated infusions of MSCs, we administered intravenous MSCs every two weeks to ten patients with severe steroid-refractory cGVHD in a prospective phase I clinical trial. Each patient received a total of four doses, with each dose containing 1 × 106 cells/kg body weight from the same donor and same passage. Patients were assessed for their response to treatment using the 2014 National Institutes of Health (NIH) response criteria during each visit. Ten patients with diverse organ involvement were enrolled, collectively undergoing 40 infusions as planned. Remarkably, the MSC infusions were well tolerated without severe adverse events. Eight weeks after the initial MSC infusion, all ten patients showed partial responses characterized by the amelioration of clinical symptoms and enhancement of their quality of life. The overall response rate was 60%, with a complete response rate of 20% and a partial response (PR) rate of 40% at the last follow-up. Overall survival was 80%, with a median follow-up of 381 days. Two patients died due to relapse of their primary disease. Immunological analyses revealed a reduction in inflammatory markers, including Suppression of Tumorigenicity 2 (ST2), C-X-C motif chemokine ligand (CXCL)10, and Secreted phosphoprotein 1(SPP1), following the MSC treatment. Repeated MSC infusions proved to be both feasible and safe, and they may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow-up are needed in the future to determine the role of MSCs in cGVHD.

Disaggregation-Activated pan-COX Imaging Agents for Human Soft tissue Sarcoma.

Cancer stem cells are pivotal players in tumors initiation, growth, and metastasis. While several markers have been identified, there remain challenges particularly in heterogeneous malignancies like adult soft tissue sarcomas, where conventional markers are inherently overexpressed. Here, we designed BODIPY scaffold fluorescence probes (BD-IMC-1, BD-IMC-2) that activate via disaggregation targeting for cyclooxygenase (COX), a potential marker for CSCs in sarcoma in clinical pathology. Based on their structures, BD-IMC-1 showcased higher susceptibility to disaggregation compared to BD-IMC-2, consistent with their selective interaction with COX. Notably, the BD-IMC-1 revealed positive cooperativity binding to COX-2 at sub-micromolar ranges. Both probes showed significant fluorescence turn-on upon LPS or PMA triggered COX-2 upregulation in live RAW264.7, HeLa, and human sarcoma cell line (Saos-LM2) up to 2-fold increase with negligible toxicity. More importantly, the BD-IMC-1 demonstrated their practical imaging for COX-2 positive cells in paraffin-fixed human sarcoma tissue. Considering the fixed tissues are most practiced pathological sample, our finding suggests a potential of disaggregation activated chemosensor for clinical applications.

NeuM: A Neuron-Selective Probe Incorporates into Live Neuronal Membranes via Enhanced Clathrin-Mediated Endocytosis in Primary Neurons.

The development of a small-molecule probe designed to selectively target neurons would enhance the exploration of intricate neuronal structures and functions. Among such probes, NeuO stands out as the pioneer and has gained significant traction in the field of research. Nevertheless, neither the mechanism behind neuron-selectivity nor the cellular localization has been determined. Here, we introduce NeuM, a derivative of NeuO, designed to target neuronal cell membranes. Furthermore, we elucidate the mechanism behind the selective neuronal membrane trafficking that distinguishes neurons. In an aqueous buffer, NeuM autonomously assembles into micellar structures, leading to the quenching of its fluorescence (Φ=0.001). Upon exposure to neurons, NeuM micelles were selectively internalized into neuronal endosomes via clathrin-mediated endocytosis. Through the endocytic recycling pathway, NeuM micelles integrate into neuronal membrane, dispersing fluorescent NeuM molecules in the membrane (Φ=0.61). Molecular dynamics simulations demonstrated that NeuM, in comparison to NeuO, possesses optimal lipophilicity and molecular length, facilitating its stable incorporation into phospholipid layers. The stable integration of NeuM within neuronal membrane allows the prolonged monitoring of neurons, as well as the visualization of intricate neuronal structures.

Cytarabine induces cachexia with lipid malabsorption via zippering the junctions of lacteal in murine small intestine.

Chemotherapy-induced cachexia causes severe metabolic abnormalities independently of cancer and reduces the therapeutic efficacy of chemotherapy. The underlying mechanism of chemotherapy-induced cachexia remains unclear. Here we investigated the cytarabine (CYT)-induced alteration in energy balance and its underlying mechanisms in mice. We compared energy balance-associated parameters among the three groups of mice: CON, CYT, and PF (pair-fed mice with the CYT group) that were intravenously administered vehicle or CYT. Weight gain, fat mass, skeletal muscle mass, grip strength, and nocturnal energy expenditure were significantly lowered in the CYT group than in the CON and PF groups. The CYT group demonstrated less energy intake than the CON group and higher respiratory quotient than the PF group, indicating that CYT induced cachexia independently from the anorexia-induced weight loss. Serum triglyceride was significantly lower in the CYT group than in the CON group, whereas the intestinal mucosal triglyceride levels and the lipid content within the small intestine enterocyte were higher after lipid loading in the CYT group than in the CON and PF groups, suggesting that CYT inhibited lipid uptake in the intestine. This was not associated with obvious intestinal damage. The CYT group showed increased zipper-like junctions of lymphatic endothelial vessel in duodenal villi compared to that in the CON and CYT groups, suggesting their imperative role in the CYT-induced inhibition of lipid uptake. CYT worsens cachexia independently of anorexia by inhibiting the intestinal lipid uptake, via the increased zipper-like junctions of lymphatic endothelial vessel.

Risk Factors for the Occurrence and Severity of Vertebral Fractures in Inflammatory Bowel Disease Patients: A Nationwide Population-Based Cohort Study.

BACKGROUND: The risk of vertebral fractures is increased in inflammatory bowel disease (IBD) patients. However, whether the severity of vertebral fractures differs between IBD patients and the general population, or between patients with Crohn's disease (CD) and ulcerative colitis (UC), is unknown. METHODS: We investigated risk factors associated with the occurrence and severity of vertebral fractures in IBD patients using The National Healthcare Insurance Service (NHIS) database. We defined the patients who underwent vertebroplasty or kyphoplasty after being diagnosed with a vertebral fracture as having a severe vertebral fracture than those with only diagnosis codes. RESULTS: From 2008 to 2018, there were 33,778 patients with IBD (24,370 UC patients and 9,408 CD patients) and 101,265 patients in the reference population. The incidence rate ratio of vertebral fractures in the IBD patients was 1.27 per 1,000 person-years (95% confidence interval [CI], 1.26-1.27). The risk of vertebral fracture was higher in CD and UC patients than in the matched reference group (hazard ratio [HR], 1.59; 95% CI, 1.31-1.92; P < 0.001 and HR, 1.26; 95% CI, 1.14-1.41; P < 0.001, respectively). In a multivariate analysis, the occurrence of vertebral fracture was associated with CD (HR, 1.31; 95% CI, 1.08-1.59; P = 0.006), older age (CD: HR, 1.09; 95% CI, 1.08-1.09; P < 0.001 and UC: HR, 1.09; 95% CI, 1.08-1.09; P < 0.001), female sex (CD: HR, 1.81; 95% CI, 1.63-2.01; P < 0.001 and UC: HR, 2.02; 95% CI, 1.83-2.22; P < 0.001), high Charlson Comorbidity Index (CCI) score (CD: HR, 1.42; 95% CI, 1.23-1.63; P < 0.001 and UC: HR, 1.46; 95% CI, 1.29-1.65, P < 0.001), and long-term steroid use (CD: HR, 3.71; 95% CI, 2.84-3.37; P < 0.001 and UC: HR, 3.88; 95% CI, 3.07-4.91; P < 0.001). The severity of vertebral fractures was associated with IBD (CD: HR, 1.82; 95% CI, 1.17-2.83; P = 0.008 and UC: HR, 1.49; 95% CI, 1.17-1.89; P < 0.001) and older age (HR, 1.06; 95% CI, 1.05-1.07; P < 0.001). CONCLUSION: Vertebral fractures occur frequently and more severely in IBD patients, particularly those with CD. Therefore, we suggest monitoring of bone density, regular vitamin D supply, and reducing the use of corticosteroids to prevent vertebral fractures in IBD patients who are older, female, or have comorbidities.

Bioinformatic Expansion of Borosins Uncovers Trans-Acting Peptide Backbone N-Methyltransferases in Bacteria.

Backbone N-methylation is one of the prominent peptide modifications that can greatly enhance the pharmacological properties of a peptide. Naturally occurring backbone N-methylated peptides are produced via nonribosomal or ribosomal pathways, the latter of which was only recently identified in the borosin family of ribosomally synthesized and post-translationally modified peptides. Although previous bioinformatic analyses have revealed new putative genes for borosin biosynthesis, the natural scope of structural and biosynthetic diversity of the borosin family has not been thoroughly explored. Here, we report a comprehensive overview of the borosin family of peptide natural products. Using a genome mining approach, we identified more than 1400 new putative biosynthetic gene clusters for borosins and demonstrated that, unlike those previously reported, most of them are found in bacterial genomes and encode a precursor peptide unfused to its cognate methyltransferase enzyme. Biochemical analysis confirmed the backbone N-methylation of the precursor peptide in trans in eight enzyme-precursor pairs and revealed two novel types of enzyme-recognizing sequences in the precursor peptide. This work significantly expands the biosynthetic diversity of borosins and paves the way for the enzymatic production of diverse backbone N-methylated peptides.

Chemical Probes and Activity-Based Protein Profiling for Cancer Research.

Chemical probes can be used to understand the complex biological nature of diseases. Due to the diversity of cancer types and dynamic regulatory pathways involved in the disease, there is a need to identify signaling pathways and associated proteins or enzymes that are traceable or detectable in tests for cancer diagnosis and treatment. Currently, fluorogenic chemical probes are widely used to detect cancer-associated proteins and their binding partners. These probes are also applicable in photodynamic therapy to determine drug efficacy and monitor regulating factors. In this review, we discuss the synthesis of chemical probes for different cancer types from 2016 to the present time and their application in monitoring the activity of transferases, hydrolases, deacetylases, oxidoreductases, and immune cells. Moreover, we elaborate on their potential roles in photodynamic therapy.

Paraplegia due to intradural cement leakage after vertebroplasty: a case report and literature review.

BACKGROUND: Vertebroplasty (VP) is considered an alternative therapy in an osteoporotic compression fracture that failed conservative treatment. However, cement leakage into the intradural space can cause catastrophic complications. To the best of our knowledge, intradural cement leakage following VP has been reported only in 7 cases. We report here a case of intradural cement leakage following VP with a literature review. CASE PRESENTATION: An 84-year-old female with an L1 osteoporotic fracture underwent percutaneous VP at a local hospital. Immediately after the procedure, she complained of weakness, numbness, and pain in both legs, and her back pain aggravated. She was transferred to our hospital. The initial muscle power was grade 2 for the right leg and grade 4 for the left leg. Computed tomography (CT) scan showed intradural cement leakage from T10 to L2. Magnetic resonance imaging showed an intradural mass lesion. Although we performed total laminectomy with durotomy and removed intradural cement completely, the neurological deficit did not completely recover. The muscle power was grade 3 for the right leg and grade 4 for the left leg at the last follow-up. CONLCUSIONS: If a neurological deficit is found after VP, a CT scan should be taken to confirm the pattern of cement leakage. In case of intradural cement leakage, surgical decompression should be recommended to improve neurological deficit. To prevent intradural cement leakage during the VP, the needle tip should not perforate the medial wall of the pedicle with appropriate viscosity of cement.

Effect of lumbar spinal stenosis on bone mineral density in osteoporosis patients treated with ibandronate.

BACKGROUND: Lumbar spinal stenosis (LSS) can cause various neurological symptoms and reduce the daily activity of patients. Many studies have shown that free physical activities and exercise can improve bone mineral density (BMD) in patients with osteoporosis. However, the effect of LSS on BMD has not been reported. The purpose of this study was to investigate the effects of LSS on BMD in patients treated with ibandronate for newly diagnosed osteoporosis. METHODS: Group 1 included 83 patients treated for osteoporosis alone, and group 2 included 76 patients treated for both osteoporosis and symptomatic LSS. We confirmed four BMD values presented as T-score at initial, and 1-, 2-, and 3-year follow-ups. Mean BMD and annual changes of BMD for three years were compared between the two groups. Correlations between initial BMD and total change of BMD, and related factors for continuous BMD improvement for three years were also evaluated. RESULTS: Mean annual BMDs were significantly higher in group 1 compared than in group 2 (-3.39 vs. -3.58 at 1-year; -3.27 vs. -3.49 at 2-year; -3.13 vs. -3.45 at 3-year; all p < 0.05). Annual change of BMD at 1-year follow-up (0.32 vs. 0.21, p = 0.036) and total change of BMD for three years (0.57 vs. 0.35, p = 0.002) were significantly higher in group 1. Group 1 had a strong negative correlation (r = -0.511, P = 0.000) between initial BMD and total change of BMD, whereas group 2 showed a weak negative correlation (r = -0.247, p = 0.032). In multivariate analysis, symptomatic LSS was the only independent risk factor for continuous BMD improvement (Odds ratio = 0.316, p = 0.001). CONCLUSIONS: Symptomatic LSS may interfere with BMD improvement in the treatment of osteoporosis with ibandronate. Active treatment for LSS with more potent treatment for osteoporosis should be taken to increase BMD for patients with osteoporosis and LSS.

High thoracic ossification of ligamentum flavum causing partial Horner syndrome.

We report a case of high thoracic ossification of the ligamentum flavum (OLF) causing a partial Horner's syndrome. A 57-year-old man developed a walking disorder, as well as right-sided miosis and anhidrosis. Magnetic resonance imaging demonstrated a spinal cord compressing T2-T3 OLF. The patient improved after surgery.

Cerebrospinal fluid-cutaneous fistula associated with post-traumatic Charcot spinal arthropathy: a case report and review of literature.

BACKGROUND: Charcot spinal arthropathy, also known as Charcot spine and neuropathic spinal arthropathy, is a progressive and destructive condition that affects an intervertebral disc and the adjacent vertebral bodies following loss of spinal joint innervation. We report the first case of Charcot spinal arthropathy (CSA) associated with cerebrospinal fluid (CSF)-cutaneous fistula. CASE PRESENTATION: A 54-year-old male who underwent T10-L2 posterior instrumented spinal fusion seven years prior for treatment of T11 burst fracture and accompanying T11 complete paraplegia visited our department complaining of leakage of clear fluid at his lower back. The patient had also undergone various types of skin graft and myocutaneous flap surgeries for treatment of repetitive pressure sores around his lumbosacral area. The patient presented with persistent CSF leakage from a cutaneous fistula (CSF-cutaneous fistula) formed in a lumbosacral pressure sore. The CSF-cutaneous fistula arose from the L5 post-traumatic CSA. Surgery was planned for management of CSF-cutaneous fistula and post-traumatic L5 CSA. We successfully treated the CSF-cutaneous fistula with ligation and transection of the dural sac and cauda equina at the L2-L3 level. In addition, the post-traumatic L5 CSA was successfully treated with a posterior four-rod spinopelvic fixation from T9 to ilium and S2 foramina. After surgery, the CSF leakage stopped and no other adverse neurological changes were found. The four-rod spinopelvic construct was well maintained five years later. CONCLUSIONS: CSA associated with CSF-cutaneous fistula is a very rare disorder. Only surgical treatment for both CSA and CSF-cutaneous fistula with ligation and transection of the dural sac and posterior four-rod spinopelvic fixation can bring satisfactory results.

Role of microRNA and Oxidative Stress in Influenza A Virus Pathogenesis.

MicroRNAs (miRNAs) are non-coding RNAs that regulate diverse cellular pathways by controlling gene expression. Increasing evidence has revealed their critical involvement in influenza A virus (IAV) pathogenesis. Host-IAV interactions induce different levels of oxidative stress (OS) by disrupting the balance between reactive oxygen species (ROS) and antioxidant factors. It is thought that miRNA may regulate the expression of ROS; conversely, ROS can induce or suppress miRNA expression during IAV infection. Thus, miRNA and OS are the two key factors of IAV infection and pathogenesis. Accordingly, interactions between OS and miRNA during IAV infection might be a critical area for further research. In this review, we discuss the crosstalk between miRNAs and OS during IAV infection. Additionally, we highlight the potential of miRNAs as diagnostic markers and therapeutic targets for IAV infections. This knowledge will help us to study host-virus interactions with novel intervention strategies.

Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway.

Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC-1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC-1 degrader can be an invaluable chemical tool in the studies of SRC-1 functions. Moreover, our findings suggest PROTACs based on the N-degron pathway as a widely useful strategy to degrade disease-relevant proteins.

A Near-Infrared Probe Tracks and Treats Lung Tumor Initiating Cells by Targeting HMOX2.

Tumor initiating cells (TIC) are resistant to conventional anticancer therapy and associated with metastasis and relapse in cancer. Although various TIC markers and their antibodies have been proposed, it is limited to the use of antibodies for in vivo imaging or treatment of TIC. In this study, we discovered heme oxygenase 2 (HMOX2) as a novel biomarker for TIC and developed a selective small molecule probe TiNIR (tumor initiating cell probe with near infrared). TiNIR detects and enriches the functionally active TIC in human lung tumors, and through the photoacoustic property, TiNIR also visualizes lung TIC in the patient-derived xenograft (PDX) model. Furthermore, we demonstrate that TiNIR inhibits tumor growth by blocking the function of HMOX2, resulting in significantly increased survival rates of the cancer model mice. The novel therapeutic target HMOX2 and its fluorescent ligand TiNIR will open a new path for the molecular level of lung TIC diagnosis and treatment.

Recent Developments in Metal-Catalyzed Bio-orthogonal Reactions for Biomolecule Tagging.

With the rapid advances in single-molecule and live-cell imaging studies to investigate biological problems, the role of chemical probes to monitor reactions in a live cell has considerably increased. However, selective labeling of a target protein or a specific residue is highly challenging due to the high complexity of the biological system. In particular, biological macromolecules (such as proteins, DNA, or RNA) share many functional groups that potentially cross-react with exogenous chemical probes. Thus, there are high demands for perfect biocompatible reactions utilizing biologically unavailable chemistry. Metal-catalyzed reactions have been extensively investigated as synthetic methodology studies, including initial attempts in applying the chemistry in aqueous solutions in vitro or even in biological conditions. Herein, the latest developments and progress in metal-catalyzed bio-orthogonal reactions for biomolecule labeling are summarized.

Expanding the "minimalist" small molecule tagging approach to different bioactive compounds.

"Minimalist" small molecule tagging (MSMT) is a promising approach that easily converts bioactive compounds into affinity-based probes (AfBPs) for proteomic studies. In this work, seven bioactive compounds targeting diversified protein classes were installed with "minimalist" linkers through common reactions to generate the corresponding AfBPs. These probes were evaluated for cell-based protein profiling and target validation. Among them, the entinostat-derived probe EN and the camptothecin-derived probe CA were further utilized in cellular imaging and SILAC-based large-scale target identification. Our extensive studies suggest that the "minimalist" small molecule tagging approach could be expanded to different classes of bioactive compounds for modification into AfBPs as a dual functional tool for both proteomics and cellular imaging.

Crosstalk between Oxidative Stress and Tauopathy.

Tauopathy is a collective term for neurodegenerative diseases associated with pathological modifications of tau protein. Tau modifications are mediated by many factors. Recently, reactive oxygen species (ROS) have attracted attention due to their upstream and downstream effects on tauopathy. In physiological conditions, healthy cells generate a moderate level of ROS for self-defense against foreign invaders. Imbalances between ROS and the anti-oxidation pathway cause an accumulation of excessive ROS. There is clear evidence that ROS directly promotes tau modifications in tauopathy. ROS is also highly upregulated in the patients' brain of tauopathies, and anti-oxidants are currently prescribed as potential therapeutic agents for tauopathy. Thus, there is a clear connection between oxidative stress (OS) and tauopathies that needs to be studied in more detail. In this review, we will describe the chemical nature of ROS and their roles in tauopathy.

Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau.

Epigenetic remodeling via histone acetylation has become a popular therapeutic strategy to treat Alzheimer's disease (AD). In particular, histone deacetylase (HDAC) inhibitors including M344 and SAHA have been elucidated to be new drug candidates for AD, improving cognitive abilities impaired in AD mouse models. Although emerged as a promising target for AD, most of the HDAC inhibitors are poorly selective and could cause unwanted side effects. Here we show that tau is one of the cytosolic substrates of HDAC and the treatment of HDAC inhibitors such as Scriptaid, M344, BML281, and SAHA could increase the level of acetylated tau, resulting in the activation of tau pathology.