Development of an anti-tauopathy mucosal vaccine specifically targeting pathologic conformers.

Alzheimer's disease (AD) and related tauopathies are associated with pathological tau protein aggregation, which plays an important role in neurofibrillary degeneration and dementia. Targeted immunotherapy to eliminate pathological tau aggregates is known to improve cognitive deficits in AD animal models. The tau repeat domain (TauRD) plays a pivotal role in tau-microtubule interactions and is critically involved in the aggregation of hyperphosphorylated tau proteins. Because TauRD forms the structural core of tau aggregates, the development of immunotherapies that selectively target TauRD-induced pathological aggregates holds great promise for the modulation of tauopathies. In this study, we generated recombinant TauRD polypeptide that form neurofibrillary tangle-like structures and evaluated TauRD-specific immune responses following intranasal immunization in combination with the mucosal adjuvant FlaB. In BALB/C mice, repeated immunizations at one-week intervals induced robust TauRD-specific antibody responses in a TLR5-dependent manner. Notably, the resulting antiserum recognized only the aggregated form of TauRD, while ignoring monomeric TauRD. The antiserum effectively inhibited TauRD filament formation and promoted the phagocytic degradation of TauRD aggregate fragments by microglia. The antiserum also specifically recognized pathological tau conformers in the human AD brain. Based on these results, we engineered a built-in flagellin-adjuvanted TauRD (FlaB-TauRD) vaccine and tested its efficacy in a P301S transgenic mouse model. Mucosal immunization with FlaB-TauRD improved quality of life, as indicated by the amelioration of memory deficits, and alleviated tauopathy progression. Notably, the survival of the vaccinated mice was dramatically extended. In conclusion, we developed a mucosal vaccine that exclusively targets pathological tau conformers and prevents disease progression.

Synthesis of 1-O-acyl- and 1-oxo-kamebanin analogues and their cytotoxic activity.

A series of 1-O-acyl- and 1-oxo-kamebanin analogues were prepared from kamebanin, isolated from Rabdosia excisa and their cytotoxicity was assayed on HL60 promyelocytic leukemia cells and HCT116 human colon cancer cells. The structure-activity relationship study showed that the presence of 1-O-acyl groups of a C3-C5 carbon chain increased the cytotoxic activity.

Microglia involvement in sex-dependent behaviors and schizophrenia occurrence in offspring with maternal dexamethasone exposure.

Fetal microglia that are particularly sensitive cells to the changes in utero environment might be involved in the sex-biased onset and vulnerability to psychiatric disorders. To address this issue, we administered a 50 µg/kg dexamethasone (DEX) to dams subcutaneously from gestational days 16 to 18 and a series of behavioral assessments were performed in the offspring. Prenatal exposure to dexamethasone (PN-DEX) induced schizophrenia (SCZ)-relevant behaviors in male mice and depressive-like behavior in female mice. SCZ-relevant behavioral patterns occurred in 10-week-old (10 W) male mice but not in 4-week-old (4 W) male mice. Microglia in the medial prefrontal cortex (mPFC) and the striatum (STR) of 10 W males prenatally treated with dexamethasone (10 W PN-DEX-M) showed hyper-ramified morphology and dramatically reduced spine density in mPFC. Immunofluorescence studies indicated that microglia in the mPFC of the 10 W PN-DEX-M group interacted with pre-synaptic Bassoon and post-synaptic density 95 (PSD95) puncta. PN-DEX-M also showed significantly changed dopamine system proteins. However, a testosterone surge during adolescence was not a trigger on SCZ-relevant behavior occurrence in 10 W PN-DEX-M. Furthermore, females prenatally treated with dexamethasone (PN-DEX-F) displayed depressive-like behavior, in addition to HPA-axis activation and inflammatory microglial phenotypes in their hippocampus (HPC). We propose that altered microglial function, such as increased synaptic pruning, may be involved in the occurrence of SCZ-relevant behavior in PN-DEX-M and sex-biased abnormal behavior in the PN-DEX model.

SUMOylation and Major Depressive Disorder.

Since the discovery of the small ubiquitin-like modifier (SUMO) protein in 1995, SUMOylation has been considered a crucial post-translational modification in diverse cellular functions. In neurons, SUMOylation has various roles ranging from managing synaptic transmitter release to maintaining mitochondrial integrity and determining neuronal health. It has been discovered that neuronal dysfunction is a key factor in the development of major depressive disorder (MDD). PubMed and Google Scholar databases were searched with keywords such as 'SUMO', 'neuronal plasticity', and 'depression' to obtain relevant scientific literature. Here, we provide an overview of recent studies demonstrating the role of SUMOylation in maintaining neuronal function in participants suffering from MDD.

Nuclear mRNA Export and Aging.

The relationship between transcription and aging is one that has been studied intensively and experimentally with diverse attempts. However, the impact of the nuclear mRNA export on the aging process following its transcription is still poorly understood, although the nuclear events after transcription are coupled closely with the transcription pathway because the essential factors required for mRNA transport, namely TREX, TREX-2, and nuclear pore complex (NPC), physically and functionally interact with various transcription factors, including the activator/repressor and pre-mRNA processing factors. Dysregulation of the mediating factors for mRNA export from the nucleus generally leads to the aberrant accumulation of nuclear mRNA and further impairment in the vegetative growth and normal lifespan and the pathogenesis of neurodegenerative diseases. The optimal stoichiometry and density of NPC are destroyed during the process of cellular aging, and their damage triggers a defect of function in the nuclear permeability barrier. This review describes recent findings regarding the role of the nuclear mRNA export in cellular aging and age-related neurodegenerative disorders.

Correlation Between Proton Pump Inhibitors and the Complications of Liver Cirrhosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Many studies and meta-analyses have investigated the associations among proton pump inhibitors (PPIs), spontaneous bacterial peritonitis (SBP), portosystemic encephalopathy (PSE), and other infections. However, these studies had limitations, including the omission of several relevant studies and drawing conclusions, based on the abstracts without consulting the full-text of the articles. To evaluate the association between PPIs and complications arising from cirrhosis and risks of PPI use in patients with cirrhosis. METHODS: Data were extracted from the EMBASE, PubMed, Cochrane, and Google Scholar databases. The Newcastle-Ottawa scale was used to assess the quality of the selected studies. RESULTS: A total of 29 studies (13 case-control and 16 cohort studies) involving 20,484 patients were included in the meta-analysis. The total relative risk (RR) for the 23 studies which investigated SBP was 1.31, and the 95% CI was 1.10-1.55 (I2 = 73.0%). The total RR for the 7 studies which examined PSE was 1.25 (95% CI 0.85-1.84, I2 = 96.1%). For the 7 studies which analyzed overall infection, the total RR was 1.37 (95% CI 1.07-1.76, I2 = 79.3%). The RR for the 2 cohort studies that assessed mortality was 1.39 (95% CI 0.85-2.27, I2 = 0.0%). CONCLUSION: PPI use in cirrhosis patients increased the SBP and overall infection risk. PPIs should be considered with appropriate indications when the benefits exceed the risks in cirrhosis patients with ascites.

Helicobacter pylori infection is not associated with portal hypertension-related gastrointestinal complications: A meta-analysis.

Despite the importance of Helicobacter pylori infection and portal hypertension (PH)-associated gastrointestinal (GI) diseases, such as esophageal varices and portal hypertensive gastropathy (PHG), the impact of H. pylori infection on PH-related GI complications has not yet been elucidated. This meta-analysis investigated the association between H. pylori infection and the risk of PH-related GI complications. An electronic search for original articles published before May 2020 was performed using PubMed, EMBASE, and the Cochrane Library. Independent reviewers conducted the article screening and data extraction. We used the generic inverse variance method for the meta-analysis, and Begg's rank correlation test and Egger's regression test to assess publication bias. A total of 1,148 cases of H. pylori infection and 1,231 uninfected controls were included from 13 studies. H. pylori infection had no significant association with esophageal varices [relative risk (RR) = 0.96, 95% confidence interval (CI) = 0.87-1.06 for all selected studies; RR = 0.95, 95% CI = 0.84-1.07 for cohort studies; odds ratio (OR) = 0.96, 95% CI = 0.60-1.54 for case-control studies]. Although H. pylori infection was significantly associated with PHG in case-control studies [OR = 1.86, 95% CI = 1.17-2.96], no significant differences were found in the cohort studies [RR = 0.98, 95% CI = 0.91-1.05] or all studies combined [RR = 1.18, 95% CI = 0.93-1.52]. In conclusion, H. pylori infection was not associated with the risk of PH-related GI complications. Clinicians should carefully treat cirrhotic patients with PH-related GI complications, regardless of H. pylori infection.

Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression.

Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, accessible, and tolerable therapies. Pharmacological regulation of histone acetylation level has been investigated as one potential clinical strategy. Histone acetylation status is considered a potential diagnostic biomarker for depression, while inhibitors of histone deacetylases (HDACs) have garnered interest as novel therapeutics. This review describes recent advances in our knowledge of histone acetylation status in depression and the therapeutic potential of HDAC inhibitors.

Chronically infused angiotensin II induces depressive-like behavior via microglia activation.

Brain inflammation is one of hypotheses explaining complex pathomechanisms of depression. Angiotensin II (ANGII), which is associated with hypertension, also induces brain inflammation. However, there is no animal study showing the direct relationship between ANGII and depression. To address this issue, ANGII-containing osmotic pumps were implanted into adult male C57BL/6 mice subcutaneously for subacute (7 days) and chronic (at least 21 days) periods and behavioral and molecular analyses were conducted. Chronic infusion of ANGII into mice induced depressive-like behaviors, including the tail suspension test and forced swimming test, which were reversed by imipramine. Chronic infusion of ANGII also induced microglial activation in the hippocampus with increase of Il-1ß mRNA and decrease of Arg1 mRNA. In addition, chronic ANGII infusion activated the hypothalamic-pituitary-adrenal axis (HPA axis) and resulted in decreased hippocampal glucocorticoid receptor level. However, subacute ANGII infusion did not induce significant molecular and behavioral changes in mice compared to that of control. The molecular and behavioral changes by chronic ANGII infusion were reversed by co-treatment of minocycline or telmisartan. In addition, ANGII treatment also induced the pro-inflammatory changes in BV-2 microglial cells. Our results indicate that ANGII can induce depressive-like behaviors via microglial activation in the hippocampus and HPA axis hyperactivation in mice. These might suggest possible mechanism on depressive symptom in chronic hypertensive state.

Human umbilical cord-derived mesenchymal stem cells alleviate schizophrenia-relevant behaviors in amphetamine-sensitized mice by inhibiting neuroinflammation.

At present, therapeutic options available for treating schizophrenia are limited to monoamine-based antipsychotic drugs. Recent genome wide association study (GWAS) indicated a close relationship between immune system and schizophrenia. To leverage the GWAS finding for therapeutic strategy, we conducted a mechanism and effect study on application of human umbilical cord-derived mesenchymal stem cells (hUC-MSC) with potent immune-modulatory effect in an animal model useful for the study of schizophrenia. Schizophrenia-relevant behaviors were induced by amphetamine administration (amphetamine-sensitized mice) and the effect of a single intravenous administration of hUC-MSC was examined in the amphetamine-sensitized mice. Schizophrenia-relevant behaviors were assessed by open field test, light/dark box, social interaction test, latent inhibition, prepulse inhibition, tail suspension test, and forced swimming test. Our results indicated that neuroinflammation along with peripheral TNF-α elevation is associated with schizophrenia-relevant behaviors in amphetamine-sensitized mice. In addition, hUC-MSC inhibited schizophrenia-relevant and the neuroinflammatory changes. The main mechanism of hUC-MSC was associated with the induction of Treg and production of the anti-inflammatory cytokine, IL-10 in periphery. In vitro study revealed that amphetamine did not directly induce a neuroinflammatory reaction, while recombinant TNF-α (rTNF-α) increased mRNA expression of TNF-α, KMO, and IL-1ß in several microglial cell lines. Moreover, recombinant IL-10 (rIL-10) and MSC conditioned media inhibited the inflammatory response in rTNF-α-treated microglial cells. Assuming that hUC-MSCs rarely reach the CNS and do not remain in the body for an extended time, these findings suggest that a single hUC-MSC infusion have long-term beneficial effect via regulatory T cell induction and secretion of IL-10 in amphetamine-sensitized mice.

Differential effect of LPS and paclitaxel on microglial functional phenotypes and circulating cytokines: the possible role of CX3CR1 and IL-4/10 in blocking persistent inflammation.

Neuroinflammation plays a role in cancer chemotherapy-induced chronic pain. Thus far, most studies have focused on neuroinflammation suppression. However, there are limited reports of which factor is involved in the transition from acute inflammation to chronic inflammation, resulting in neuroinflammation and chronic pain. Here, we compared the inflammatory reaction and pain response induced by LPS and paclitaxel. LPS (0.5 mg/kg) or paclitaxel (2 mg/kg/day for 5 days) was administered intraperitoneally to mice, and mechanical allodynia was examined by von Frey test. LPS induced transient mechanical allodynia, whereas paclitaxel induced persistent mechanical allodynia. The CD86/CX3CR1 ratio remained unchanged due to CX3CR1 elevation following LPS injection, whereas the ratio was increased on day 1 after paclitaxel injection. LPS also increased CD45, CCL2, and CCL5 mRNA in the spinal cord and circulating pro- and anti-inflammatory cytokines 1 day after injection; however, the pattern was not consistent. Paclitaxel gradually increased inflammatory cytokines in the spinal cord. CX3CR1 might be involved in blocking the transition from acute pain to persistent pain in the LPS group. In addition, serum IL-4 and IL-10 elevation in the LPS group may be associated with chronic pain prevention. Therefore, targeting CX3CR1, IL-4, and IL-10 might be an alternative therapeutic strategy.

Adipose-derived stem cells attenuate atopic dermatitis-like skin lesions in NC/Nga mice.

There is an unmet need in novel therapeutics for atopic dermatitis (AD). We examined the effects of autologous adipose-derived stem cells (ADSCs) on AD-like skin lesions induced by the application of 2,4-dinitrochlorobenzene (DNCB) in NC/Nga mice. Autologous ADSCs and ADSC-conditioned medium (ADSC-CM) were injected intralesionally three times. Clinical severity and histopathologic findings were compared in sham naïve control, saline-treated, ADSC-treated, ADSC-CM-treated and 2.5% cortisone lotion-applied animals. The severity index, skin thickness, mast cell number, as well as expression levels of thymic stromal lymphopoietin, CD45, chemoattractant receptor-homologous molecule, chemokine ligand 9 and chemokine ligand 20 were significantly lower in mice treated with ADSC, ADSC-CM, or 2.5% cortisone lotion. Tissue levels of interferon-γ as well as serum levels of interleukin-33 and immunoglobulin E levels were also decreased in those groups. We conclude that autologous ADSCs improved DNCB-induced AD-like skin lesions in NC/Nga mice by reducing inflammation associated with Th2 immune response and interferon-γ.

Psoriasis increases the risk of concurrent inflammatory bowel disease: A population-based nationwide study in Korea.

BACKGROUND: The epidemiology of the association between psoriasis and inflammatory bowel disease is poorly defined and remains controversial. AIM: To evaluate the prevalence of inflammatory bowel disease in patients with psoriasis compared with the general population. METHODS: We searched the nationwide health claims database between 2011 and 2015 and evaluated the prevalence of inflammatory bowel disease, including Crohn's disease and ulcerative colitis. RESULTS: Prevalence of inflammatory bowel disease, Crohn's disease and ulcerative colitis in patients with psoriasis vs the general population in 2011 were 0.16, 0.05 and 0.12% vs 0.08, 0.03 and 0.06%, respectively, which increased significantly with time between 2011 and 2015. Patients with psoriasis consistently revealed higher standardized prevalence (age and sex adjusted) of inflammatory bowel disease, Crohn's disease and ulcerative colitis compared with the general population. Subgroup analysis revealed the highest risk of prevalent inflammatory bowel disease in patients younger than 19 years (crude odds ratio 5.33, 95% confidence interval 3.74-7.59). Severe psoriasis demonstrated higher odds of inflammatory bowel disease (odds ratio 2.96, 95% confidence interval 2.54-3.45) than mild psoriasis (odds ratio 1.68, 95% confidence interval 1.51-1.88). LIMITATIONS: Limited data for doing adjustment and cross-sectional study design. CONCLUSIONS: Psoriasis patients revealed higher risk of inflammatory bowel disease. In particular, young patients and those with severe psoriasis may require closer monitoring and comprehensive management.

Comparison of the Treatment Outcome of Oral Tofacitinib with Other Conventional Therapies in Refractory Alopecia Totalis and Universalis: A Retrospective Study.

Treatment of alopecia totalis and alopecia universalis is often challenging and unsatisfactory. Recently, Janus kinase inhibitor has shown promising results. The aim of this study is to compare the efficacy and tolerability of oral tofacitinib and conventional modalities for treating refractory alopecia totalis/universalis. A total of 74 patients (18 treated with tofacitinib, 26 treated with conventional oral treatment (steroid ± cyclosporine), and 30 treated with diphenylcyclopropenone) were included in the study. The patients' medical records were reviewed retrospectively. After 6 months, 44.4% of patients in the tofacitinib group, 37.5% in the conventional oral treatment group, and 11.1% in the diphenylcyclopropenone group achieved 50% improvements in the Severity of Alopecia Tool score. During treatment, 10% of patients in the tofacitinib group, 73.1% in the conventional oral treatment group, and 10% in the diphenylcyclopropenone group experienced adverse drug reactions. In conclusion, oral tofacitinib was more effective than diphenylcyclopropenone immunotherapy and more tolerable than conventional oral treatment after 6 months of treatment.

Dexamethasone Induces a Specific Form of Ramified Dysfunctional Microglia.

The functional status of dynamic microglial cells plays an important role in maintaining homeostasis of microenvironment in CNS. In a previous study, we reported that microglia phenotype might be involved in stress vulnerability and depression recurrence. Here, we aimed to clarify a character of microglia exposed persistently to glucocorticoid (GC), which is representative a stress hormone, in primary cultured microglial cells. Five nanomolars of dexamethasone (DEX, GC agonist) for 72 h decreased CX3CR1 and CD200R expression and induced ramified form of microglial cells in similar morphology to in vivo resident microglia. However, the ramified form of microglia did not increase microglia signature genes such as P2RY12, OLFML3, TMEM119, and TGFBR1. In addition, DEX-treated microglia showed a reduction of phagocytosis function, pro-and anti-inflammatory cytokine production, and cell proliferation. DEX washout did not restore these changes. Based on transcriptomic analysis and functional characters of DEX-treated microglia, we performed senescence-associated beta-galactosidase (SA-ß gal) assay in DEX-treated microglia and DEX-treated microglia showed more SA-ß gal activity with alteration of cell cycle-related genes. Thus, our results suggest that DEX can induce a specific phenotype of microglia (like-senescence).

Efficacy and Safety of Oral Alitretinoin in Hand Eczema and Palmoplantar Pustulosis in Korean Patients.

BACKGROUND: Previous studies have demonstrated efficacy and safety of oral alitretinoin in hand eczema (HE) whereas in palmoplantar pustulosis (PPP), which can be difficult to distinguish from HE, efficacy of alitretinoin is still controversial. OBJECTIVE: This study aimed to investigate the efficacy and safety of oral alitretinoin in HE and PPP and factors that affect the response of these disorders to alitretinoin. METHODS: We retrospectively analyzed Korean adult patients with moderate-to-severe HE and PPP treated with oral alitretinoin, 46 patients for efficacy assessment and 55 patients for safety assessment. RESULTS: Among 46 patients who were treated with alitretinoin for at least 1 month, 29 patients (61.1% in HE and 40.0% in PPP) showed response to alitretinoin in the median 14 weeks after treatment. Hyperkeratotic HE showed higher response rate than either vesicular HE or PPP (p=0.026 and p=0.026, respectively). However, PPP with hyperkeratotic features showed as much response as hyperkeratotic HE (p=0.554). When responders and non-responders in total patients were compared, morphology, not diagnosis or initial severity, was the only significantly different factor between the two groups. After alitretinoin discontinuation in responders, relapse rate was 63.6% (7/11) and median time to relapse was 150 days (range, 76~730 days). Adverse events occurred in 47.3% (26/55); however, there were no serious adverse events. CONCLUSION: In HE or PPP, lesions with hyperkeratotic morphology can be predicted to respond well to alitretinoin regardless of diagnosis.