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Primary sclerosing cholangitis (PSC) is a progressive cholestatic, inflammatory, and fibrotic disease that is strongly associated with inflammatory bowel disease (IBD). PSC-IBD represents a unique disease entity and patients with this disease have an increased risk of malignancy development, such as colorectal cancer and cholangiocarcinoma. The pathogenesis of PSC-IBD involves genetic and environmental factors such as gut dysbiosis and bile acids alteration. However, despite the advancement of disease characteristics, no effective medical therapy has proven to have a significant impact on the prognosis of PSC. The treatment options for patients with PSC-IBD do not differ from those for patients with PSC alone. Potential candidate drugs have been developed based on the pathogenesis of PSC-IBD, such as those that target modulation of bile acids, inflammation, fibrosis, and gut dysbiosis. In this review, we summarize the current medical treatments for PSC-IBD and the status of new emerging therapeutic agents.
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Objective To explore the effect of activation of mammalian target of rapmycin complex 2(mTORC2)/Akt signaling pathway on dopaminergic neurons and behavior in 6-hydroxydopamine (6-OHDA) model mice and its possible mechanism. Methods Selecting 36 mice which The Nestin-CreERTM and ROSA26-LacZ reporter genes were detected at the same time in 3-month-old male C57BL/6J mice weighing 20-25 g divideng them into 4 gruops, NS+ corn oil group, 6-OHDA+corn oil group, 6-OHDA+PP242 group and 6-OHDA+A-443654 group, and 6-OHDA was injected into the right striatum of the brain to replicate the Parkinson’s disease (PD) model of mice, and then daily intraperitoneal injection of mTORC2/Akt signaling pathway agonist A-443654 or inhibitor PP242. Serum interleukin-1β (IL-1β) and tumor necrosis factor-α(TNF-α)levels were measured by enzyme-linked immunosorbent assay. Immunohistochemistry and immunofluorescence staining were performed to investigate the change of microglia, dopaminergic neurons as well as neural progenitor cells (NPCs). Western blotting was used to detect the expression of related protein of mTORC2/Akt signaling pathway including rictor, p-Akt and regulated in development and DNA dgmage responses 1(REDD1) and the interaction between them were verified by immunoprecipitation. Finally, the behavioral performance of each group of mice was observed. Results With the activation of microglia and the increase of inflammatory factors in PD model mice, the number of dopaminergic neurons in the substantia nigra(SN) decreased significantly, and the motor function of the mice was impaired, but the number of NPCs increased significantly compared with the control mice, mTORC2/Akt signaling pathway related protein expression was also significantly up-regulated. A-443654 treatment further up-regulated the expression of these proteins, meanwhile the indicators mentioned above were ameliorated. However, the inhibitor PP242 treatment group showed completely opposite result with the agonist group. Conclusion A-443654 can promote the proliferation of NPCs and the number of new-born dopaminergic neurons by up-regulating related proteins of mTORC2/Akt signaling pathway, and reducing the activation of microglia and the level of inflammation factors, which ultimately lead to the amelioration of SN-striatal dopaminergic neurons and behavioral performance in PD model mice.
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[Abstract] Objective To study whether the regulation of mammalian target of rapamycin complex 2(mTORC2) / Akt signaling pathway has a protective effect on SH-SY5Y cell line damaged by 6-hydroxydopamine (6-OHDA), and to clarify its molecular mechanism. Methods SH-SY5Y cells treated with retinoic acid (RA) were given 6-OHDA, mTORC2 signaling pathway inhibitor PP242 and agonist A-443654 respectively. The changes of cell number in each group were investigated by immunofluorescent staining; The total protein was extracted and the expression level and interaction of key proteins in mTORC2 signaling pathway were determined by Western blotting and co-immunoprecipitation (CoIP); The apoptosis rate of cells in each group was detected by flow cytometry. At the same time, the co-culture Parkinson’ s disease (PD) model was made using SH-SY5Y cell line and Bv-2 cell line; MTT colorimetric method was used to detect the cell viability of each group; ELISA was used to detect the content of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in cell culture supernatant. Results The number of tyrosine hydroxylase(TH) / proliferating cell nuclear antigen (PCNA) / hochest-, TH / 5-bronmo-2’ -deoxyuridine(BrdU) -labeled positive cells in 6-OHDA-lesioned PD cell model group was significantly lower than that in the normal group; The apoptosis rate was higher; The expression of Rictor, p-Akt and regulated in DNA damage and development 1(REDD1) was increased; There was an interaction between Rictor and p-Akt or REDD1; The cell viability was significantly reduced in the co-culture model; the content of TNF-α and IL-β increased in the cell culture supernatant. With further up-regulation of the abovementioned protein expressions, the cell survival, apoptosis and pro-inflammatory cytokine levels in A-443654 group were significantly ameliorated, while PP242 group showed the opposite changes. Conclusion A-443654 activates mTORC2 signaling pathway by p-Akt, which increases the expression of Rictor and REDD1 protein. These changes contribute to the amelioration in cell survival rate, apoptosis rate, and the proliferation and differentiation and decreasion of apoptosis rate of SH-SY5Y cells. These result improved 6-OHDA-induced cell damage and inhibited the release of pro-inflammatory cytokines.
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Background/Aims@#We investigated the real-world effectiveness and safety of ustekinumab (UST) as induction treatment for Koreans with Crohn’s disease (CD). @*Methods@#CD patients who started UST were prospectively enrolled from 4 hospitals in Korea. All enrolled patients received intravenous UST infusion at week 0 and subcutaneous UST injection at week 8. Clinical outcomes were assessed using Crohn’s Disease Activity Index (CDAI) scores at weeks 8 and 20 among patients with active disease (CDAI ≥150) at baseline. Clinical remission was defined as a CDAI <150, and clinical response was defined as a reduction in CDAI ≥70 points from baseline. Safety and factors associated with clinical remission at week 20 were also analyzed. @*Results@#Sixty-five patients were enrolled between January 2019 and December 2020. Among 49 patients with active disease at baseline (CDAI ≥150), clinical remission and clinical response at week 8 were achieved in 26 (53.1%) and 30 (61.2%) patients, respectively. At week 20, 27 (55.1%) and 35 (71.4%) patients achieved clinical remission and clinical response, respectively. Twenty-seven patients (41.5%) experienced adverse events, with serious adverse events in 3 patients (4.6%). One patient (1.5%) stopped UST therapy due to poor response. Underweight (body mass index <18.5 kg/m2) (odds ratio [OR], 0.085; 95% confidence interval [CI], 0.014–0.498; P=0.006) and elevated C-reactive protein at baseline (OR, 0.133; 95% CI, 0.022–0.823; P=0.030) were inversely associated with clinical remission at week 20. @*Conclusions@#UST was effective and well-tolerated as induction therapy for Korean patients with CD.
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Objective To explore the effect of recombination signal binding protein for immunoglobulin Kappa J region (RBP-Jκ) on the proliferation and differentiation of CD133￣positive ependymal cells and its possible mechanism. Methods RBP-Jκ in CD133-positive ependymal cells of lateral ventricle was interfered with siRNA in the fetuses of embryos which were isolated from 12-day pregnant Institute of Cancer Research(ICR) mouse (3 mice) and knocked out in CD133-CreER
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Colonic diverticulosis is one of the most common conditions of the digestive system and patients generally remain asymptomatic. However, about 20% of patients develop symptomatic diverticular disease such as acute diverticulitis or diverticular hemorrhage, and these have become a huge burden on healthcare systems worldwide. Recent understanding of the pathophysiology of diverticulosis and diverticular disease suggests the role of multiple factors including genetic and environment. Based on this understanding, a preventive strategy to reduce the risk factors of diverticulosis and diverticular disease is highly recommended. The diagnosis of the acute diverticulitis relies on imaging modalities such as an abdominal-pelvic CT scan together with symptoms and signs. Treatment of diverticular disease should be individualized and include modification of lifestyle, use of antibiotics, and surgery. Recent guidelines recommend pursuing less aggressive treatment for patients with acute diverticulitis. This review will provide an overview of both the existing and evolving understanding regarding colonic diverticulosis and diverticular disease and can help clinicians in the management of their patients with diverticular disease.
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Background/Aims@#Recently, 1-L polyethylene glycol-ascorbic acid (PEG-Asc) has been used to reduce the volume of preparation agents in colonoscopy. This clinical trial aimed to compare the efficacy and safety of two types of 1-L PEG-Asc (CleanViewAL ® [Tae Joon Pharmaceutical Company, Seoul, Korea] and Plenvu ® [Norgine, Harefield, United Kingdom]) in average-aged adults. @*Methods@#This study was a prospective, randomized, non-inferiority, open-label, phase 4 clinical trial. The primary endpoint was the efficacy evaluated using the Boston bowel preparation scale (BBPS), and the secondary endpoint was clinical safety. @*Results@#In total, 173 patients were assigned to either the CleanViewAL ® (n=84) or Plenvu ® (n=89) group. Overall cleansing successes of 97.6% (82/84) and 98.8% (88/89) were achieved in the CleanViewAL ® group and in the Plenvu ® group, respectively, showing that CleanViewAL ® has similar bowel cleansing efficacy to Plenvu ® (95% CI, -0.052 to 0.027; p=0.207). The total BBPS score was 8.67±1.00 and 8.70±0.76 in the CleanViewAL ® group and Plenvu ® group, respectively (p=0.869). The most common adverse symptom was nausea, and no adverse symptoms requiring hospitalization were reported in either group. There were no cases of critical hypernatremia and liver dysfunction exceeding the common terminology criteria for adverse events grade I. An overall satisfaction score (scale of 1 to 10) showed no difference between the two groups (p=0.289). However, the CleanViewAL ® group showed a higher taste satisfaction score (scale of 1 to 5) than the Plenvu ® group (CleanViewAL ® : 2.90±0.91, Plenvu ® : 2.60±0.86, p=0.028). @*Conclusions@#Both types of 1-L PEG-Asc, CleanViewAL ® and Plenvu ® , are effective and safe bowel cleansing agents in average-aged adults. CleanViewAL ® was preferred in terms of taste satisfaction.
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Background/Aims@#Nutritional status influences quality of life among patients with inflammatory bowel disease (IBD), although there is no clear method to evaluate nutritional status in this setting. Therefore, this study examined whether bioelectrical impedance analysis (BIA) could be used to evaluate the nutritional status of patients with IBD. @*Methods@#We retrospectively analyzed data from 139 Korean patients with IBD who were treated between November 2018 and November 2019. Patients were categorized as having active or inactive IBD based on the Harvey-Bradshaw index (a score of ≥5 indicates active Crohn’s disease) and the partial Mayo scoring index (a score of ≥2 indicates active ulcerative colitis). BIA results and serum nutritional markers were analyzed according to disease activity. @*Results@#The mean patient age was 45.11±17.71 years. The study included 47 patients with ulcerative colitis and 92 patients with Crohn’s disease. Relative to the group with active disease (n=72), the group with inactive disease (n=67) had significantly higher values for hemoglobin (P<0.001), total protein (P<0.001), and albumin (P<0.001). Furthermore, the group with inactive disease had higher BIA values for body moisture (P=0.047), muscle mass (P=0.046), skeletal muscle mass (P=0.042), body mass index (P=0.027), and mineral content (P=0.034). Moreover, the serum nutritional markers were positively correlated with the BIA results. @*Conclusions@#Nutritional markers evaluated using BIA were correlated with serum nutritional markers and inversely correlated with disease activity. Therefore, we suggest that BIA may be a useful tool that can help existing nutritional tests monitor the nutritional status of IBD patients.
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Background/Aims@#This study assessed the efficacy and safety of adalimumab (ADA) and explored predictors of response in Korean patients with ulcerative colitis (UC). @*Methods@#A prospective, observational, multicenter study was conducted over 56 weeks in adult patients with moderately to severely active UC who received ADA. Clinical response, remission, and mucosal healing were assessed using the Mayo score. @*Results@#A total of 146 patients were enrolled from 17 academic hospitals. Clinical response rates were 52.1% and 37.7% and clinical remission rates were 24.0% and 22.0% at weeks 8 and 56, respectively. Mucosal healing rates were 39.0% and 30.1% at weeks 8 and 56, respectively. Prior use of anti-tumor necrosis factor-α (anti-TNF-α) did not affect clinical and endoscopic responses. The ADA drug level was significantly higher in patients with better outcomes at week 8 (P<0.05). In patients with lower endoscopic activity, higher body mass index, and higher serum albumin levels at baseline, the clinical response rate was higher at week 8. In patients with lower Mayo scores and C-reactive protein levels, clinical responses, and mucosal healing at week 8, the clinical response rate was higher at week 56. Serious adverse drug reactions were identified in 2.8% of patients. @*Conclusions@#ADA is effective and safe for induction and maintenance in Korean patients with UC, regardless of prior anti-TNF-α therapy. The ADA drug level is associated with the efficacy of induction therapy. Patients with better short-term outcomes were predictive of those with an improved long-term response.
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Background@#The interest in Clostridioides difficile infection (CDI) has increased, and the choice of assays became wider since the first national survey in Korea on CDI diagnosis in 2015. We conducted a survey of the domestic CDI assays with more varied questions to understand the current situation in Korea. @*Methods@#In April 2018, about 50 questions on the current status of CDI assays and details on implementation and perceptions were written, and a survey questionnaire was administered to laboratory medicine specialists in 200 institutions. @*Results@#One-hundred and fifty institutions responded to the questionnaire, of which 90 (60.0%) including one commercial laboratory, performed CDI assays. The toxin AB enzyme immunoassay (toxin AB EIA), nucleic acid amplification test (NAAT), and C. difficile culture, glutamate dehydrogenase assay, alone or in combination with other assays, were used in 75 (84.3%), 52 (58.4%), 35 (36.0%), and 23 (25.8%), respectively, and 65 (73.0%) institutions performed a combination of two or more assays. The sensitivity of toxin AB EIA was more negatively perceived, and that on specificity was more positively perceived. The perception of sensitivity and specificity of NAAT was mostly positive. Perception on the algorithm test projected it as useful but in need of countermeasures. Sixty-three (73.3%) institutions responded that they performed surveillance on CDI. @*Conclusion@#This study provides useful evidence on the current status of CDI laboratory diagnosis in Korea as well as on items that require improvement and is thought to aid in standardizing and improving the CDI laboratory diagnosis in Korea.
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Background/Aims@#There is a recent increase in the use of stool multiplex PCR assay-based diagnostic tests in patients with acute diarrhea. We used multiplex PCR assays to analyze the distribution of diarrhea-causing bacteria and viruses, as well as the clinical features of patients with acute diarrhea. @*Methods@#We retrospectively reviewed stool specimens of inpatients complaining of acute diarrhea from October 2018 to July 2020.The stool specimens had been tested for bacteria and viruses using multiplex PCR assays. @*Results@#A total of 414 stool specimens from 346 patients were tested, and 152 pathogens were detected in 131 stool samples (131/414, 31.6%). Co-infection was detected in 20 patients (20/346, 5.8%). The common pathogens detected as causes of acute diarrhea, including co-infection, were Clostridium perfringens (34.9%), Clostridioides difficile (19.7%), and Campylobacter spp. (18.4%). The average age of patients with multiplex PCR-positive tests was lower than those with multiplex PCR-negative tests (p=0.001). In patients with suspected C. difficile infection (CDI), the RT-PCR for toxin gene assay was performed in 370 stool samples, 35 of which were positive (9.5%). Furthermore, 16 of the 35 samples were positive on the multiplex PCR assay (45.7%). @*Conclusions@#The multiplex PCR assay revealed that C. perfringens was the most common diarrhea-causing pathogen. In addition, in patients with suspected CDI, the multiplex PCR assay alone was insufficiently sensitive to detect pathogens and a conventional CDI test was additionally required.
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Croup is an acute upper respiratory disease primarily caused by the parainfluenza virus.Owing to inflammation and edema of the upper airways, children present with barky cough and stridor, and some may experience respiratory distress. We investigated children aged < 5 years with coronavirus disease 2019 (COVID-19) admitted to two hospitals in Seoul, South Korea, and observed a spike in croup cases during the omicron surge. Among the 569 children admitted from March 1, 2021 to February 25, 2022, 21 children (3.7%) had croup, and the proportion of croup cases was significantly higher during the omicron wave than that during the delta wave (12.4% vs. 1.2%, P < 0.001). With the immediate administration of corticosteroids and epinephrine via nebulizer, the symptoms improved rapidly. During the current omicron surge, careful monitoring of the symptoms of croup in young children is needed for the diagnosis of COVID-19 and its timely management.
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Objective To clarify the protective effect of allopregnanolone (APα) on cell line SH-SY5Y damaged by 6-hydroxydopamine (6-OHDA) and its possible molecular mechanism. Methods 6-OHDA, APα, γ-aminobutyric acid A receptor (GABAAR) antagonist, voltage-gated L-type Ca2
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The elevated expression of the hyaluronan-mediated motility receptor (HMMR) is known to be highly associated with tumor progression in prostate cancer, but the molecular mechanisms underlying the regulation of HMMR expression remain unclear. Here, we report that mammalian target of rapamycin (mTOR) is a key regulator of HMMR expression, for which its kinase activity is required. Pharmacological inhibitors of mTOR, such as rapamycin and Torin2, markedly suppressed the mRNA level as well as the protein level of HMMR in LNCaP and PC-3 cells. Our data demonstrate that such regulation occurs at the transcription level.HMMR promoter reporter assays revealed that the transcription factor SRF is responsible for the mTOR-mediated transcriptional regulation of HMMR gene. Consistently, the suppression of HMMR expression by Torin2 was noticeably reversed by the overexpression of SRF. Moreover, our findings suggest that the SRF binding sites responsible for the transcriptional regulation of HMMR through the mTOR-SRF axis are located in HMMR promoter sequences carrying the first intron, downstream of the translational start site. Furthermore, the upregulation of HMMR by DHT was abolished by stimulation with rapamycin, prior to DHT treatment, suggesting that mTOR activity is required for the induction of HMMR expression by androgen. Collectively, our study provides new mechanistic insights into the role of mTOR/SRF/AR signaling in HMMR regulation in prostate cancer cells.
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Recently, the incidence and prevalence rates of inflammatory bowel disease (IBD) have increased worldwide, including in Korea. Although there has been considerable progress in the management of IBD following the discovery of biologic agents, 5-aminosalicylate (5-ASA) and immunomodulators are still considered cornerstones in the management of mild to moderate IBD.Current Concepts: 5-ASA plays a key role in inducing remission in patients with mild to moderate ulcerative colitis. High doses of 5-ASA are more effective in inducing remission in patients with moderate ulcerative colitis, and combination therapy of oral 5-ASA and topical 5-ASA agents is recommended. Although the effect of 5-ASA in patients with Crohn disease is limited, high doses of 5-ASA can be effective for patients with mild disease, inflammatory behavior, and colonic involvement. Maintaining remission is essential for patients with IBD. Good doctor-patient relationships and encouraging drug adherence are recommended. Regarding drug adherence, a once-daily regimen is preferred for patients’ satisfaction. Thiopurines, the most important immunomodulators, show therapeutic benefits, such as steroid-sparing effects and remission maintenance in ulcerative colitis and Crohn disease after induction therapy. However, several side effects, including severe leukopenia, can induce the discontinuation of thiopurines. Close monitoring and management decisions should be individualized according to the risk of relapse and adverse events.Discussion and Conclusion: In conclusion, 5-ASA and immunomodulators are cornerstones in the management of IBD. As such, clinicians should have knowledge of these drugs and patients’ characteristics for proper prescription.
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Background/Aims@#Our study aimed to evaluate the long-term outcomes and risk factors forrelapse after anti-tumor necrosis factor (TNF)-α cessation in inflammatory bowel disease (IBD) patients because they are not well established. @*Methods@#A retrospective multicenter cohort study was conducted involving patients with Crohn’s disease (CD) or ulcerative colitis (UC) from 10 referral hospitals in Korea who discontinued firstline anti-TNF therapy after achieving clinical remission. @*Results@#A total of 109 IBD patients (71 CD and 38 UC) with a median follow-up duration of 56months were analyzed. The cumulative relapse rates at 1, 3, and 5 years were 11.3%, 46.7%, and 62.5% for CD patients and 28.9%, 45.3%, and 60.9% for UC patients. Multivariable Coxanalysis revealed that discontinuation owing to the clinician’s decision was associated with lower risk of relapse (vs patient’s preference: hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.04 to 0.48; p=0.002) and adalimumab use was associated with higher risk of relapse (vs infliximab: HR, 4.42; 95% CI, 1.24 to 17.74; p=0.022) in CD patients. Mucosal healing was associated with lower risk of relapse (vs nonmucosal healing: HR, 0.12; 95% CI, 0.02 to 0.83; p=0.031) in UC patients. Anti-TNF re-induction was provided to 52 patients, and a response was obtained in 50 patients. However, 25 of them discontinued retreatment owing to a loss of response (n=15), the patient’s preference (n=6), and other factors (n=4). @*Conclusions@#More than 60% of IBD patients in remission under anti-TNF therapy relapsed within 5 years of treatment cessation. Anti-TNF re-induction was effective. However, half of the patients discontinued anti-TNF therapy, and 50% of these patients discontinued treatment owing to loss of response.
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Recently, the incidence and prevalence rates of inflammatory bowel disease (IBD) have increased worldwide, including in Korea. Although there has been considerable progress in the management of IBD following the discovery of biologic agents, 5-aminosalicylate (5-ASA) and immunomodulators are still considered cornerstones in the management of mild to moderate IBD.Current Concepts: 5-ASA plays a key role in inducing remission in patients with mild to moderate ulcerative colitis. High doses of 5-ASA are more effective in inducing remission in patients with moderate ulcerative colitis, and combination therapy of oral 5-ASA and topical 5-ASA agents is recommended. Although the effect of 5-ASA in patients with Crohn disease is limited, high doses of 5-ASA can be effective for patients with mild disease, inflammatory behavior, and colonic involvement. Maintaining remission is essential for patients with IBD. Good doctor-patient relationships and encouraging drug adherence are recommended. Regarding drug adherence, a once-daily regimen is preferred for patients’ satisfaction. Thiopurines, the most important immunomodulators, show therapeutic benefits, such as steroid-sparing effects and remission maintenance in ulcerative colitis and Crohn disease after induction therapy. However, several side effects, including severe leukopenia, can induce the discontinuation of thiopurines. Close monitoring and management decisions should be individualized according to the risk of relapse and adverse events.Discussion and Conclusion: In conclusion, 5-ASA and immunomodulators are cornerstones in the management of IBD. As such, clinicians should have knowledge of these drugs and patients’ characteristics for proper prescription.
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Background/Aims@#Our study aimed to evaluate the long-term outcomes and risk factors forrelapse after anti-tumor necrosis factor (TNF)-α cessation in inflammatory bowel disease (IBD) patients because they are not well established. @*Methods@#A retrospective multicenter cohort study was conducted involving patients with Crohn’s disease (CD) or ulcerative colitis (UC) from 10 referral hospitals in Korea who discontinued firstline anti-TNF therapy after achieving clinical remission. @*Results@#A total of 109 IBD patients (71 CD and 38 UC) with a median follow-up duration of 56months were analyzed. The cumulative relapse rates at 1, 3, and 5 years were 11.3%, 46.7%, and 62.5% for CD patients and 28.9%, 45.3%, and 60.9% for UC patients. Multivariable Coxanalysis revealed that discontinuation owing to the clinician’s decision was associated with lower risk of relapse (vs patient’s preference: hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.04 to 0.48; p=0.002) and adalimumab use was associated with higher risk of relapse (vs infliximab: HR, 4.42; 95% CI, 1.24 to 17.74; p=0.022) in CD patients. Mucosal healing was associated with lower risk of relapse (vs nonmucosal healing: HR, 0.12; 95% CI, 0.02 to 0.83; p=0.031) in UC patients. Anti-TNF re-induction was provided to 52 patients, and a response was obtained in 50 patients. However, 25 of them discontinued retreatment owing to a loss of response (n=15), the patient’s preference (n=6), and other factors (n=4). @*Conclusions@#More than 60% of IBD patients in remission under anti-TNF therapy relapsed within 5 years of treatment cessation. Anti-TNF re-induction was effective. However, half of the patients discontinued anti-TNF therapy, and 50% of these patients discontinued treatment owing to loss of response.
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[ Abstract] Objective To investigate the effects of allopregnanolone (APα) on the dopaminergic neurons in substantia nigra, striatal dopaminergic neural fibers and behavioral performance in Parkinson’ s disease (PD) model mice, as well as its possible molecular mechanisms. Methods C57BL / 6 adult male mice with 20-25 g at 3-month old (n = 90) were successively injected with 6-hydroxydopamine (6-OHDA) to generate a PD animal model. APα and its receptor γ-aminobutyric acid A receptor (GABAAR) antagonist—bicuculline (Bic) were successively injected. ELISA was used to detect the APα or dopamine concentration in the serum, cerebral cortex and striatum. The number of tyrosine hydroxylase (TH) in the substantia nigra (SN) and striatal dopaminergic neural projections were examined by immunohistochemical staining. The expression levels of GABAAR in membrane fractions and Ca
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Sestrin2 (Sesn2), a metabolic regulator, accumulates in response to a diverse array of cellular stresses. Sesn2 regulates cellular metabolism by inhibiting the mammalian target of rapamycin complex 1 through the AMP-activated protein kinase (AMPK) signaling pathway. Recently, researchers reported that Sesn2 regulates the differentiation and function of innate immune cells and T cells; however, the role of Sesn2 in B cells is largely unknown. In this study, we investigated the role of Sesn2 in Ig class switching and Ig production in mouse B cells. We observed that mouse B cells express Sesn2 mRNA. Interestingly, the expression of germline ε transcripts (GLTε) was selectively decreased in lipopolysaccharide-stimulated Sesn2−/− splenocytes. Overexpression of Sesn2 increased GLTε promoter activity in B cells. In addition, AICAR (an activator of AMPK) selectively increased IL-4-induced GLTε expression and surface IgE (sIgE) expression in splenocytes. Furthermore, AICAR selectively enhanced IL-4-induced GLTε expression, sIgE expression, and IgE production by anti-CD40-stimulated B cells. We observed that ovalbumin (OVA)-specific IgE concentration was reduced in OVA-challenged Sesn2−/− mice. Taken together, these results indicate that Sesn2-AMPK signaling selectively enhances IL-4-induced IgE class switching and IgE production by B cells, suggesting that this could be a therapeutic strategy targeting Sesn2 in IgE-mediated allergic diseases.