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Purpose@#Studies about the effect of radiation therapy (RT) on immune cells are usually limited to a high-grade glioma mostly exposed to chemotherapy and a high dose of steroid which also could affect immune cells. The purpose of this retrospective analysis of low-grade brain tumor patients treated by RT alone is to determine significant factors influencing neutrophil-to-lymphocyte ratio (NLR), absolute neutrophil counts (ANC), and absolute lymphocyte counts (ALC). @*Materials and Methods@#A total of 41 patients who received RT between 2007 and 2020 were analyzed. Patients who received chemotherapy and high-dose of steroid were excluded. ANC and ALC were collected before starting RT (baseline) and within one-week before ending RT (post-treatment). Changes of ANC, ALC, and NLR between baseline and post-treatment were calculated. @*Results@#ALC decreased in 32 patients (78.1%). NLR increased in 31 patients (75.6%). No patients developed grade 2 or higher hematologic toxicities. The decrease of ALC was significantly correlated with the dose to brain V15 in a simple and multiple linear regression (p = 0.043). Brain V10 and V20 adjacent to V15 were also marginally significant factors determining the reduction of lymphocytes (p = 0.050 and p = 0.059, respectively). However, it was difficult to find predictive factors affecting changes of ANC and NLR. @*Conclusion@#In low-grade brain tumor patients who are treated by RT alone, ALC decreased and NLR increased in three-fourth of patients, although the magnitude was minimal. The decrease of ALC was mainly affected by low dose to the brain. However, RT dose was not correlated with changes of ANC or NLR.
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BACKGROUND/OBJECTIVES@#Zanthoxylum schinifolium is traditionally used as a spice for cooking in East Asian countries. This study was undertaken to evaluate the anti-proliferative potential of ethanol extracts of Z. schinifolium leaves (EEZS) against human bladder cancer T24 cells.MATERIALS/METHODS: Subsequent to measuring the cytotoxicity of EEZS, the anti-cancer activity was measured by assessing apoptosis induction, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP). In addition, we determined the underlying mechanism of EEZS-induced apoptosis through various assays, including Western blot analysis. @*RESULTS@#EEZS treatment concentration-dependently inhibited T24 cell survival, which is associated with apoptosis induction. Exposure to EEZS induced the expression of Fas and Fas-ligand, activated caspases, and subsequently resulted to cleavage of poly (ADPribose) polymerase. EEZS also enhanced the expression of cytochrome c in the cytoplasm by suppressing MMP, following increase in the ratio of Bax:Bcl-2 expression and truncation of Bid. However, EEZS-mediated growth inhibition and apoptosis were significantly diminished by a pan-caspase inhibitor. Moreover, EEZS inhibited activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, and the apoptosis-inducing potential of EEZS was promoted in the presence of PI3K/Akt inhibitor. In addition, EEZS enhanced the production of ROS, whereas N-acetyl cysteine (NAC), a ROS scavenger, markedly suppressed growth inhibition and inactivation of the PI3K/Akt signaling pathway induced by EEZS. Furthermore, NAC significantly attenuated the EEZS-induced apoptosis and reduction of cell viability. @*CONCLUSIONS@#Taken together, our results indicate that exposure to EEZS exhibits anticancer activity in T24 bladder cancer cells through ROS-dependent induction of apoptosis and inactivation of the PI3K/Akt signaling pathway.
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Purpose@#Preimplantation genetic testing for monogenic disorders (PGT-M) has been successfully used to prevent couples with monogenic disorders from passing them on to their child. Charcot–Marie–Tooth Disease (CMT) is a genetic disorder characterized by progressive extremity muscle degeneration and loss of sensory function. For the first time in Korea, we report our experience of applying single nucleotide polymorphism genotyping and karyomapping for PGT-M of CMT disease. @*Materials and Methods@#Prior to clinical PGT-M, preclinical tests were performed using genotypes of affected families to identify informative single-nucleotide polymorphisms associated with mutant alleles. We performed five cycles of in vitro fertilization PGT-M in four couples with CMT1A, CMT2A, and CMT2S in CHA Fertility Center, Seoul Station. @*Results@#From July 2020 through August 2021, five cycles of PGT-M with karyomapping in four cases with CMT1 and CMT2 were analyzed retrospectively. A total of 17 blastocysts were biopsied and 15 embryos were successfully diagnosed (88.2%).Ten out of 15 embryos were diagnosed as unaffected (66.7%). Five cycles of PGT-M resulted in four transfer cycles, in which four embryos were transferred. Three clinical pregnancies were achieved (75%) and the prenatal diagnosis by amniocentesis for all three women confirmed PGT-M of karyomapping. One woman delivered a healthy baby uneventfully and two pregnancies are currently ongoing. @*Conclusion@#This is the first report in Korea on the application of karyomapping in PGT-M for CMT patients. This study shows that karyomapping is an efficient, reliable and accurate diagnostic method for PGT-M in various types of CMT diseases.
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Background and Objectives@#Currently, safety pharmacological tests for the central nervous system depend on animal behavioral analysis. However, due to the subjectivity of behavioral analysis and differences between species, there is a limit to appropriate nervous system toxicity assessment, therefore a new neurotoxicity assessment that can simulate the human central nervous system is required. @*Methods@#and Results: In our study, we developed an in vitro neurotoxicity assessment focusing on neuronal function. To minimize the differences between species and fast screening, hiPSC-derived neurons and a microelectrode array (MEA) that could simultaneously measure the action potentials of the neuronal networks were used. After analyzing the molecular and electrophysiological characters of our neuronal network, we conducted a neurotoxicity assessment on neurotransmitters, neurotoxicants, illicit drugs, and new psychoactive substances (NPS). We found that most substances used in our experiments responded more sensitively to our MEA-based neurotoxicity assessment than to the conventional neurotoxicity assessment. Also, this is the first paper that evaluates various illicit drugs and NPS using MEA-based neurotoxicity assessment using hiPSC-derived neurons. @*Conclusions@#Our study expanded the scope of application of neurotoxicity assessment using hiPSC-derived neurons to NPS, and accumulated evaluation data of various toxic substances for hiPSC-derived neurons.
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Charcot–Marie-Tooth disease (CMT) is the most common hereditary motor and sensory peripheral neuropathy. CMT is usually classified into two categories based on pathology: demyelinating CMT type 1 (CMT1) and axonal CMT type 2 (CMT2) neuropathy. CMT1 can be distinguished by assessing the median motor nerve conduction velocity as greater than 38 m/s. The main clinical features of axonal CMT2 neuropathy are distal muscle weakness and loss of sensory and areflexia. In addition, they showed unusual clinical features, including delayed development, hearing loss, pyramidal signs, vocal cord paralysis, optic atrophy, and abnormal pupillary reactions. Recently, customized treatments for genetic diseases have been developed, and pregnancy diagnosis can enable the birth of a normal child when the causative gene mutation is found in CMT2. Therefore, accurate diagnosis based on genotype/phenotypic correlations is becoming more important. In this review, we describe the latest findings on the phenotypic characteristics of axonal CMT2 neuropathy. We hope that this review will be useful for clinicians in regard to the diagnosis and treatment of CMT.
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Kawasaki disease (KD) is an acute pediatric vasculitis that affects genetically susceptible infants and children. To identify coding variants that influence susceptibility to KD, we conducted whole exome sequencing of 159 patients with KD and 902 controls, and performed a replication study in an independent 586 cases and 732 controls. We identified five rare coding variants in five genes (FCRLA, PTGER4, IL17F, CARD11, and SIGLEC10) associated with KD (odds ratio [OR], 1.18–4.41; p = 0.0027–0.031). We also performed association analysis in 26 KD patients with coronary artery aneurysms (CAAs; diameter > 5 mm) and 124 patients without CAAs (diameter < 3 mm), and identified another five rare coding variants in five genes (FGFR4, IL31RA, FNDC1, MMP8, and FOXN1), which may be associated with CAA (OR, 3.89–37.3; p = 0.0058–0.0261). These results provide insights into new candidate genes and genetic variants potentially involved in the development of KD and CAA.
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Background@#and Purpose Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) are known to cause Charcot-Marie-Tooth disease (CMT). These mutations are very rare in most countries, but not in certain Mediterranean countries. The purpose of this study was to identify the clinical and neuroimaging characteristics of Korean CMT patients with GDAP1 mutations. @*Methods@#Gene sequencing was applied to 1,143 families in whom CMT had been diagnosed from 2005 to 2020. PMP22 duplication was found in 344 families, and whole-exome sequencing was performed in 699 patients. Magnetic resonance imaging (MRI) were obtained using either a 1.5-T or 3.0-T MRI system. @*Results@#We found ten patients from eight families with GDAP1 mutations: five with autosomal dominant (AD) CMT type 2K (three families with p.R120W and two families with p.Q218E) and three with autosomal recessive (AR) intermediate CMT type A (two families with homozygous p.H256R and one family with p.P111H and p.V219G mutations). The frequency was about 1.0% exclusive of the PMP22 duplication, which is similar to that in other Asian countries. There were clinical differences among AD GDAP1 patients according to mutation sites. Surprisingly, fat infiltrations evident in lower-limb MRI differed between AD and AR patients. The posterior-compartment muscles in the calf were affected early and predominantly in AD patients, whereas AR patients showed fat infiltration predominantly in the anterolateral-compartment muscles. @*Conclusions@#This is the first cohort report on Korean patients with GDAP1 mutations. The patients with AD and AR inheritance routes exhibited different clinical and neuroimaging features in the lower extremities. We believe that these results will help to expand the knowledge of the clinical, genetic, and neuroimaging features of CMT.
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The global crisis caused by the coronavirus disease 2019 (COVID-19) led to the most significant economic loss and human deaths after World War II. The pathogen causing this disease is a novel virus called the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). As of December 2020, there have been 80.2 million confirmed patients, and the mortality rate is known as 2.16% globally. A strategy to protect a host from SARS-CoV-2 is by suppressing intracellular viral replication or preventing viral entry. We focused on the spike glycoprotein that is responsible for the entry of SARS-CoV-2 into the host cell. Recently, the US Food and Drug Administration/EU Medicines Agency authorized a vaccine and antibody to treat COVID-19 patients by emergency use approval in the absence of long-term clinical trials. Both commercial and academic efforts to develop preventive and therapeutic agents continue all over the world. In this review, we present a perspective on current reports about the spike glycoprotein of SARS-CoV-2 as a therapeutic target.
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Background@#Pembrolizumab, an anti-cancer drug, is known to increase the activity of the immune system, leading to side effects called immune-related adverse events (irAE), including type 1 diabetes. This study analyzed the correlation between blood glucose level and pembrolizumab administration and investigated the covariates that affect those changes in cancer treatment. @*Methods@#The information of 133 adult cancer patients was obtained from the electronic medical record (EMR) to identify the changes in random blood glucose (RBG) levels during the pembrolizumab treatment. Subjects were classified into subgroups according to their baseline RBG level, history of diabetes, and the use of steroids, and linear regression analysis was conducted. In addition, a secondary analysis was performed within the group of subjects having a strong correlation to glycemic change, which was based on the Pearson correlation coefficient being less than -0.7 or greater than +0.7. Univariate and multivariate logistic regressions were conducted to identify the risk factors to glycemic increase. @*Results@#The RBG level tended to descend without significant differences in total patients during the administration period of pembrolizumab. Despite the insignificance, the logistic regression analysis presents that the odds ratios of baseline RBG less than 130 mg/dL, prophylactic steroid use, and higher dose of pembrolizumab per cycle (mg/kg/ cycle) were greater than 1. @*Conclusions@#Prophylactic administration of steroids and a higher dose of pembrolizumab per cycle may increase the blood glucose level as irAE in cancer patients with a strong tendency to glycemic change.
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Purpose@#This study aimed to systematically evaluate literature related to the effects of exercise intervention programs on physical or psychological variables of post-operative breast cancer patients in Korea, and identify the effectiveness of exercise intervention through meta-analysis. @*Methods@#The review question was defined according to PICO-SD (Participants, Intervention, Comparisons, Outcomes, Study Design) to achieve a systematic literature review: “How does exercise intervention affect the physical or psychological outcome in post-operative breast cancer patients compared to the control group?” The subjects were randomized clinical trials (RCTs) studies released in Korea between 2010 and December 2020. Literature searches were conducted using four electronic databases, including Korean Studies Information Service System (KISS), Research Information Sharing Service (RISS), National Assembly Library, and DBpia. The search terms were ‘breast neoplasms’ or ‘breast cancer’ with ‘exercise’ or ‘exercise intervention’ or ‘exercise program.’ A total of 13 RCTs were finally selected. Results: The outcome variables were in the upper extremity range of motion (ROM), shoulder disability, pain and edema. The effect size of exercise intervention on ROM was 0.95(95% CI:0.58, 1.33)( p<.001); shoulder disability was -1.16(95% CI:-1.77, -0.55)(p<.001); pain was -1.24(95% CI:-1.58, -0.89) (p<.001); and edema was -0.03(95% CI:-0.39, 0.33)(p=.858). @*Conclusion@#This result suggests that oncology nurses may apply exercise intervention to improve ROM, shoulder disability, and to alleviate pain in post-op breast cancer patients.
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Background@#Pembrolizumab, an anti-cancer drug, is known to increase the activity of the immune system, leading to side effects called immune-related adverse events (irAE), including type 1 diabetes. This study analyzed the correlation between blood glucose level and pembrolizumab administration and investigated the covariates that affect those changes in cancer treatment. @*Methods@#The information of 133 adult cancer patients was obtained from the electronic medical record (EMR) to identify the changes in random blood glucose (RBG) levels during the pembrolizumab treatment. Subjects were classified into subgroups according to their baseline RBG level, history of diabetes, and the use of steroids, and linear regression analysis was conducted. In addition, a secondary analysis was performed within the group of subjects having a strong correlation to glycemic change, which was based on the Pearson correlation coefficient being less than -0.7 or greater than +0.7. Univariate and multivariate logistic regressions were conducted to identify the risk factors to glycemic increase. @*Results@#The RBG level tended to descend without significant differences in total patients during the administration period of pembrolizumab. Despite the insignificance, the logistic regression analysis presents that the odds ratios of baseline RBG less than 130 mg/dL, prophylactic steroid use, and higher dose of pembrolizumab per cycle (mg/kg/ cycle) were greater than 1. @*Conclusions@#Prophylactic administration of steroids and a higher dose of pembrolizumab per cycle may increase the blood glucose level as irAE in cancer patients with a strong tendency to glycemic change.
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Purpose@#This study aimed to systematically evaluate literature related to the effects of exercise intervention programs on physical or psychological variables of post-operative breast cancer patients in Korea, and identify the effectiveness of exercise intervention through meta-analysis. @*Methods@#The review question was defined according to PICO-SD (Participants, Intervention, Comparisons, Outcomes, Study Design) to achieve a systematic literature review: “How does exercise intervention affect the physical or psychological outcome in post-operative breast cancer patients compared to the control group?” The subjects were randomized clinical trials (RCTs) studies released in Korea between 2010 and December 2020. Literature searches were conducted using four electronic databases, including Korean Studies Information Service System (KISS), Research Information Sharing Service (RISS), National Assembly Library, and DBpia. The search terms were ‘breast neoplasms’ or ‘breast cancer’ with ‘exercise’ or ‘exercise intervention’ or ‘exercise program.’ A total of 13 RCTs were finally selected. Results: The outcome variables were in the upper extremity range of motion (ROM), shoulder disability, pain and edema. The effect size of exercise intervention on ROM was 0.95(95% CI:0.58, 1.33)( p<.001); shoulder disability was -1.16(95% CI:-1.77, -0.55)(p<.001); pain was -1.24(95% CI:-1.58, -0.89) (p<.001); and edema was -0.03(95% CI:-0.39, 0.33)(p=.858). @*Conclusion@#This result suggests that oncology nurses may apply exercise intervention to improve ROM, shoulder disability, and to alleviate pain in post-op breast cancer patients.
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Fentanyl intoxication has occasionally been reported since fentanyl patches became available for medical use. Delayed post-hypoxic leukoencephalopathy is a complication of hypoxia. However, its neuropsychiatric symptoms can be delayed, and it can progress to leukoencephalopathy even after full recovery from coma due to acute intoxication. Herein, we report a case of fentanyl intoxication in a 65-year-old man who was presented to the hospital because of unconsciousness for 13 hours after using ten fentanyl patches simultaneously. Initial brain CT findings were non-specific. Twenty days later, delayed neuropathologic symptoms manifested, and MRI showed bilaterally symmetrical, heterogeneous, confluent high signal intensities on T2-weighted/fluid attenuated inversion recovery MRI in the cerebral white matter with diffusion restriction. This was followed by rapid exacerbation of neuropathological symptoms with diffuse severe cerebral atrophy over 1 year.
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Cri-du-chat syndrome is a rare genetic disorder in which the patient presents with a characteristic high-pitched monotonous cry and recurrent aspiration pneumonia, attributed to abnormalities in the larynx, epiglottis, and nervous system. The most prominent brain MRI findings are the presence of pontine and cerebellar hypoplasia, which primarily involve posterior cranial fossa structures. Although atrophy of supratentorial structures were also a common radiological finding, it was considered to be a secondary change due to pontine hypoplasia. Here, we present the case of a three-month-old patient presenting with cri-du-chat at our institution. The patient also showed the presence of prominent pontine hypoplasia similar to previously reported cases; however, contrary to other cases, there was a general delayed myelination of brain instead of decreased myelination of anterior limb of internal capsule. Since the larynx, pons, and cerebellum all originated from similar notochord level, which suggests anomaly in early stage of development, laryngeal, and brain anomaly characteristically observed in the cridu- chat syndrome.
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Inherited peripheral neuropathy (IPN) is caused by heterogeneous genetic mutations in more than 100 genes. So far, several treatment options for IPN have been developed and clinically evaluated using small molecules. However, gene therapy-based therapeutic strategies have not been aggressively investigated, likely due to the complexities of inheritance in IPN. Indeed, because the majority of the causative mutations of IPN lead to gainof- function rather than loss-of-function, developing a therapeutic strategy is more difficult, especially considering gene therapy for genetic diseases began with the simple idea of replacing a defective gene with a functional copy. Recent advances in gene manipulation technology have brought novel approaches to gene therapy and its clinical application for IPN treatment. For example, in addition to the classically used gene replacement for mutant genes in recessively inherited IPN, other techniques including gene addition to modify the disease phenotype, modulations of target gene expression, and techniques to edit mutant genes have been developed and evaluated as potent therapeutic strategies for dominantly inherited IPN. In this review, the current status of gene therapy for IPN and future perspectives will be discussed.
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Background@#Limited data exist regarding mucosal healing (MH) and therapeutic drug monitoring (TDM) in pediatric Crohn's disease (CD) patients treated with adalimumab (ADL). We aimed to investigate the associations between ADL trough levels (TLs) and MH, and between ADL TLs and histologic remission (HR) at 16 weeks from ADL treatment in pediatric CD patients. @*Methods@#This was a prospective study on moderate-to-severe luminal pediatric CD patients receiving ADL. Ileocolonoscopies and biopsies, as well as clinical activity assessments, laboratory examinations, including tests for ADL TLs and antibody to ADL, were performed 16 weeks after ADL initiation. MH was defined as a Simple Endoscopic Score for CD of 0. HR was defined as the complete absence of microscopic inflammation. @*Results@#Seventeen subjects (13 males, 4 females) were included. At 16 weeks from ADL initiation, 14 (82.4%), 8 (47.1%), and 4 (23.5%) patients achieved clinical remission, MH, and HR, respectively. ADL TLs were significantly higher in patients who achieved MH compared to those who did not (13.0 ± 6.5 vs. 6.2 ± 2.6 μg/mL, respectively; P = 0.023) and also significantly higher in patients who achieved HR compared to those who did not (17.9 ± 5.3 vs. 6.8 ± 2.5 μg/mL, respectively; P = 0.02). The optimal TL for predicting MH was 8.76 μg/mL. @*Conclusion@#Serum ADL TLs at 16 weeks were significantly higher in pediatric patients with CD who achieved MH and HR, respectively. TDM may guide in optimizing treatment efficacy and better target MH in the era of treat-to-target.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a positive-sense singlestranded RNA (+ssRNA) that causes coronavirus disease 2019 (COVID-19). The viral genome encodes twelve genes for viral replication and infection. The third open reading frame is the spike (S) gene that encodes for the spike glycoprotein interacting with specific cell surface receptor – angiotensin converting enzyme 2 (ACE2) – on the host cell membrane. Most recent studies identified a single point mutation in S gene. A single point mutation in S gene leading to an amino acid substitution at codon 614 from an aspartic acid 614 into glycine (D614G) resulted in greater infectivity compared to the wild type SARS-CoV2. We were interested in investigating the mutation region of S gene of SARS-CoV2 from Korean COVID-19 patients. New mutation sites were found in the critical receptor binding domain (RBD) of S gene, which is adjacent to the aforementioned D614G mutation residue. This specific sequence data demonstrated the active progression of SARS-CoV2 by mutations in the RBD of S gene.The sequence information of new mutations is critical to the development of recombinant SARS-CoV2 spike antigens, which may be required to improve and advance the strategy against a wide range of possible SARS-CoV2 mutations.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a positive-sense singlestranded RNA (+ssRNA) that causes coronavirus disease 2019 (COVID-19). The viral genome encodes twelve genes for viral replication and infection. The third open reading frame is the spike (S) gene that encodes for the spike glycoprotein interacting with specific cell surface receptor – angiotensin converting enzyme 2 (ACE2) – on the host cell membrane. Most recent studies identified a single point mutation in S gene. A single point mutation in S gene leading to an amino acid substitution at codon 614 from an aspartic acid 614 into glycine (D614G) resulted in greater infectivity compared to the wild type SARS-CoV2. We were interested in investigating the mutation region of S gene of SARS-CoV2 from Korean COVID-19 patients. New mutation sites were found in the critical receptor binding domain (RBD) of S gene, which is adjacent to the aforementioned D614G mutation residue. This specific sequence data demonstrated the active progression of SARS-CoV2 by mutations in the RBD of S gene.The sequence information of new mutations is critical to the development of recombinant SARS-CoV2 spike antigens, which may be required to improve and advance the strategy against a wide range of possible SARS-CoV2 mutations.
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The authors would like to publish this corrigendum to change the corresponding author in the above article.
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The metabolic burden caused by hyperglycemia can result in direct and immediate metabolic injuries, such as oxidative stress and tissue inflammation, in the kidney. Furthermore, chronic hyperglycemia can lead to substantial structural changes such as formation of advanced glycation end-products, glomerular and tubular hypertrophy, and tissue fibrosis. Glomerular hypertrophy renders podocytes vulnerable to increased glomerular filtration, leading to podocyte instability and loss. Thus, prevention of glomerular hypertrophy and attenuation of glomerular hyperfiltration may have therapeutic potential for diabetic nephropathy (DN). Adiponectin is an adipokine that improves insulin sensitivity in obesity-related metabolic disorders, including diabetes, but its efficacy is unknown. Moreover, the recently developed adiponectin receptor agonist, AdipoRon, shows therapeutic potential for DN. In this review, we focus on the role of glomerular hypertrophy in the pathogenesis of DN and discuss the role of adiponectin in its prevention.