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1.
Microbiota-Gut-Brain Axis in Major Depression: A New Therapeutic Approach.
Kim, IB, Park, SC, Kim, YK
Advances in experimental medicine and biology. 2023;:209-224
Abstract
Major depression is impacted by the disruption of gut microbiota. Defects in gut microbiota can lead to microbiota-gut-brain axis dysfunction and increased vulnerability to major depression. While traditional chemotherapeutic approaches, such as antidepressant use, produce an overall partial therapeutic effect on depression, the gut microbiome has emerged as an effective target for better therapeutic outcomes. Recent representative studies on the microbiota hypothesis to explore the association between gut pathophysiology and major depression have indicated that restoring gut microbiota and microbiota-gut-brain axis could alleviate depression. We reviewed studies that supported the gut microbiota hypothesis to better understand the pathophysiology of depression; we also explored reports suggesting that gut microbiota restoration is an effective approach for improving depression. These findings indicate that gut microbiota and microbiota-gut-brain axis are appropriate new therapeutic targets for major depression.
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Efficacy of recurrent transcutaneous magnetic stimulation in the treatment of diabetic peripheral neuropathy: Multicenter randomized trial.
Rao, VP, Kim, YK, Ghazi, A, Park, JY, Munir, KM
Pain practice : the official journal of World Institute of Pain. 2023;(8):914-921
Abstract
AIMS: Transcutaneous magnetic stimulation (TCMS) is successful in decreasing pain in several neurologic conditions. This multicenter parallel double-blind phase II clinical trial is a follow-up to a pilot study that demonstrated pain relief in patients with diabetic peripheral neuropathy (DPN) treated with TCMS. METHODS Thirty-four participants with confirmed DPN and baseline pain score ≥ 5 were randomized to treatment at two sites. Participants were treated with either TCMS (n = 18) or sham (n = 16) applied to each foot once a week for four weeks. Pain scores using the Numeric Pain Rating Scale after 10 steps on a hard floor surface and answers to Patient-Reported Outcomes Measurement Information System pain questions were recorded by participants daily for 28 days. RESULTS Thirty-one participants completed the study and were analyzed. Average pain scores decreased from baseline in both the groups. The difference in pain scores between TCMS and sham treatments was -0.55 for morning, -0.13 for evening, and -0.34 overall, below the pre-determined clinically relevant difference of -2. Moderate adverse events that resolved spontaneously were experienced in both treatment arms. CONCLUSION In this two-arm trial, TCMS failed to demonstrate a significant benefit over sham in patient reported pain suggesting a substantial placebo effect in our previous pilot study. TRIAL REGISTRATION TCMS for the Treatment of Foot Pain Caused By Diabetic Neuropathy, https://clinicaltrials.gov/ct2/show/NCT03596203, ID-NCT03596203.
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Vitamin C and catheter-related bladder discomfort after transurethral resection of bladder tumor: A double-blind, randomized, placebo-controlled study.
Park, JY, Baek, JW, Yu, J, Kim, CS, Bae, J, Kim, YK
Journal of clinical anesthesia. 2023;:111191
Abstract
STUDY OBJECTIVE We evaluated the effect of vitamin C administration on postoperative catheter-related bladder discomfort (CRBD). DESIGN A double-blind, randomized controlled trial. SETTING University tertiary hospital. PATIENTS The participants were patients undergoing transurethral resection of bladder tumor. INTERVENTION Patients were randomly assigned to either vitamin C (n = 59) or control (n = 59). The vitamin C group received 1 g of vitamin C intravenously and the control group received normal saline, administered after the induction of anesthesia. MEASUREMENTS The primary endpoint was moderate or greater CRBD immediately postoperatively. Secondary outcomes included the incidence of moderate or greater CRBD at 1, 2, and 6 h postoperatively. The symptom of CRBD is either a burning sensation with an urge to void or discomfort in the suprapubic area. Moderate CRBD was defined as spontaneously reported by the patient without any behavioral responses, such as attempts to remove the urinary catheter, intense verbal reactions, and flailing limbs. Severe CRBD was spontaneously reported by the patient with behavioral responses. Patient satisfaction scores were also evaluated. MAIN RESULTS The group that received vitamin C exhibited a significantly lower incidence of moderate or greater CRBD immediately postoperatively compared with the control group (17 [28.8%] vs. 40 [67.8%], p < 0.001, relative risk [95% confidence interval] = 0.426 [0.274-0.656]). The vitamin C group also showed a significantly lower incidence of moderate or greater CRBD at 1 and 2 h postoperatively compared with the control group (10 [16.9%] vs. 25 [42.4%], p = 0.003; and 5 [8.5%] vs. 16 [27.1%], p = 0.008, respectively). However, there was no significant difference in the incidence of moderate or greater CRBD 6 h postoperatively. Patient satisfaction scores were significantly higher in the vitamin C group than in the control group (5.0 ± 1.3 vs. 4.4 ± 1.4, p = 0.009). CONCLUSIONS Patients who received vitamin C had decreased CRBD and improved patient satisfaction following transurethral resection of bladder tumor.
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4.
Emerging drugs for the treatment of diabetic nephropathy.
Kim, YK, Ning, X, Munir, KM, Davis, SN
Expert opinion on emerging drugs. 2022;(4):417-430
Abstract
INTRODUCTION Diabetic nephropathy remains a significant economic and social burden on both the individual patient and health-care systems as the prevalence of diabetes increases in the general population. The complex pathophysiology of diabetic kidney disease poses a challenge in the development of effective medical treatments for the disease. However, the multiple facets of diabetic nephropathy also offer a variety of potential strategies to manage this condition. AREAS COVERED We retrieved PubMed, Cochrane Library, Scopus, Google Scholar, and ClinicalTrials.gov records to identify studies and articles focused on new pharmacologic advances to treat diabetic nephropathy. EXPERT OPINION RAAS blockers have remained the mainstay of therapy for DM nephropathy for many years, with only recent advancements with SGLT2 inhibitors and nonsteroidal MRAs. Better understanding of the long-term renal effects of ambient hyperglycemia, ranging from hemodynamic changes to increased production of oxidative and pro-inflammatory substances, has evolved our approach to the treatment of diabetic nephropathy. With continuing research for new therapeutics as well as combination therapy, the medical community may be able to better ease the burden of diabetic kidney disease.
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Validity and safety of ID-JPL934 in lower gastrointestinal symptom improvement.
Shin, CM, Choi, YJ, Lee, DH, Moon, JS, Kim, TY, Kim, YK, Lee, WH, Yoon, H, Park, YS, Kim, N
Scientific reports. 2021;(1):13046
Abstract
The study evaluated the efficacy of ID-JPL934, a probiotic preparation containing Lactobacillus johnsonii IDCC 9203, Lactobacillus plantarum IDCC 3501 and Bifidobacterium lactis IDCC 4301, in relieving lower gastrointestinal symptoms. A total of 112 subjects with lower gastrointestinal symptoms were consecutively enrolled. They were randomized into either ID-JPL934 administration group or placebo group. Bristol stool form, stool frequency, and abnormal bowel movement symptoms were recorded at baseline and week 2, 6, and 8. Primary endpoint was improvement in overall symptoms at week 8. Fecal samples were collected to measure the probiotic levels in feces using quantitative polymerase chain reaction (qPCR), and to perform metagenomic analysis of microbiome originating from bacteria-derived extracellular vesicles and bacterial cells via 16S rDNA sequencing. Of the 112 subjects, 104 (54 in ID-JPL934 group and 50 in placebo group) completed the entire study protocol. A higher relief of overall symptoms was found in ID-JPL934 group than in placebo group (p = 0.016). Among lower gastrointestinal symptoms, abdominal pain and bloating scores were more decreased in ID-JPL934 group than in placebo group (p < 0.05). The fecal microbiome profiles of the two groups did not differ. However, the qPCR analysis showed significant increase in the levels of Lactobacillus johnsonii and Bifidobacterium lactis in feces post-treatment in ID-JPL934 group than in placebo group (p < 0.05 by repeated measure ANOVA). In conclusion, ID-JPL934 is effective in relieving lower gastrointestinal symptoms. Exposure to ID-JPL934 may increase the abundance of Lactobacillus johnsonii and Bifidobacterium lactis in the gut.Trial registration: ClinicalTrials.gov number, NCT03395626.
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The roles of non-coding RNAs in vascular calcification and opportunities as therapeutic targets.
Ryu, J, Ahn, Y, Kook, H, Kim, YK
Pharmacology & therapeutics. 2021;:107675
Abstract
Vascular calcification (VC) is characterized by an accumulation of calcium phosphate crystals inside the vessel wall. VC is often associated with diabetes, chronic kidney disease (CKD), atherosclerosis, and cardiovascular disease (CVD). Even though the number of patients with VC remains prevalent, there are still no approved therapies for the treatment of VC. Since the pathogenesis of VC is diverse and involves multiple factors and mechanisms, it is critical to reveal the novel mechanisms involved in VC. Although protein-coding RNAs involved in VC have been extensively studied, the roles of non-coding RNAs (ncRNAs) are not yet fully understood. The field of ncRNAs has recently received attention, and accumulating evidence from studies in VC suggests that ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play an important role in the regulation of VC. NcRNAs can modulate VC by acting as promoters or inhibitors and may be useful in the clinical diagnosis and treatment of VC. In this article, we review and discuss ncRNAs that regulate VC and present the therapeutic implications of these ncRNAs.
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Investigation of gene-environment interactions in relation to tic severity.
Abdulkadir, M, Yu, D, Osiecki, L, King, RA, Fernandez, TV, Brown, LW, Cheon, KA, Coffey, BJ, Garcia-Delgar, B, Gilbert, DL, et al
Journal of neural transmission (Vienna, Austria : 1996). 2021;(11):1757-1765
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Abstract
Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.
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No Relevant Pharmacokinetic Drug-Drug Interaction Between the Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin and Lobeglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, in Healthy Subjects.
Kim, YK, Hwang, JG, Park, MK
Drug design, development and therapy. 2021;:1725-1734
Abstract
PURPOSE Combination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects. SUBJECTS AND METHODS A randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25. RESULTS The steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well. CONCLUSION The lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment. TRIAL REGISTRATION NUMBER NCT02854748, Registered on August 7, 2016.
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Therapeutic Applications of Resveratrol in Hepatic Encephalopathy through Its Regulation of the Microbiota, Brain Edema, and Inflammation.
Kim, YK, Song, J
Journal of clinical medicine. 2021;(17)
Abstract
Hepatic encephalopathy is a common complication in patients with liver cirrhosis and portosystemic shunting. Patients with hepatic encephalopathy present a variety of clinical features, including neuropsychiatric manifestations, cognitive dysfunction, impaired gut barrier function, hyperammonemia, and chronic neuroinflammation. These pathogeneses have been linked to various factors, including ammonia-induced oxidative stress, neuronal cell death, alterations in the gut microbiome, astrocyte swelling, and blood-brain barrier disruptions. Many researchers have focused on identifying novel therapeutics and prebiotics in the hope of improving the treatment of these conditions. Resveratrol is a natural polyphenic compound and is known to exert several pharmacological effects, including antioxidant, anti-inflammatory, and neuroprotective activities. Recent studies suggest that resveratrol contributes to improving the neuropathogenic effects of liver failure. Here, we review the current evidence describing resveratrol's effects in neuropathogenesis and its impact on the gut-liver axis relating to hepatic encephalopathy. We highlight the hypothesis that resveratrol exerts diverse effects in hepatic encephalopathy and suggest that these effects are likely mediated by changes to the gut microbiota, brain edema, and neuroinflammation.
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Understanding the Connection Between the Gut-Brain Axis and Stress/Anxiety Disorders.
Lee, Y, Kim, YK
Current psychiatry reports. 2021;(5):22
Abstract
PURPOSE OF REVIEW We review the association of the microbiota-gut-brain axis and anxiety disorder or stress. RECENT FINDING The microbiota-gut-brain axis mechanism encompasses a bidirectional relationship between the brain and gastrointestinal organs. Dysregulation of the microbiota-gut-brain axis has been actively revealed in the context of various psychiatric diseases such as neurodevelopmental disorders, schizophrenia, anxiety disorders, and depression. We suggest that onset of anxiety disorders may be correlated with activation of a microbiota-gut-brain mechanism involving the immune system, neurotransmitters, and the hormonal system. By applying a microbiota-gut-brain axis mechanism, the possibility of using gastrointestinal system drugs such as probiotics and antibiotics as treatments for anxiety disorders is a possibility. Although modification of the microbiota-gut-brain axis mechanism has yet to be adopted clinically, it is expected that novel strategies employing this mechanism will be developed and deployed as new treatments not only for anxiety disorders, but also other psychiatric diseases.
