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IntroductionImmune dysfunction is a major cause of neuroinflammation and accelerates the progression of Parkinson’s disease (PD). Numerous studies have shown that stimulation of specific acupuncture points (acupoints) can ameliorate PD symptoms. The purpose of this study was to investigate whether attaching microneedles to acupoints would improve PD pathology by recovering immune dysfunction.MethodsThe PD mouse model was induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA), and microneedle patches (MPs) or sham patches (SPs) were attached to GB20 and GB34, representative acupoints for treating PD for 14 days.ResultsFirst, the behavioral experiment showed that motor disorders induced by 6-OHDA were significantly improved by MP. Simultaneously, 6-OHDA-induced dopaminergic neuronal death and brain neuroinflammation decreased. Conversely, SP had no effect on behavioral disorders, neuronal death, or neuroinflammation. Measurement results from flow cytometry of immune cells in the brain and blood revealed a disruption in the CD4+/CD8+ ratio in the 6-OHDA group, which was significantly restored in the MP group. The brain mRNA expression of cytokines was significantly increased in the 6-OHDA group, which was significantly decreased by MP.DiscussionOverall, our results suggest that the attachment of MPs to GB20 and GB34 is a new method to effectively improve the pathology of PD by restoring peripheral and brain immune function.

BackgroundMild cognitive impairment (MCI) is a growing concern among older adults, with limited effective pharmacological treatments available. Despite the potential of herbal medicine and acupuncture in managing MCI, there is a lack of research on their long-term effects on cognitive function and brain activity in clinical practice settings. This study aimed to address this gap by exploring the effects of a community-based program integrating herbal medicine and acupuncture on cognitive function and neural responses in older individuals with MCI.MethodsNineteen individuals were enrolled from a pool of 250 individuals registered in the 2021 Busan Dementia Prevention & Care Program. Participants with MCI received herbal medicine, acupuncture, and pharmacopuncture treatments over a 6-month period. The Montreal Cognitive Assessment (MoCA) was administered at baseline and after 3 and 6 months to evaluate cognitive function. Functional near-infrared spectroscopy (fNIRS) was used to measure prefrontal cortex activity during cognitive task performance, including verbal fluency, Stroop color and word, and digit span backward tests.ResultsSeventeen participants (13 female; mean age, 69.5 years) with MCI completed the study. Following the 6-month intervention, they exhibited a significant increase in the MoCA total score over time [F(2.32) =10.59, p < 0.0001]. Additionally, the deoxygenated hemoglobin beta coefficient in the left frontopolar prefrontal cortex significantly decreased during the Stroop task after the intervention.ConclusionThe Dementia Prevention & Care Program, which integrates herbal medicine and acupuncture, may enhance cognitive function in individuals with MCI. Moreover, the observed changes in prefrontal cortex activity after completion of the program suggest a need for further investigation of the underlying mechanisms.

IntroductionSystematic collection of diverse adverse events during herbal medicine administration is crucial. The Korea Adverse Event Reporting System (KAERS) compiles spontaneously reported adverse event data for medicinal products including herbal medicines. This study focused on extracting and analyzing adverse event data specifically related to herbal medicine products from the KAERS database.MethodsIndividual case safety reports (ICSRs) encompassing 84 types of herbal medicine products, identified by item codes from 2012 to 2021, were extracted from the KAERS database. Descriptive statistics were employed to analyze the characteristics of the extracted reports, and adverse event information was systematically categorized and analyzed based on the MedDRA System Organ Class and preferred term classification.ResultsIn total, 1,054 ICSRs were extracted, with some documenting multiple adverse events in a single ICSR, resulting in 1,629 extracted adverse events. When categorized by the MedDRA System Organ Class, gastrointestinal disorders were the most prevalent (28.7%), followed by skin and subcutaneous tissue disorders (20.1%). Based on the preferred terms, the most frequently reported adverse events were diarrhea (5.8%), urticaria (5.3%), pruritus (4.7%), rash (4.4%), and abdominal discomfort (4.2%). The most frequently reported herbal medicines were Bangpungtongseong-san (297 cases), Kyeongok-go (144 cases), and Eunkyo-san (108 cases).ConclusionSpontaneously reported adverse events associated with herbal medicine products were systematically documented using the KAERS database. This study, which focused on voluntarily reported adverse reactions, underscores the need for additional research to estimate the incidence rate of adverse events and assess causality.

BackgroundPersistent post-infectious symptoms, predominantly fatigue, characterize Long COVID. This study investigated the efficacy of Myelophil (MYP), which contains metabolites extracted from Astragalus membranaceus and Salvia miltiorrhiza using 30% ethanol, in alleviating fatigue among subjects with Long COVID.MethodsIn this prospective observational study, we enrolled subjects with significant fatigue related to Long COVID, using criteria of scores of 60 or higher on the modified Korean Chalder Fatigue scale (mKCFQ11), or five or higher on the Visual Analog Scale (VAS) for brain fog. Utilizing a single-arm design, participants were orally administered MYP (2,000 mg daily) for 4 weeks. Changes in fatigue severity were assessed using mKCFQ11, Multidimensional Fatigue Inventory (MFI-20), and VAS for fatigue and brain fog. In addition, changes in quality of life using the short form 12 (SF-12) were also assessed along with plasma cortisol levels.ResultsA total of 50 participants (18 males, 32 females) were enrolled; 49 were included in the intention-to-treat analysis with scores of 66.9 ± 11.7 on mKCFQ11 and 6.3 ± 1.5 on the brain fog VAS. After 4 weeks of MYP administration, there were statistically significant improvements in fatigue levels: mKCFQ11 was measured at 34.8 ± 17.1 and brain fog VAS at 3.0 ± 1.9. Additionally, MFI-20 decreased from 64.8 ± 9.8 to 49.3 ± 10.8, fatigue VAS dropped from 7.4 ± 1.0 to 3.4 ± 1.7, SF-12 scores rose from 53.3 ± 14.9 to 78.6 ± 14.3, and plasma cortisol levels also elevated from 138.8 ± 50.1 to 176.9 ± 62.0 /mL. No safety concerns emerged during the trial.ConclusionCurrent findings underline MYP’s potential in managing Long COVID-induced fatigue. However, comprehensive studies remain imperative.Clinical Trial Registrationhttps://cris.nih.go.kr, identifier KCT0008948.

Extrarenal clear cell renal cell carcinoma (eccRCC) is a rare type of RCC that arises in areas other than the kidney. Given its rarity, consensus guidelines for optimal treatment of eccRCC have not been established, and the literature is lacking any reports of patient response to systemic therapy and any reports of administration of immunotherapy to patients with ecRCC. Here, we present the case of a patient in their 60s with eccRCC arising in the spleen. The patient underwent splenic resection and then received systemic therapy, due to disease recurrence, with a combination of immunotherapy (IO) and tyrosine kinase inhibitor targeted therapy (VEGF-TKI). The patient had an excellent and durable response to this therapeutic regimen with minimal adverse effects, completing 2 years of therapy of nivolumab and cabozantinib. At the time of this report, the disease remains stable. This case demonstrates that combination therapy with IO+VEGF-TKI represents a reasonable and well-tolerated treatment option with activity in eccRCC and reveals interesting correlative data, including nests of stem-like CD8+T-cell infiltration in tumor tissue, which provide important biological context to this patient’s exceptional therapeutic response.

IntroductionParkinson’s disease (PD) is a representative neurodegenerative disease, and its diagnosis relies on the evaluation of clinical manifestations or brain neuroimaging in the absence of a crucial noninvasive biomarker. Here, we used non-targeted metabolomics profiling to identify metabolic alterations in the colon and plasma samples of Proteus mirabilis (P. mirabilis)-treated mice, which is a possible animal model for investigating the microbiota-gut-brain axis.MethodsWe performed gas chromatography–mass spectrometry to analyze the samples and detected metabolites that could reflect P. mirabilis-induced disease progression and pathology.Results and discussionPattern, correlation and pathway enrichment analyses showed significant alterations in sugar metabolism such as galactose metabolism and fructose and mannose metabolism, which are closely associated with energy metabolism and lipid metabolism. This study indicates possible metabolic factors for P. mirabilis-induced pathological progression and provides evidence of metabolic alterations associated with P. mirabilis-mediated pathology of brain neurodegeneration.

IntroductionHibiscus syriacus L. flower (HSF) is a food ingredient commonly used for tea, and previous animal studies have reported its sleep-promoting effect. This study aims to test the potential of HSF extract as functional food that improves sleep in humans.Methods and analysisEighty participants with sleep disturbances who meet the inclusion/exclusion criteria will be enrolled in this study. Since the effect of HSF extract on sleep is considered to be that of a functional food rather than a medicine, participants with severe insomnia will be excluded from the study. The enrolled participants will be randomly assigned to the HSF extract or placebo groups in a 1:1 ratio. The HSF extract and placebo capsules will look identical, and participants, investigators, and outcome assessors will be blinded to the allocation. Four capsules of HSF extract or placebo will be orally administered 30–60 min before bedtime for 4 weeks. The primary outcome of this study will be the change in the Pittsburgh Sleep Quality Index (PSQI) global score from the baseline after 4 weeks. The subjective and objective changes in the participants’ sleep will be evaluated using the Insomnia Severity Index (ISI), Epworth Sleep Scale (ESS), sleep diary, and polysomnography (PSG). The occurrence of adverse events will be closely monitored.DiscussionThe results of this trial will provide data on the efficacy and safety of HSF extract in enhancing sleep quality. Based on the results, the potential of HSF extract as a functional food that improves sleep in humans will be evaluated, and the findings of the trial will be submitted to the Korean Ministry of Food and Drug Safety for consideration as a new functional ingredient that may help to improve sleep quality.Clinical trial registration: Clinical Research Information Service: KCT0007314; Registered 19 May 2022, https://cris.nih.go.kr/cris/search/detailSearch.do/21497.

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease characterized by the deposition of amyloid-beta (Aβ) peptide and neurofibrillary tangles in the brain. The approved drug for AD has certain limitations such as a short period of cognitive improvement effect; moreover, the development of drug for AD therapeutic single target for Aβ clearance in brain ended in failure. Therefore, diagnosis and treatment of AD using a multi-target strategy according to the modulation of the peripheral system, which is not only limited to the brain, is needed. Traditional herbal medicines can be beneficial for AD based on a holistic theory and personalized treatment according to the time-order progression of AD. This literature review aimed to investigate the effectiveness of herbal medicine therapy based on syndrome differentiation, a unique theory of traditional diagnosis based on the holistic system, for multi-target and multi-time treatment of mild cognitive impairment or AD stage. Possible interdisciplinary biomarkers including transcriptomic and neuroimaging studies by herbal medicine therapy for AD were investigated. In addition, the mechanism by which herbal medicines affect the central nervous system in connection with the peripheral system in an animal model of cognitive impairment was reviewed. Herbal medicine may be a promising therapy for the prevention and treatment of AD through a multi-target and multi-time strategy. This review would contribute to the development of interdisciplinary biomarkers and understanding of the mechanisms of action of herbal medicine in AD.

Pattern identification (PI) is a diagnostic method used in Traditional East Asian medicine (TEAM) to select appropriate and personalized acupuncture points and herbal medicines for individual patients. Developing a reproducible PI model using clinical information is important as it would reflect the actual clinical setting and improve the effectiveness of TEAM treatment. In this paper, we suggest a novel deep learning-based PI model with feature extraction using a deep autoencoder and k-means clustering through a cross-sectional study of sleep disturbance patient data. The data were obtained from an anonymous electronic survey in the Republic of Korea Army (ROKA) members from August 16, 2021, to September 20, 2021. The survey instrument consisted of six sections: demographics, medical history, military duty, sleep-related assessments (Pittsburgh sleep quality index (PSQI), Berlin questionnaire, and sleeping environment), diet/nutrition-related assessments [dietary habit survey questionnaire and nutrition quotient (NQ)], and gastrointestinal-related assessments [gastrointestinal symptom rating scale (GSRS) and Bristol stool scale]. Principal component analysis (PCA) and a deep autoencoder were used to extract features, which were then clustered using the k-means clustering method. The Calinski-Harabasz index, silhouette coefficient, and within-cluster sum of squares were used for internal cluster validation and the final PSQI, Berlin questionnaire, GSRS, and NQ scores were used for external cluster validation. One-way analysis of variance followed by the Tukey test and chi-squared test were used for between-cluster comparisons. Among 4,869 survey responders, 2,579 patients with sleep disturbances were obtained after filtering using a PSQI score of >5. When comparing clustering performance using raw data and extracted features by PCA and the deep autoencoder, the best feature extraction method for clustering was the deep autoencoder (16 nodes for the first and third hidden layers, and two nodes for the second hidden layer). Our model could cluster three different PI types because the optimal number of clusters was determined to be three via the elbow method. After external cluster validation, three PI types were differentiated by changes in sleep quality, dietary habits, and concomitant gastrointestinal symptoms. This model may be applied to the development of artificial intelligence-based clinical decision support systems through electronic medical records and clinical trial protocols for evaluating the effectiveness of TEAM treatment.

Objectives: Emerging studies found the potential effects of acupuncture for treating chronic pain and mental disorders, namely, depressive and anxiety disorders. Acupuncture is widely used for treating culture-related anger syndrome, Hwa-byung. This pilot trial aimed to investigate the feasibility of a clinical trial testing acupuncture for the psychosomatic symptoms of Hwa-byung.Methods: A total of 26 patients with Hwa-byung planned to be randomly assigned to the acupuncture or sham acupuncture groups. About 10 treatment sessions were applied over 4 weeks. The 100-mm visual analog scale was used to measure the six major Hwa-byung symptoms: stuffiness in the chest, heat sensations, pushing-up in the chest, feeling a mass in the throat, feelings of unfairness, and hard feelings. The criteria for assessing the success of this pilot trial were defined as improvement in three or more of the six Hwa-byung symptoms after treatment, with an effect size >0.2.Results: A total of 15 patients were finally included and randomly assigned to the acupuncture group (n = 7) or the sham acupuncture group (n = 8). After 10 treatment sessions, the Cohen's d effect sizes for acupuncture compared to sham acupuncture were >0.2 for each one of the six major Hwa-byung symptoms, which met our a priori criteria for success. Also, the effect size for the somatic symptoms of “stuffiness in the chest” was 0.81 (95% CI −0.40, 2.20), referring to a large effect size.Conclusions: Our results suggest that acupuncture treatment would be regarded as an acceptable intervention for a full-scale study of psychosomatic symptoms in patients with Hwa-byung.Trial Registration:cris.nih.go.kr, identifier: KCT0001732.

Five types of Escherichia coli strains were obtained and sequenced: colistin-susceptible (CL-S) strains, in vitro induced colistin-resistant (CL-IR) strains, mcr-1-negative colistin-resistant strains from livestock (CL-chrR), mcr-1-positive colistin-resistant strains (CL-mcrR), and mcr-1-transferred transconjugants (TC-mcr). Amino acid alterations of PmrAB, PhoPQ, and EptA were identified, and their mRNA expression was measured. Their growth rate was evaluated, and an in vitro competition assay was performed. Virulence was compared through serum resistance and survival in macrophages and Drosophila melanogaster. CL-IR and CL-chrR strains were colistin-resistant due to amino acid alterations in PmrAB, PhoPQ, or EptA, and their overexpression. All colistin-resistant strains did not show reduced growth rates compared with CL-S strains. CL-IR and CL-chrR strains were less competitive than the susceptible strain, but CL-mcrR strains were not. In addition, TC-mcr strains were also significantly more competitive than their respective parental susceptible strain. CL-IR strains had similar or decreased survival rates in human serum, macrophages, and fruit flies, compared with their parental, susceptible strains. CL-chrR strains were also less virulent than CL-S strains. Although CL-mcrR strains showed similar survival rates in human serum and fruit fly to CL-S strains, the survival rates of TC-mcr strains decreased significantly in human serum, macrophages, and fruit flies, compared with their susceptible recipient strain (J53). Chromosome-mediated, colistin-resistant E. coli strains have a fitness cost, but plasmids bearing mcr-1 do not increase the fitness burden of E. coli. Along with high usage of polymyxins, the no fitness cost of mcr-1-positive strains may facilitate rapid spread of colistin resistance.