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Malnutrition-inflammation-atherosclerosis (MIA) syndrome is a significant risk factor for mortality in patients undergoing hemodialysis. This study aimed to investigate the association between MIA syndrome and oral health status in hemodialysis patients. A cross-sectional study was conducted on 254 hemodialysis patients. Comprehensive medical and dental examinations were performed. Three components were included to define MIA syndrome: Geriatric Nutritional Risk Index, serum high-sensitivity C-reactive protein, and history of cardiovascular events as indicators of malnutrition, inflammation, and atherosclerosis, respectively. The association of MIA syndrome components with periodontitis and occlusal support was examined by multiple-ordered logistic regression analysis. Of 254 participants, 188 (74.0%) had at least one component of MIA syndrome. After adjusting for possible confounding factors, severe periodontitis was significantly associated with presence of more components of MIA syndrome (odds ratio [OR]: 2.64, 95% confidence interval [CI], 1.44-4.84, p = 0.002) and inflammation and malnutrition components (OR: 2.47 and 3.46, 95% CI 1.16-5.28 and 1.70-7.05, p = 0.020 and 0.001). On the other hand, occlusal support, evaluated by Eichner index, was not significantly associated with MIA syndrome or any of its components. In conclusion, periodontitis is associated with MIA syndrome, particularly with inflammation and malnutrition in hemodialysis patients, independent of occlusal support.

Background: This study aimed to investigate the effects of low‐level erbium‐doped: yttrium, aluminum, and garnet (Er:YAG) laser irradiation on periodontal tissue healing and regeneration through angiogenesis in vivo and in vitro studies. Methods: Intrabony defects were surgically created in the bilateral maxilla molar of rats. The defects were treated by open flap debridement (OFD) with Er:YAG laser, including low‐level laser irradiation (LLLI) to bone and blood clot surfaces, or conventional procedures. The mRNA expression of vascular endothelial growth factor (VEGF) in the surgical sites was quantified using real‐time polymerase chain reaction. The decalcified specimens were prepared for histometric analysis. Also, LLLI was performed on human umbilical vein endothelial cells to evaluate the effects on angiogenesis. Cell proliferation, VEGF expression, and tube formation were assessed. In addition, capsazepine (CPZ), a selective inhibitor of transient receptor potential vanilloid 1 (TRPV1), treatment was performed before LLLI for the same assays. Results: OFD using Er:YAG laser did not generate thermal damage on bone or root surfaces. LLLI accelerated hemostasis by coagulation of the superficial layers of blood clots in the laser‐treated group. Postoperative healing was sound in all animals in both groups. VEGF expression and bone formation were significantly increased in the laser‐treated group compared to those in the conventional treatment group. In vitro, cell proliferation and VEGF expression were significantly increased in the LLLI group compared to the control group. Tube‐formation assays showed that LLLI significantly promoted angiogenesis. CPZ treatment significantly suppressed VEGF expression and tube formation following LLLI. Conclusions: This study suggests that Er:YAG laser irradiation may promote periodontal tissue healing by enhancing angiogenetic effect of endothelial cells via TRPV1. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the mechanisms underlying the impaired healing response by diabetes after periodontal therapy. Background: Outcomes of periodontal therapy in patients with diabetes are impaired compared with those in patients without diabetes. However, the mechanisms underlying impaired healing response to periodontal therapy have not been sufficiently investigated. Materials and Methods: Zucker diabetic fatty (ZDF) and lean (ZL) rats underwent experimental periodontitis by ligating the mandibular molars for one week. The gingiva at the ligated sites was harvested one day after ligature removal, and gene expression was comprehensively analyzed using RNA‐Seq. In patients with and without type 2 diabetes (T2D), the corresponding gene expression was quantified in the gingiva of the shallow sulcus and residual periodontal pocket after non‐surgical periodontal therapy. Results: Ligation‐induced bone resorption and its recovery after ligature removal were significantly impaired in the ZDF group than in the ZL group. The RNA‐Seq analysis revealed 252 differentially expressed genes. Pathway analysis demonstrated the enrichment of downregulated genes involved in the peroxisome proliferator‐activated receptor (PPAR) signaling pathway. PPARα and PPARγ were decreased in mRNA level and immunohistochemistry in the ZDF group than in the ZL group. In clinical, probing depth reduction was significantly less in the T2D group than control. Significantly downregulated expression of PPARα and PPARγ were detected in the residual periodontal pocket of the T2D group compared with those of the control group, but not in the shallow sulcus between the groups. Conclusions: Downregulated PPAR subtypes expression may involve the impaired healing of periodontal tissues by diabetes. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract harbors trillions of microorganisms known to influence human health and disease, and next-generation sequencing (NGS) now enables the in-depth analysis of their diversity and functions. Although a significant amount of research has been conducted on the GI microbiome, comprehensive metagenomic datasets covering the entire tract are scarce due to cost and technical challenges. Despite the widespread use of fecal samples, integrated datasets encompassing the entire digestive process, beginning at the mouth and ending with feces, are lacking. With this study, we aimed to fill this gap by analyzing the complete metagenome of the GI tract, providing insights into the dynamics of the microbiota and potential therapeutic avenues. In this study, we delved into the complex world of the GI microbiota, which we examined in five healthy Japanese subjects. While samples from the whole GI flora and fecal samples provided sufficient bacteria, samples obtained from the stomach and duodenum posed a challenge. Using a principal coordinate analysis (PCoA), clear clustering patterns were identified; these revealed significant diversity in the duodenum. Although this study was limited by its small sample size, the flora in the overall GI tract showed unwavering consistency, while the duodenum exhibited unprecedented phylogenetic diversity. A visual heat map illustrates the discrepancy in abundance, with Fusobacteria and Bacilli dominating the upper GI tract and Clostridia and Bacteroidia dominating the fecal samples. Negativicutes and Actinobacteria were found throughout the digestive tract. This study demonstrates that it is possible to continuously collect microbiome samples throughout the human digestive tract. These findings not only shed light on the complexity of GI microbiota but also provide a basis for future research. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the effects of diabetes care on periodontal inflammation. Materials and Methods: This prospective cohort study included 51 Japanese patients with type 2 diabetes who underwent intensive diabetes care including educational hospitalization and regular outpatient treatment for 6 months. Dental prophylaxis without subgingival scaling was provided three times during the observational period. Associations between changes in periodontal parameters and glycaemic control levels were evaluated using multiple regression analysis. Results: Overall, 33 participants (mean age: 58.7 ± 12.9) were followed up for 6 months. At baseline examination, 82% were diagnosed with Stage III or IV periodontitis. Haemoglobin A1c (HbA1c) level changed from 9.6 ± 1.8% at baseline to 7.4 ± 1.3% at 6 months. The ratio of probing pocket depth (PPD) ≥4 mm, bleeding on probing (BOP), full‐mouth plaque control record (PCR), periodontal epithelial surface area (PESA) and periodontal inflamed surface area (PISA) also significantly improved. The reduction in PPD and PESA was significantly associated with changes in both HbA1c and fasting plasma glucose (FPG) levels, and the reduction in PISA was significantly associated with an improvement in FPG after adjusting for smoking, change in body mass index and full‐mouth PCR. Conclusions: This is the first study to report a significant improvement in PPD and BOP after intensive diabetes care and dental prophylaxis without subgingival scaling. Clinical trial registration number: UMIN000040218. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is associated with periodontal disease. Clinically, periodontal treatment is less effective for patients with DM. Oxidative stress is one of the mechanisms that link DM to periodontitis. The production of reactive oxygen species (ROS) is increased in the periodontal tissues of patients with DM and is involved in the development of insulin resistance in periodontal tissues. Insulin resistance decreases Akt activation and inhibits cell proliferation and angiogenesis. This results in the deterioration of wound healing and tissue repair in periodontal tissues. Antioxidants and insulin resistance ameliorants may inhibit ROS production and improve wound healing, which is worsened by DM. This manuscript provides a comprehensive review of the most recent basic and clinical evidence regarding the generation of ROS in periodontal tissues resulting from microbial challenge and DM. This study also delves into the impact of oxidative stress on wound healing in the context of periodontal and dental implant therapies. Furthermore, it discusses the potential benefits of administering antioxidants and anti-insulin resistance medications, which have been shown to counteract ROS production and inflammation. This approach may potentially enhance wound healing, especially in cases exacerbated by hyperglycemic conditions. [ABSTRACT FROM AUTHOR]

Background: The origin of hangekobokuto (HKT) is from Jin Gui Yao Lue (Kinkiyōryaku in Japanese), and it has been indicated for treating throat discomfort in women. Key Findings: HKT consists of five crude drugs. Clinical studies have shown that HKT can improve the swallowing reflex by increasing the substance P level in saliva; improve the cough reflex; reduce pneumonia in patients with dementia, cerebrovascular disease, Alzheimer's disease, or Parkinson's disease; reduce postoperative aspiration pneumonia in patients who undergo cardiovascular surgery; and improve depression and anxiety scores in patients with globus hystericus. Furthermore, HKT has been reported to increase serotonin (5‐HT) and noradrenaline levels in the hypothalamus, and dopamine (DA) levels in the striatum in a healthy rodent model; improve 5‐HT levels in the striatum and hippocampus, and ameliorate 5‐HT and DA reductions in the whole brain in an acute stress model; improve 5‐HT levels in the striatum, and ameliorate 5‐HT and DA reductions in the prefrontal cortex in a chronic stress model; and decrease corticosterone and corticotropin‐releasing factor levels in a chronic stress model. Reported adverse events of HKT include interstitial pneumonia (0.38 per 100 000 cases) and liver damage (0.89 per 100 000 cases), which are rare. Conclusion: HKT is widely used and shows a low rate of adverse events. Several clinical studies have reported its effects in reducing aspiration pneumonia and improving depression and anxiety, some of which may be explained by the regulation of monoamines and stress hormones in the brain and substance P levels in the oral cavity. [ABSTRACT FROM AUTHOR]

Background: "Long COVID" or "post‐COVID conditions" describes prolonged symptoms after the acute phase of coronavirus disease 2019 (COVID‐19). However, there is a paucity of published reports on its treatment. Method: This retrospective cohort study included adult, non‐hospitalized patients with COVID‐19 symptoms at least one month after the onset who had been examined at the isolation facility in Miyagi prefecture between October 2020 and September 2021. Results: In total, 70 patients with a median age of 46 (21–69) years were included, and 37 were women (52.9%). The median time from onset to the end of treatment was 46 (28–396) days. Thirty‐eight patients (53.5%) showed improvement in all symptoms, while four (5.7%) did not recover within the study period. The symptoms at six months with high residual rates were dizziness (33.3%), fatigue (14.3%), myalgia (14.3%), abdominal discomfort (14.3%), and taste dysfunction (11.8%). For treatment of prolonged symptoms, formulae of Kampo medicine (Japanese traditional medicine) were used alone or in combination with Western medications in 76%, 66%, 53%, and 66% of patients at 1–2 months, 2–3 months, 3–6 months, and over 6 months respectively. Kampo formulae with anti‐inflammatory effects were used in the early period; however, tonifying formulae and blood stasis‐resolving formulae were used in the late period. Conclusion: Non‐hospitalized patients with COVID‐19 may suffer from persistent symptoms after the acute phase of infection. For the management of long COVID, a comprehensive and holistic approach is needed. Kampo medicine should be considered as a treatment option for long COVID. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) induces microangiopathy in various tissues, leading to several complications. However, limited studies have reported the impact of diabetes on gingival capillaries. The aim of this study was to investigate the morphological evaluation and to analyze the influence of diabetes on gingival capillaries. Medical interviews and periodontal examinations were performed on 29 patients with periodontitis. The subjects were divided into two groups: those with or without type 2 diabetes (DM or non-DM group). Gingival capillary density and morphology in the buccal marginal gingiva were evaluated using a capillary blood flow scope (magnification: × 560). Probing pocket depth, plaque index, and gingival index were not significantly different between the DM and non-DM groups. The mean HbA1c was 7.9 ± 1.5% in the DM group (n = 14). Using an oral moisturizing gel as immersion agent, gingival capillaries can be observed under high magnification. The gingival capillary density was 10.5 ± 3.9/mm2 and 9.1 ± 2.7/mm2 in the non-DM group and DM group, respectively. There were no significant differences between the groups. Gingival capillary density was not significantly associated with probing pocket depth, plaque index, or gingival index. The proportion of capillary morphological abnormalities was significantly higher in the DM group than non-DM group. However, capillary morphological abnormalities were not significantly associated with the HbA1c. The present study first documented the morphological abnormalities of gingival capillaries in patients with type 2 diabetes using the capillary blood flow scope. Gingival capillary density might not be affected by diabetes. [ABSTRACT FROM AUTHOR]

Background: Diabetes involves metabolic disorders in various tissues via hyperglycemia-induced oxidative stress. This study aimed to investigate the antioxidative effect of enamel matrix derivative (EMD) on periodontal regeneration in diabetes.Methods: Twenty-two rats were equally divided into streptozotocin (STZ)-induced diabetes or control group. Two months after induction of hyperglycemia, systemic oxidative stress was measured using urinary 8-hydroxy-2'-deoxyguanosine. EMD or saline was applied into the intrabony defects created in the bilateral maxillary molar. mRNA expressions of inflammatory and oxidative stress markers were quantified (n = 6). Histometric analyses and immunohistochemistry of superoxide dismutase-1 (SOD-1) were performed 7 days postoperatively (n = 5). For in vitro experiments, the bone marrow-derived mesenchymal stem cells were isolated from rat femur and cultured in a high glucose (HG) or control medium. Reactive oxygen species (ROS) measurement and alizarin red staining were performed with/without EMD.Results: Systemic oxidative stress was significantly higher in the diabetic group. The connective tissue attachment and cementum formation were significantly increased at EMD-treated sites in both diabetic and non-diabetic groups. The expression of nicotinamide adenine dinucleotide phosphate oxidase two and four was significantly lower at EMD-treated sites than at EMD-untreated sites in both diabetic and non-diabetic rats. Immunohistochemistry showed significantly higher SOD-1 expression at the EMD-treated site. In vitro, HG culture had significantly higher ROS production compared with control, which was downregulated by EMD. EMD treatment significantly recovered the impaired calcification in HG.Conclusion: EMD promoted early-phase wound healing and periodontal tissue regeneration in the surgically created bony defect of STZ-induced diabetic rat by suppressing hyperglycemia-induced oxidative stress. [ABSTRACT FROM AUTHOR]

Disruption of eshA, which encodes a 52-kDa protein that is produced late during the growth of Streptomyces coelicolor A3(2), resulted in elimination of actinorhodin production. In contrast, disruption of eshB, a close homologue of eshA, had no effect on antibiotic production. The eshA disruptant accumulated lower levels of ppGpp than the wild-type strain accumulated. The loss of actinorhodin production in the eshA disruptant was restored by expression of a truncated relA gene, which increased the ppGpp level to the level in the wild-type strain, indicating that the reduced ppGpp accumulation in the eshA mutant was solely responsible for the loss of antibiotic production. Antibiotic production was also restored in the eshA mutant by introducing mutations into rpoB (encoding the RNA polymerase [3 subunit) that bypassed the requirement for ppGpp, which is consistent with a role for EshA in modulating ppGpp levels. EshA contains a cyclic nucleotide-binding domain that is essential for its role in triggering actinorhodin production. EshA may provide new insights and opportunities to unravel the molecular signaling events that occur during physiological differentiation in streptomycetes.

This study is focused on the involvement of the unusual nucleotide (p)ppGpp during the morphological and physiological differentiation of Streptomyces clavuligerus. In particular, the functional and structural elements of two genes encoding the proteins RelA and Rsh were identified. The relA gene encodes an 843 aa protein (RelA), while the rsh gene encodes a 738 aa protein (Rsh). The relA and rsh genes were disrupted by the insertion of a hygromycin resistance gene and an apramycin resistance gene, respectively. The synthesis of ppGpp in the relA gene-disrupted mutant was completely eliminated under conditions of starvation for amino acids, whereas synthesis persisted, but was greatly reduced in the rsh gene-disrupted mutant. The relA gene-disrupted mutant had a bald appearance on agar plate cultures and retarded growth in submerged culture, while the rsh-disrupted mutant was unchanged in growth characteristics relative to the wild-type culture. The production of both clavulanic acid and cephamycin C were completely abolished in the relA-disrupted mutant. Thus, it is concluded that the relA gene rather than rsh is essential for morphological and physiological differentiation in S. clavuligerus and that RelA primarily governs the stringent response of S. clavuligerus to starvation for amino acids.

Background: Limited evidence are available regarding the influence of diabetes on periodontitis in hemodialysis patients, although the association between diabetes and periodontal disease is well-known. Objective: This study aimed to investigate the influence of type 2 diabetes mellitus (T2D) and its control level on periodontal disease and the number of missing teeth in patients undergoing hemodialysis. Subjects and methods: A single-center cross-sectional study was conducted on 246 Japanese patients with end-stage renal disease undergoing hemodialysis. Comprehensive medical and dental examinations were performed. The association between severity of periodontitis and T2D was examined by multiple ordered logistic regression analysis. A multiple linear regression model was fitted to assess the association of periodontal probing depth (PPD) ≥4 mm and the number of missing teeth with T2D (n = 125). A subgroup analysis involving only the patients with T2D was performed to investigate the factors associated with missing teeth among them. Results: After adjusting for confounders, the classification of periodontitis severity was significantly advanced in patients with T2D (odds ratio: 1.64, 95% confidence interval [CI]: 1.02–2.65, p = 0.04). The proportion of PPD≥4 mm sites and the number of missing teeth was significantly associated with T2D (coefficient: 4.1 and 5.7, 95% CI: 0.2–8.0 and 3.4–8.0, p = 0.04 and <0.001, respectively). Subgroup analysis of T2D patients revealed that glycoalbumin levels (coefficient: 0.4, 95% CI: 0.03–0.80, p = 0.03), but not hemoglobin A1c levels (coefficient: 0.8, 95% CI: -1.0–2.7, p = 0.37), were significantly associated with the number of missing teeth. Conclusion: T2D was significantly associated with periodontitis and the number of missing teeth in hemodialysis patients. Moreover, it is first documented that poor glycemic control, as determined by glycoalbumin levels, was significantly associated with the number of missing teeth in hemodialysis patients with T2D. [ABSTRACT FROM AUTHOR]

Research has been conducted on the 52-kDa protein from Streptomyces coelicolor A3(2) recovered in the sediment after ultracentrifugation. Results of the molecular and functional analysis of this protein have been examined and described.

Objective: Few studies have reported on the impact of oxidative stress on the dental implant failure. The aim of this study was to investigate the impact of hyperglycemia‐induced oxidative stress on dental implant osseointegration in diabetes mellitus (DM). Methods: Acid‐treated titanium implants were bilaterally placed in the maxillary alveolar ridge of streptozotocin‐induced diabetic (DM group) and control rats after extraction of first molars. Histological analysis and micro‐push‐out test were performed 4 weeks after surgery. Oxidative stress and osteogenic markers in the surrounding bone were quantified by real‐time polymerase chain reaction. In the in vitro study, rat bone marrow‐derived mesenchymal stem cells (BMMSCs) were cultured on acid‐treated titanium discs in a high‐glucose (HG) or normal environment. Intracellular reactive oxygen species (ROS), cell proliferation, alkaline phosphatase (ALP) activity, and extracellular calcification were evaluated following antioxidant treatment with N‐acetyl‐L‐cysteine (NAC). Results: The implant survival rate was 92.9% and 75.0% in control and DM group, respectively. Bone‐implant contact and push‐out loads were significantly lower in the DM group. Expression of superoxide dismutase 1 at the mRNA level and on immunohistochemistry was significantly lower in the DM group. In vitro experiments revealed that the HG condition significantly increased ROS expression and suppressed the proliferation and extracellular calcification of BMMSCs, while NAC treatment significantly restored ROS expression, cell proliferation, and calcification. The ALP activity of both groups was not significantly different. Conclusion: In diabetes, high‐glucose‐induced oxidative stress downregulates proliferation and calcification of BMMSCs, impairing osseointegration and leading to implant failure. [ABSTRACT FROM AUTHOR]

Background: Olfactory dysfunction is a common symptom in patients with coronavirus disease 2019, and it significantly deteriorates patients' quality of life. Effective treatments remain unknown. Purpose: To assess the effect of Japanese traditional (Kampo) medicine on coronavirus disease 2019-related olfactory dysfunction. Study Design: Retrospective observational study. Methods: In total, 87 patients aged ≥18 years with coronavirus disease 2019 and severe dysosmia or anosmia (Numeric Rating Scale, ≥7) at isolation facilities in Miyagi Prefecture, Japan, were enrolled from October 2020 to March 2021. Patients were divided into the Kampo group (N = 52) and the control group (N = 35) based on the treatment received. Changes in Numeric Rating Scale scores were evaluated at the first visit and 2 weeks after. Results: The median reduction in the olfactory dysfunction score at both 1 and 2 weeks after the first visit was significantly greater in the Kampo group (6 and 8, respectively; p = 0.03) than in the control group (3 and 7, respectively; p = 0.04). We defined improvement in olfactory dysfunction as a median reduction in the olfactory dysfunction score of ≥5. Multiple logistic regression analysis demonstrated that only Kampo treatment was significantly associated with improvement in olfactory dysfunction. Conclusion: This study suggests that Kampo medication promotes early recovery from coronavirus disease 2019-related olfactory dysfunction. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the effects of metformin on gingival wound healing in insulin-resistant prediabetes.Methods: C57BL/6J mice were fed normal diet (ND) or high-fat diet (HFD) for 10 weeks; half of the HFD mice were treated with metformin (HFD+ Met) for the last 2 weeks. Insulin and glucose tolerance tests were performed. The palatal gingiva (2.0 × 0.5 mm) was surgically removed adjacent to the maxillary molars. Post-surgical wound closure was histomorphometrically evaluated for 1 week. The mRNA expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in the tissue were quantified by real-time polymerase chain reaction. In vitro, the proliferation and migration of human gingival fibroblasts (HGFs) cultured under high-glucose or control conditions with/without metformin were analyzed. Akt phosphorylation and VEGF expression following the insulin stimulation were evaluated with/without metformin in high-glucose or control media.Results: HFD mice showed significantly higher plasma glucose levels and insulin resistance than ND mice. Gingival wound healing was delayed in HFD group compared with ND group but significantly improved in HFD + MET group. The decreased expression of VEGF and eNOS in HFD group was significantly elevated in the HFD + MET group. The proliferation and migration of HGFs were significantly impaired in high-glucose conditions compared with control; metformin treatment partially attenuated these effects. Metformin treatment significantly recovered the downregulated Akt phosphorylation and VEGF expression in high-glucose conditions.Conclusions: Metformin improved delayed gingival wound healing in insulin-resistant prediabetes by accelerating HGFs proliferation and migration via Akt phosphorylation in insulin signaling pathway. [ABSTRACT FROM AUTHOR]

Rhinovirus (RV) is a primary etiologic agent of common cold that can subsequently acutely exacerbate bronchial asthma or chronic obstructive pulmonary disease. Kakkonto (Ge-gen-tang in Chinese), one of the most frequently prescribed traditional Japanese (Kampo) medicines, is used for treating common cold, shoulder stiffness, or inflammatory diseases of the upper body. Previous experimental studies have indicated that kakkonto exerts antiviral and anti-inflammatory effects on the influenza virus and the human respiratory syncytial virus. However, there is a lack of reports investigating the efficacy of kakkonto in RV infection. Hence, the aim of the current study was to investigate the effects of kakkonto on RV infection of human nasal epithelial (HNE) cells. HNE cells obtained via endoscopic sinus surgery were cultured and infected with RV14, with or without kakkonto treatment. The supernatants from the cells were collected, and the RV14 titer and cytokine levels were assessed. Reverse transcription-polymerase chain reaction was performed to determine the amount of viral RNA, while the level of nuclear factor kappa B (NF-κB) subunits in the nucleus was assessed by enzyme-linked immunosorbent assay. Although kakkonto treatment did not reduce RV14 titer or RNA levels, indicating that it did not inhibit RV14 proliferation, it was found to reduce the production of specific pro-inflammatory cytokines, including interleukin (IL)-8, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein-1 (MCP-1). Unlike that observed with the kakkonto extract, none of the crude drugs contained in kakkonto reduced IL-8 level. Furthermore, though kakkonto treatment significantly reduced p50 levels, it did not impact the p65 subunit of NF-κB. These results indicated that kakkonto can inhibit inflammation caused by RV infection and may exert an immunomodulatory effect on HNE cells. This is the first report to elucidate the effects of kakkonto extract on RV infection in primary cultures of HNE cells, providing evidence that kakkonto may act as an effective therapy for RV infection and subsequent airway inflammation. [ABSTRACT FROM AUTHOR]

Acetate overflow refers to the metabolism by which a large part of carbon incorporated as glucose into Escherichia coli cells is catabolized and excreted as acetate into the medium. We previously found that mutants for the acetate overflow pathway enzymes phosphoacetyltransferase (Pta) and acetate kinase (AckA) showed significant diauxic growth after glucose depletion in E. coli. Here, we analyzed the underlying mechanism in the pta mutant. Proteomic and other analyses revealed an increase in pyruvate dehydrogenase complex subunits and a decrease in glyoxylate shunt enzymes, which resulted from pyruvate accumulation. Since restoration of these enzyme levels by overexpressing PdhR (pyruvate‐sensing transcription factor) or deleting iclR (gene encoding a pyruvate‐ and glyoxylate‐sensing transcription factor) alleviated the growth lag of the pta mutant after glucose depletion, these changes were considered as the reason for the phenotype. Given the evidence for decreased coenzyme A (HS‐CoA) levels in the pta mutant, the growth inhibition after glucose depletion was partly explained by limited availability of HS‐CoA in the cell. The findings provide insights into the role of acetate overflow in metabolic regulation, which may be useful for biotechnological applications. [ABSTRACT FROM AUTHOR]

Abstract Background With the advent of metabolomics as a powerful tool for both functional and biomarker discovery, the identification of specific differences between complex metabolite profiles is becoming a major challenge in the data analysis pipeline. The task remains difficult, given the datasets' size, complexity, and common shifts in migration (elution/retention) times between samples analyzed by hyphenated mass spectrometry methods. Results We present a Mathematica (Wolfram Research, Inc.) package MathDAMP (Mathematica package for Differential Analysis of Metabolite Profiles), which highlights differences between raw datasets acquired by hyphenated mass spectrometry methods by applying arithmetic operations to all corresponding signal intensities on a datapoint-by-datapoint basis. Peak identification and integration is thus bypassed and the results are displayed graphically. To facilitate direct comparisons, the raw datasets are automatically preprocessed and normalized in terms of both migration times and signal intensities. A combination of dynamic programming and global optimization is used for the alignment of the datasets along the migration time dimension. The processed datasets and the results of direct comparisons between them are visualized using density plots (axes represent migration time and m/z values while peaks appear as color-coded spots) providing an intuitive overall view. Various forms of comparisons and statistical tests can be applied to highlight subtle differences. Overlaid electropherograms (chromatograms) corresponding to the vicinities of the candidate differences from any result may be generated in a descending order of significance for visual confirmation. Additionally, a standard library table (a list of m/z values and migration times for known compounds) may be aligned and overlaid on the plots to allow easier identification of metabolites. Conclusion Our tool facilitates the visualization and identification of differences between complex metabolite profiles according to various criteria in an automated fashion and is useful for data-driven discovery of biomarkers and functional genomics.

Aim: We present the study protocol of a multicenter, retrospective observational study that aims to investigate the efficacy of the actual treatment (the efficacy of conventional and Kampo medicines) of patients with mild to moderate or suspected coronavirus disease (COVID‐19). Methods: This study is designed as a multicenter, retrospective observational study. Outpatients and inpatients will be recruited from Japanese hospitals. The inclusion criteria are as follows: having or suspected to have COVID‐19, mild to moderate COVID‐19, symptomatic, ≥20 years of age, male or female, able to communicate in Japanese, and treated with conventional and Kampo medicine. The exclusion criteria are: unable to provide informed consent due to dementia, psychosis, or psychiatric symptoms, severe COVID‐19, or determined unsuitable for this study. The sample size is set at 1000, as this number of people can be treated at the collaborating medical institutions during the study period. Results: The main outcome is the number of days without fever, with a body temperature of less than 37°C. The secondary outcome is set at common cold‐like symptoms other than fever (fatigue, cough, shortness of breath, sputum, diarrhea) and severity of illness and hospitalization up to 14 days after the visit. Trial registration: The trial was registered in the University Hospital Medical Information Network (Reservation No. UMIN000041301) on August 4, 2020. Conclusion: Our study will explore the contribution of conventional and Kampo medicine in the treatment of patients with mild and moderate COVID‐19. [ABSTRACT FROM AUTHOR]

Aim: Traditional Japanese (Kampo) medicine has been used to treat viral infectious diseases. In particular, saikatsugekito (a combination drug of kakkonto, shosaikoto, Platicodon glandiflorum root, and gypsum) has been reported to be useful during the past influenza pandemic. The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has spread worldwide, causing the novel coronavirus disease (COVID‐19) to emerge as a pandemic. In this article, we conducted a literature review on the pharmacological activities of the components present in saikatsugekito against viral infection and respiratory inflammation. Methods: We searched PubMed and the Cochrane Library for English articles, as well as Ichushi and J‐stage for Japanese articles. Articles published until January 1, 2000 were retrieved using the keywords 'kakkonto', 'shosaikoto', 'Platycodon', and 'gypsum'. We then extracted articles on basic research investigating viral infections, inflammation, cytokine, the immune response, and lung tissue damage. Results: We extracted 28 eligible articles. Kampo medicines have antiviral activities by interfering with the attachment, internalization, replication, progeny virion release, and cell‐to‐cell spreading of single‐strand RNA viruses. They also enhance the immunomodulating activities of the host, including cytokine production, regulation of multiple immune cells, and protection from lung tissue injury. Furthermore, Kampo medicine has been found to regulate body temperature and airway mucin release. Conclusion: The results demonstrated that Kampo medicine has therapeutic activities against single‐strand RNA virus infections and respiratory inflammation, and may also have activities against SARS‐CoV‐2. Further research is required to investigate the activity of Kampo medicines, such as saikatsugekito, against SARS‐CoV‐2. [ABSTRACT FROM AUTHOR]

Alopecia has several causes, but its relationship with ischemia/hypoxia has not yet been investigated in detail. In this study, we studied the changes of hair follicles induced by ischemia and potential effects of normobaric hyperoxygenation (NBO) on the hair cycle and growth. We found that skin ischemia reduced hair growth rate, hair shaft size, and its pigmentation in the anagen phase of mice, which may reflect an aspect of pathophysiology of hair loss (alopecia) and depigmentation (gray/white hairs). Hyperoxygenation increased hair growth rate in organ culture of both human and murine hair follicles. Systemic NBO promoted hair growth in early anagen and mid-anagen, and delayed catagen onset in mice. However, telogen-to-anagen transition was not affected by NBO as far as non-ischemic skin is concerned. The results of this study indicated that the hair follicle is very sensitive to oxygen tension and oxygen tension affects the regulation of hair growth and cycle in vitro and in vivo. It was suggested that systemic NBO can be safely applied for a long period and can be a noninvasive therapeutic approach to alter hair growth and cycle by manipulating the microenvironment of hair follicles. [ABSTRACT FROM AUTHOR]

Background: A recent investigation reported that 92.7% Japanese family physicians have prescribed Kampo medicine (KM). KM can treat a wide variety of conditions from mental disorders to physical weaknesses. However, the characteristics and course of patients treated with KM at the Department of General Medicine remain unclear. Aims: To investigate the characteristics and course of patients treated with KM in our hospital. Methods: Data on medical history, complaints, course after Kampo treatment, and Hamilton Depression Rating Scale (HAM‐D) scores were retrogradely collected. The background of patients who received Kampo treatment was compared to that of patients who did not. Result: Of 362 patients, 51 were treated with KM. Symptoms for which KM was prescribed included pain, general malaise, or sensory disturbance of extremities. All patients treated with KM were screened and initially diagnosed with a functional disorder or noncritical condition. KM including a crude drug of saiko such as hochuekkito, shigyakusan, shosaikoto, and yokukansan, was frequently prescribed for patients. Subjective symptoms showed improvement (53%) and no change (47%), while worsening was not observed in any patient. HAM‐D scores showed that patients treated with KM had higher anxiety levels and related symptoms as well as a higher frequency of mental disorders prior to presenting at the hospital. Conclusion: Most complaints of the patients treated with KM were pain, general malaise, and sensory disturbance. KM is more likely to be prescribed in patients with health‐related anxiety or a history of mental disorders. [ABSTRACT FROM AUTHOR]

Aim: Traditional Japanese (kampo) medicine has recently been included in the medical education curriculum in Japan; hence, an education program in kampo physical examination for beginners is needed. The aim of the present study was to develop an education program using a simulator of kampo abdominal palpation that would enable beginners to acquire this skill, and to assess the effectiveness and usefulness of the education program. Methods: First, we conducted a preliminary trial. Fifteen beginners received a lecture about abdominal findings and the associated representative kampo formulas and underwent a simulator palpation test. Following this trial, we created and conducted a 1 day education program as a prospective study. The program included a general lecture on physical examination in kampo medicine, followed by a pre‐test assessment involving palpation of the simulators, a specific lecture about abdominal palpation, and finally a post‐test assessment. The pre‐ and post‐test accuracy rates were evaluated. Results: High accuracy rates were obtained in the preliminary trial, but the research protocol did not enable an assessment of the effectiveness or usefulness of the trial. In the subsequent education program, 41 participants had significantly higher accuracy rates after the lecture than before the lecture, in both abdominal findings (from 78.2% to 94.4% on average, P < 0.001) and in the associated representative kampo formulas (from 21.8% to 59.7% on average, P < 0.001). Conclusion: An education program using simulators for kampo abdominal palpation can be effective and useful for beginners in kampo medicine. [ABSTRACT FROM AUTHOR]

Aim: Daisaikoto has been used for the treatment of shoulder stiffness and abdominal distention with constipation, which makes stool changes associated with the prescription a concern. The aim of this retrospective observational study was to investigate the effect of daisaikoto on shoulder stiffness and the relation between its effects on stiffness relief and stool condition. Methods: We reviewed the medical records of middle‐aged women who were treated with daisaikoto for menopause‐like symptoms and shoulder stiffness from December 2014 through November 2015 at Red Cross Maebashi Hospital. Two or 4 weeks after the prescription of daisaikoto, symptoms were evaluated and categorized as improved, no change, or worse. Stool condition was also evaluated and categorized as constipation, normal, or diarrhea. Change in symptoms from before to after treatment was analyzed using the Wilcoxon signed‐rank test. The relationship between symptom changes and stool condition was analyzed using Spearman's rank correlation coefficient. Results: Of 24 patients who received daisaikoto, shoulder stiffness was relieved in 79% (P < 0.05). Diarrhea was reported in 8% of patients, all of whom were classified in the non‐improvement group, which included depressed patients. Improvement of shoulder stiffness and stool condition had a correlation coefficient of 0.542. Daisaikoto did not worsen stool condition in the patients in whom it was effective. Conclusion: Daisaikoto effectively relieves shoulder stiffness in middle‐aged women, and did not worsen stool condition in those with improvement in shoulder stiffness. Daisaikoto without Rhubarb or other formulas may be an alternative treatment choice for diarrhea patients with shoulder stiffness. [ABSTRACT FROM AUTHOR]

Tumor biomarkers are highly desirable for the screening of patients with a risk of tumor development and progression. Here, we report a beta-galactosidase (β-gal)-responsive acetaminophen (β-GR-APAP) as a synthetic plasma biomarker for targeted tumor detection. Tumor β-gal labeling via the recognition of tumor-related antigen enabled the detection of a tumor using β-GR-APAP. [ABSTRACT FROM AUTHOR]