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In Vitro and In Vivo Genotoxicity Assessments and Phytochemical Analysis of the Traditional Herbal Prescription Siryung-Tang.

ABSTRACT: Siryung-tang (SRT) is a traditional herbal prescription containing Oryeong-san and Soshiho-tang that is used to treat digestive system diseases. We performed safety evaluations of SRT based on genotoxicity and developed an assay for quality control using high-performance liquid chromatography with a photodiode array detector. Genotoxicity was evaluated based on bacterial reverse mutation (Salmonella typhimurium TA1535, TA98, TA100, and TA1537, and Escherichia coli WP2 uvrA), chromosomal aberration (Chinese hamster lung cells), and micronucleus (mouse) tests. Quality control analysis was conducted using a SunFire C₁₈ column and gradient elution with a distilled water-acetonitrile mobile phase system containing 0.1% (v/v) formic acid for 12 markers (5-(hydroxy-methyl)furfural, 3,4-dihydroxybenzaldehyde, liquiritin apioside, liquiritin, coumarin, baicalin, wogonoside, cinnamaldehyde, baicalein, glycyrrhizin, wogonin, and atractylenolide III). SRT showed no genotoxicity in three tests. Ames tests showed that SRT at 313-5000 μg/plate did not significantly increase the number of revertant colonies with or without metabolic activation among five bacterial strains. Moreover, in vivo micronucleus testing showed that SRT did not increase the frequency of bone marrow micronuclei. The number of chromosomal aberrations associated with SRT was similar to that observed in the negative controls. The 12 markers were detected at 0.04-16.86 mg/g in a freeze-dried SRT sample and completely eluted within 45 min. The extraction recovery was 95.39-104.319% and the relative standard deviation value of the precision was ≤2.09%. Our study will be used as basic data for the safety and standardization of SRT.

SUBMITTER: Seo CS

PROVIDER: S-EPMC9268686 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tang Luo Ning (TLN), a traditional Chinese compound prescription, has been used clinically to treat diabetic peripheral neuropathy (DPN) in China. However, the exact mechanisms remain unclear. The objective of this study is to unravel the effects of TLN on mitochondrial dynamics of DPN in streptozotocin-induced rat models and Schwann cells cultured in 150 mM glucose. Mitochondrial function was determined by Ca2+ and ATP levels of streptozotocin (STZ)-induced DPN rats and mitochondria structure, mitochondrial membrane potential (MMP), and mtDNA of high glucose incubated SCs. Mitochondrial dynamics protein including mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), optic atrophy 1 (Opa1), and dynamin-related protein 1 (Drp1) were investigated using Western blot or immunofluorescence. Myelin basic protein (MBP), myelin protein zero (MPZ), and sex-determining region Y (SRY)-box 10 (Sox10) were measured to represent schwannopathy. Our results showed that TLN increased ATP levels (0.38 of model, 0.69 of HTLN, 0.61 of LTLN, P＜0.01; 0.52 of 150 mM glucose, 1.00 of 10% TLN, P＜0.01, 0.94 of 1% TLN, P＜0.05), MMP (0.56 of 150 mM glucose, P＜0.01, 0.75 of 10% TLN, P＜0.05, 0.83 of 1% TLN, P＜0.01), and mtDNA (0.32 of 150 mM glucose, 0.43 of 10% TLN, P＜0.01) while decreased Ca2+ (1.54 of model, 1.06 of HTLN, 0.96 of LTLN, P＜0.01) to improve mitochondrial function in vivo and in vitro. TLN helps maintain balance of mitochondrial dynamics: it reduces the mitochondria number (1.60 of 150 mM glucose, 1.10 of 10% TLN, P＜0.01) and increases the mitochondria coverage (0.51 of 150 mM glucose, 0.80 of 10% TLN, 0.87 of 1% TLN, P＜0.01), mitochondrial network size (0.51 of 150 mM glucose, 0.95 of 10% TLN, 0.94 of 1% TLN, P＜0.01), and branch length (0.63 of 150 mM glucose, P＜0.01, 0.73 of 10% TLN, P＜0.05, 0.78 of 1% TLN, P＜0.01). Further, mitochondrial dynamics-related Mfn1 (0.47 of model, 0.82 of HTLN, 0.77 of LTLN, P＜0.01; 0.42 of 150 mM glucose, 0.56 of 10% TLN, 0.57 of 1% TLN, P＜0.01), Mfn2 (0.40 of model, 0.84 of HTLN, 0.63 of LTLN, P＜0.01; 0.46 of 150 mM glucose, 1.40 of 10% TLN, 1.40 of 1% TLN, P＜0.01), and Opa1 (0.58 of model, 0.71 of HTLN, 0.90 of LTLN, P＜0.01; 0.69 of 150 mM glucose, 0.96 of 10% TLN, 0.98 of 1% TLN, P＜0.05) were increased, while Drp1 (1.39 of model, 0.96 of HTLN, 1.18 of LTLN, P＜0.01; 1.70 of 150 mM glucose, 1.20 of 10% TLN, 1.10 of 1% TLN, P＜0.05), phosphorylated Drp1 (2.61 of model, 1.44 of HTLN, P＜0.05; 2.80 of 150 mM glucose, 1.50 of 10% TLN, 1.30 of 1% TLN, P＜0.01), and Drp1 located in mitochondria (1.80 of 150 mM glucose, 1.00 of 10% TLN, P＜0.05) were decreased after treatment with TLN. Additionally, TLN improved schwannopathy by increasing MBP (0.50 of model, 1.05 of HTLN, 0.94 of HTLN, P＜0.01; 0.60 of 150 mM glucose, 0.78 of 10% TLN, P＜0.01, 0.72 of 1% TLN, P＜0.05), Sox101 (0.41 of model, 0.99 of LTLN, P＜0.01; 0.48 of 150 mM glucose, 0.65 of 10% TLN, P＜0.05, 0.69 of 1% TLN, P＜0.01), and MPZ (0.48 of model, 0.66 of HTLN, 0.55 of HTLN, P＜0.01; 0.60 of 150 mM glucose, 0.78 of 10% TLN, P＜0.01, 0.75 of 1% TLN, P＜0.05) expressions. In conclusion, our study indicated that TLN's function on DPN may link to the improvement of the mitochondrial dynamics, which provides scientific evidence for the clinical application.

Project description:Dysregulated lipid metabolism is a prominent feature of prostate cancers (PCas); several enzymes involved in lipid accumulation are highly expressed. Here, we elucidated efficacy of TJ001, a traditional herbal decoction, in inhibiting de novo lipogenesis. TJ001 had significant cytotoxicity against DU145 but not PC3 and LNCaP cells and, similarly, TJ001 markedly AMPK phosphorylation only in DU145 cells. This was accompanied by the downregulation of phosphorylated-acetyl coenzyme A carboxylase (ACC) expression and sterol regulatory element-binding protein 1 (SREBP1) proteolytic cleavage, thereby inhibiting its role as a transcription factor to induce lipid biosynthesis. When Oil Red O staining was performed, it is reflected in the reduction of lipid droplets (LDs). TJ001 also induced G1/S cell cycle arrest via a cell cycle inhibitor (CKI) p21WAF1/CIP1 upregulation. Although p53 proteins remained unchanged, both cyclin E and cyclin D1 were decreased. Moreover, TJ001 suppressed the mammalian target of rapamycin (mTOR) signaling pathway. Generally, the prolonged G1/S phase arrest accompanies apoptosis, but TJ001 failed to work as a trigger apoptosis in DU145 cells. We showed that mutant p53 proteins were required for the survival of DU145 cells. In presence of TJ001, inhibition of endogenous mutant p53 by RNAi led to cell viability reduction and induction of the p-AMPK/AMPK ratio. In addition, it induced apoptotic cell death in DU145 cells. At the cellular level, induction of PARP, caspase-3, and caspase-9 cleavages was observed, and caspase-3 activity was increased in the p53 knockdown cells treated with TJ001. Taken together, we demonstrated that TJ001 inhibited cell growth in DU145 prostate cancer cells as indicated by blocking lipogenesis and induction in G1/S cell cycle arrest. In addition, we may provide an evidence that mutant p53 protein has potential role as an oncogenic action in DU145 cells. Collectively, the combination of mutant p53 targeting and TJ001 treatment resulted in decreased cell growth in DU145 cells.

Project description:BackgroundMulti-walled carbon nanotubes (MWCNT) have received attention due to extraordinary properties, resulting in concerns for occupational health and safety. Costs and ethical concerns of animal testing drive a need for in vitro models with predictive power in respiratory toxicity. The aim of this study was to assess pro-inflammatory response (Interleukin-8 expression, IL-8) and genotoxicity (DNA strand breaks) caused by MWCNT with different physicochemical properties in different pulmonary cell models and correlate these to previously published in vivo data. Seven MWCNT were selected; two long/thick (NRCWE-006/Mitsui-7 and NM-401), two short/thin (NM-400 and NM-403), a pristine (NRCWE-040) and two surface modified; hydroxylated (NRCWE-041) and carboxylated (NRCWE-042). Carbon black Printex90 (CB) was included as benchmark material. Human alveolar epithelial cells (A549) and monocyte-derived macrophages (THP-1a) were exposed to nanomaterials (NM) in submerged conditions, and two materials (NM-400 and NM-401) in co-cultures of A549/THP-1a and lung fibroblasts (WI-38) in an air-liquid interface (ALI) system. Effective doses were quantified by thermo-gravimetric-mass spectrometry analysis (TGA-MS). To compare genotoxicity in vitro and in vivo, we developed a scoring system based on a categorization of effects into standard deviation (SD) units (< 1, 1, 2, 3 or 4 standard deviation increases) for the increasing genotoxicity.ResultsEffective doses were shown to be 25 to 53%, and 21 to 57% of the doses administered to A549 and THP-1a, respectively. In submerged conditions (A549 and THP-1a cells), all NM induced dose-dependent IL-8 expression. NM-401 and NRCWE-006 caused the strongest pro-inflammatory response. In the ALI-exposed co-culture, only NM-401 caused increased IL-8 expression, and no DNA strand breaks were observed. Strong correlations were found between in vitro and in vivo inflammation when doses were normalized by surface area (also proxy for diameter and length). Significantly increased DNA damage was found for all MWCNT in THP-1a cells, and for short MWCNT in A549 cells. A concordance in genotoxicity of 83% was obtained between THP-1a cells and broncho-alveolar lavaged (BAL) cells.ConclusionThis study shows correlations of pro-inflammatory potential in A549 and THP-1a cells with neutrophil influx in mice, and concordance in genotoxic response between THP-1a cells and BAL cells, for seven MWCNT.

Project description:IntroductionFor situations in which effective and safe natural-derived products to treat hypertension are needed, recent studies suggest that an herbal medicine, Sihogayonggolmoryeo-tang (SYM), can improve both hypertension and concurrent mood symptoms. We aimed to evaluate the effectiveness and safety of SYM in treating hypertension.MethodsThirteen English, Korean, and Chinese databases were comprehensively searched from their inception to May 2020. Randomized controlled trials (RCTs) using SYM as a monotherapy or adjunctive therapy for hypertension were evaluated. The primary outcome was the systolic and diastolic blood pressure (BP). Descriptive analyses of the relevant data were conducted, and where appropriate data were available, a meta-analysis was performed, and the results were presented as a risk ratio or mean difference with 95% confidence intervals. The risk of bias was assessed using the Cochrane risk of bias tool, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.ResultsSeven RCTs with 711 participants were included. Compared with placebo, SYM significantly lowered systolic and diastolic BP and concurrent depression. SYM significantly lowered systolic and diastolic BP compared with active controls; however, subgroup analysis revealed no differences between SYM and antihypertensives. In addition, SYM significantly decreased the level of concurrent depression compared with antidepressants. There was no consistent difference in BP reduction between SYM combined with antihypertensives and antihypertensives alone. No serious adverse events were reported following SYM administration. Most of the included studies had an unclear risk of bias, and the quality of evidence was generally rated "low."ConclusionCurrent evidence suggests that SYM may have the potential to lower hypertension and concurrent depressive symptoms without serious adverse events. Additional high-quality, placebo-controlled RCTs should be conducted to confirm the efficacy of SYM.

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In Vitro and In Vivo Genotoxicity Assessments and Phytochemical Analysis of the Traditional Herbal Prescription Siryung-Tang.

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